Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4].C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>CN(C=O)C>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4])(=[O:25])=[O:26]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCO/C(C)=N/O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C(C)=N/OS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
To a solution of ethyl (1E)-N-hydroxyethanimidate (8.4 g, 81.5 mmol) in DMF (20 mL) is added triethylamine (12 mL, 86.24 mmol) and the mixture is stirred for 20 minutes. 2,4,6-Trimethylbenzene-1-sulfonyl chloride (20 g, 81.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts are dried over sodium sulphate, filtered, and evaporated to dryness to give the title compound as white solid (15 g, 64%). The crude material is used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]#[N:21].CO>CCCCCCC>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:22][CH:23]([CH3:25])[CH3:24])#[N:21]
Reactant: CC(C)CC(N)C#N
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CO
Product: CC(C)CC(C#N)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-amino-4-methyl-pentanenitrile (CAN 65451-12-9) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/15% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 328.2026 (M+H)+, αD20 (MeOH)=−8.0°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:34][C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:38])[CH:36]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:38][C:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:34])[CH3:36])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Solvent: CCO
Product: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)C(C#N)=CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 35 %

Procedure:
To a sealed tube was added N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide (160 mg, 0.36 mmol), tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (0.13 mL, 0.54 mmol) piperidine (0.02 mL, 0.18 mmol) and ethanol (4 mL). The tube was capped and heated to 110° C. for 2 hrs. The reaction was cooled and concentrated then dissolved in ethyl acetate (30 mL) and washed with water (30 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified by isolera (25 g column, 2%-7% MeOH/DCM) to obtain 77 mg, (35%) of tert-butyl N-[4-[[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]amino]-3-cyano-1,1-dimethyl-4-oxo-but-2-enyl]carbamate as a solid. MS (pos. ion) m/z: 615 (M+1).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19]([CH3:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:22])[CH:10]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19]([CH3:21])(=[O:1])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: OO
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(S(C)=O)c2n1
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(S(C)(=O)=O)c2n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
H2O2 (30%, 18.0 mg, 0.53 mmole) was added dropwise to a solution of (3,4-dichlorobenzyl)-(8-methanesulfinyl-2-methylquinolin-4-yl)-amine (50 mg, 0.132 mmole) in acetic acid (3.5 mL) at 0° C. The mixture was stirred at 70° C. for 16 hrs, concentrated by half, 2N NaOH was added and the resulting mixture was extracted with ethyl acetate. The organic phases were dried and concentrated. Precipitation in ethyl acetate gave the product as white solid (32 mg, 61%).
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][SH:11])=[CH:6][CH:5]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][CH2:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: SCc1ccncc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CSCc1ccncc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (0.52 g., 9.6 mmoles) was dissolved in 15 ml. of absolute ethanol and cooled to 0°-5° C. 4-Picolyl mercaptan (1.2 g., 9.6 mmoles) in 15 ml. of ethanol was added over 5 minutes time. Alpha-bromo-p-nitro-acetophenone (2.3 g., 9.6 mmoles) in 20 ml. of warm ethanol was then added over 5 minutes, the mixture was warmed to room temperature and left to stir for approximately 16 hours. The reaction mixture was filtered and the filtrate concentrated to an oil (4.3 g.). The oil was chromatographed on 175 g. of silica gel with 1:1 hexane:ethyl acetate as eluant. Product-containing fractions were combined and evaporated to yield alpha-(4-picolylthio)-p-nitro-acetophenone [1.40 g.; oil; pnmr/CDCl3 /TMS/delta: 6.5 (3, 4H), 2.7 (d, 2H), 1.9 (d, 4H), 1.5 (d, 2H); mass spectra: m/e calcd.: 288; found: 288, 242, 165, 150, 138, 124, 104, 92, 76, 65, 39; ir (film): 3-3.5, 5.95, 6.25, 6.55, 7.35, 7.85, 11.70,μ].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@H:8]([C:10]1[CH:11]=[C:12]([NH:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(NCc2cccnc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(NCc2cccnc2)c1
Yield: 91.2 %

Procedure:
A mixture of (S)-(1-{3-[(pyridin-3-ylmethyl)-amino]-phenyl}-ethyl)carbamic acid tert-butyl ester (3 g) and 9 mL of 4 N HCl in dioxane (20 mL) was heated at 60° for 2 h. The reaction mixture was concentrated in vacuo, and the residue was neutralized with 10 N NaOH followed by extraction with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound (1.9 g) as an oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].Br.[CH3:44][N:45]([CH2:47][CH2:48]Br)[CH3:46]>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:48][CH2:47][N:45]([CH3:46])[CH3:44])[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Reactant: CN(C)CCBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
In a 10 mL pear-shaped flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (280 mg, 0.48 mmol) was combined with DMF (8 ml) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 70 mg, 1.74 mmol) was added and the reaction was stirred at 0° C. for 10 min. Dimethylaminoethyl bromide hydrobromide (169 mg, 0.73 mmol) was added and the reaction was stirred at 0° C. for 30 min then allowed to warm up to room temperature and stirred for 2 h. The reaction was quenched with 5 ml of brine and 10 ml of water then extracted with EtOAc (2×). The combined organics were washed with water and brine then dried and purified by SiO2 chromatography (0% to 10% MeOH/CH2Cl2 to isolate 135 mg (43%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a foaming solid. MS: (M+H)+=651.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][C:16]([CH3:29])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:16]([CH3:29])([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: CC(CNC(=O)c1cccc(F)c1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=416.1, tR (minutes, Method G)=2.48
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([OH:27])=[CH:16][N:15]=2)=[N:6]1.[CH3:32][C:33]1([CH3:40])[O:37][CH:36]([CH2:38]Br)[CH2:35][O:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][O:27][C:17]2[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:19][C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]([CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[N:6]=3)=[N:15][CH:16]=2)[CH2:35][O:34]1
Reactant: CC1(C)OCC(CBr)O1
Reactant: Oc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2cnc(-c3nn(Cc4ccccc4F)c4ccccc34)nc2Nc2ccncc2)O1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
200 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-3, 0.49 mmol, 1 eq.), 94.6 mg of 2,2-dimethyl-4(R)-4-bromomethyl-1,3-dioxalane (0.49 mmol, 1 eq.) and 134 mg of potassium carbonate (0.97 mmol, 2 eq.) were suspended in 3.7 ml of dry DMF. The reaction mixture was stirred at 50° C. oil bath temperature for 18 hours. 201 mg of potassium carbonate (1.46 mmol, 3 eq.) were added and the mixture was stirred at 90° C. oil bath temperature for further 24 hours. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 126 mg (0.27 mmol, 44%) of the analytically pure target compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH3:21][NH2:22]>CN(C)C=O.C(O)C>[CH3:21][NH:22][CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: CN
Solvent: CCO
Solvent: CN(C)C=O
Product: CNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 150 mg of 2-chloro-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-acetamide (XV) (0.52 mmol) in N,N-dimethylformamide (1.4 mL), 9 mL of a 33% solution of methylamine in ethanol were added (mM). The reaction mixture was stirred at room temperature for 3 hours. The ethanol was then evaporated under reduced pressure and the mixture was diluted with diethyl ether and filtered. A light-yellow solid was then collected, washed with ether then with cold water and dried. The title compound was obtained in moderate yield (100 mg, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([OH:27])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:27])[N:29]([CH3:28])[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: CNCCc1ccccn1
Product: COc1cc2c(CC(=O)N(C)CCc3ccccn3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with methyl-(2-pyridin-2-yl-ethyl)-amine to give 78 mg of (6,7-dimethoxy-4-{[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-methyl}-isoquinolin-1-ylmethyl)-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C27H34N4O5+H 495.6; found 495.1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[C:7]([Cl:6])[C:12]=1[N+:13]([O-:15])=[O:14])[CH3:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Product: CCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting diethylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in ethanol to give the product melting at 35°-36° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1
Reactant: OCc1ccc(NCc2ccncc2Cl)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccncc2Cl)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-yl-methanol (556, 0.50 g, 2.00 mmol) in tetrahydrofuran (20.0 mL) was added Dess-Martin periodinane (1.02 g, 2.40 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound (557, 0.45 g, 91%) that was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6]([C@H:8]([OH:33])[C@H:9]([NH:18][C:19]([CH2:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:7])CCC.C1COCC1.[OH-].[Na+]>CC(O)=O>[C:6]([C@H:8]([OH:33])[C@H:9]([NH:18][C:19]([CH2:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])([OH:7])=[O:5]
Reactant: CCCCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1C(=O)O)N[C@H](Cc1ccccc1Cl)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
2-{3-[(1R,2R)-2-Butoxycarbonyl-1-(2-chloro-benzyl)-2-hydroxy-ethylcarbamoyl]-propyl}-benzoic acid (110 mg, 230 μmol, 1.0 eq.) was combined with THF (2.1 mL), and 1 M aqueous NaOH (480 μL, 2.0 eq.). The mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was completed, AcOH (1 mL) was added and the product was purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (95 mg, 99% purity). MS m/z [M+H]+ calc'd for C21H22ClNO6, 420.11. found 420.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:10]([N:12]([CH3:35])[C@H:13]([C:17]([NH:19][C@H:20]([C:32]([NH2:34])=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N:29]([CH3:31])[CH3:30])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl.C(NCC)C>[NH2:1][C@H:2]([C:10]([N:12]([CH3:35])[C@H:13]([C:17]([NH:19][C@H:20]([C:32]([NH2:34])=[O:33])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N:29]([CH3:30])[CH3:31])[CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(N(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(N(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of Fmoc-Phe-N-Me-Val-Tyr(3-NMe2)—NH2 (163 mg, 0.227 mmol) in methylene chloride (1.5 ml), diethylamine (1 ml) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=10:1:0.1) to give the titled compound (91.2 mg, 81%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([O:41][CH:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:32]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:23]=1)[C@H:15]([OH:40])[CH2:14][N:13]([O:41][CH:42]([CH2:43][CH3:44])[CH2:45][CH3:46])[S:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)(=[O:11])=[O:12]
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)ON(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 5 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To an ice cold solution of tert-Butyl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl) (1-ethylpropoxy)amino]-1-[4-(benzyloxy)benzyl]-2-hydroxypropylcarbamate (1.5 g, 2.3 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (10 mL). After stirring at 5° C. for 3 h, the reaction was concentrated in vacuo, taken up in ethyl acetate (80 mL), washed with saturated sodium bicarbonate (2×50 ml), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (1.27 g, quant.) as an off-white foam. 1H NMR (DMSO-d6): δ 0.77 (6H, dt), 1.07-1.72 (4H, m), 1.82 (2H, br), 2.28 (1H, t), 2.58-3.05 (4H, m), 3.43-3.53 (1H, m), 3.95-4.03 (1H, m), 4.86 (1H, br s), 5.01 (2H, s), 6.16 (2H, s), 6.86 (2H, d), 7.03 (2H, d), 7.12-7.40 (8H, m);
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 51.3 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (2.0 g, 1.50 mL, 14 mmol), piperidine-4-carboxylic acid ethyl ester (2.2 g, 2.15 mL, 14 mmol), and potassium carbonate (9.7 g, 70 mmol) in CH3CN (20 mL) was stirred at room temperature overnight. The resulting mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (gradient elution with 5-50% ethyl acetate in hexanes) to produce 2.0 g of 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester as a yellow solid. 1.0 g of the above 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester was hydrogenated using 10% Pd/C (200 mg) in MeOH, under 50 psi pressure of hydrogen for 2 hours. The catalyst was filtered, and the residue was concentrated to produce 1-(4-amino-phenyl)-piperidine-4-carboxylic acid ethyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:24]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:24])=[CH:8]2
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a mixture of (5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (35.3 g, 148.9 mmol) and pyridine (24 mL, 298 mmol) in 300 mL of carbon tetrachloride was added bromine (15.3 mL, 298 mmol) in a dropwise fashion. The mixture was heated to reflux for 2 hrs before being cooled to ambient temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water, dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography eluting with petroleum ether/ethyl acetate (40/1˜3/1) to return 31.5 g (67% yield) of the title compound as white crystalline solid. 1H NMR (DMSO-d6): δ 8.92 (d, 1H), 8.50 (d, 1H), 7.57˜7.61 (m, 1H), 3.91 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:15](OC1C=CC([N+]([O-])=O)=CC=1)=[O:16]>C(OCC)(=O)C.ClCCl>[CH:15]([N:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH:9]1[C:11]([O:13][CH3:14])=[O:12])=[O:16]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CC2(CCN1)OCCO2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CC2(CCN1C=O)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 g of methyl 1,4-dioxa-8-azaspiro[4.5]decane-9-carboxylate (111 mmol) are dissolved in 80 mL of ethyl acetate and 80 mL of dichloromethane. There are added 26 g of (4-nitrophenyl) formate (155 mmol), and the whole is stirred at ambient temperature for one hour. The reaction mixture is evaporated to dryness and taken up in ethyl acetate. The organic phase is subsequently washed in succession with a 1 N NaOH solution, water, and then with a saturated NH4Cl solution until a neutral pH is reached. It is subsequently dried over magnesium sulphate, filtered and concentrated to dryness. The oil so obtained is purified by flash chromatography (heptane/ethyl acetate gradient). The title product is obtained in the form of an oil.