Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].Cl>C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@@H:14]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Yield: 79 %

Procedure:
Condensation of BocLeuOH (3.49 g.) and HDMetNH2 (2.0 g.) by the mixed anhydride method using isobutyl chloroformate gave BocLeu-DMetNH2 in 70% yield. De-t-butoxycarbonylation of BocLeu-DMetNH2 (2.74 g.) using hydrogen chloride in ethyl acetate gave HLeu-DMetNH2 in 91% yield. Condensation of BocGlyOSu (2.66 g.) and HLeu-DMetNH2 (1.95 g.) by the active ester method gave BocGly-Leu-DMetNH2 in 92% yield. De-t-butoxycarbonylation of BocGly-Leu-DMetNH2 (2.30 g.) using hydrogen chloride in acetic acid gave HGly-Leu-DMetNH2 in 79% yield.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH2:11][C:12]#[N:13]
Reactant: N#CCCCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Product: N#CCCCC(O)c1ccccc1

Procedure:
A mixture of 41 g. (0.25 mole) of 5-hydroxy-5-phenylvaleronitrile, obtained from 4-benzoylbutyronitrile by lithium borohydride reduction by the procedure of Colonge et. al., Bull. Soc. Chem. France, 2005-2011 (1966); Chem. Abstr., 65, 18547d (1966), and 0.30 mole of potassium hydroxide in 200 ml. of water was heated at reflux for eight hours. The mixture was cooled to room temperature and neutralized with 10 M hydrochloric acid, saturated with sodium chloride and extracted with ether several times. The extracts were washed with water, dried (Na2SO4) and the ether evaporated to obtain dl-5-phenyl-5-hydroxyvaleric acid lactone which was recrystallized from dilute alcohol, M.P. 62.5° C., 79% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:28][CH:27]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(CC(CCN1CC=C(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(CC(CCN1CCC(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 2.5 h
Yield: 72.9 %

Procedure:
A solution of N-[2-(3,4-dichlorophenyl)-4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-N-methylbenzamide (0.28 g) in methanol (10 mL) was treated with methanolic hydrogen chloride (2 mL), and 10% (w/w) palladium on carbon (0.03 g) was added. The reaction mixture was subjected to hydrogenation at atmospheric pressure for 2.5 hours. At the end of this period, the reaction mixture was treated with additional 10% palladium on carbon (0.03 g); and the hydrogenation was continued for an additional 16 hours. The reaction mixture was filtered through diatomaceous earth and evaporated. The resulting material was treated with ether and evaporated; and the process was repeated twice. The residue was crystallized from a mixture of ethyl acetate, methanol, ether and hexane; washed with a mixture of ether and hexane; and dried under vacuum to afford the title compound as a white solid (0.11 g); mp 142°-148° C.; NMR (CD3OD): 1.8-2.4 (m, 6), 2.6-3.2 (m, 9), 3.5-3.9 (m, 4), 7.0-7.6 (m, 13); MS: m/z=495(M+1). Analysis for C29H32Cl2N2O·HCl·H2O: Calculated: C, 63.33; H, 6.41; N, 5.09; Found: C, 63.46; H, 6.12; N, 5.13.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.C(#N)C>[CH2:41]([O:40][C:36](/[CH:37]=[CH:38]/[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2)=[O:39])[CH3:42]
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc2[nH]c(C(=O)O)cc2c1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
5-Bromoindole-2-carboxylic acid (400 mg, 1.66 mmol) and tri-O-tolylphosphine (96 mg, 0.32 mmol) were added to a microwave tube. Ethyl acrylate (0.56 ml, 5.6 mmol), Et3N (0.92 ml, 6.6 mmol), acetonitrile (2.5 ml) and Pd(OAc)2 (40 mg, 0.18 mmol) were added. The reaction was placed in a CEM microwave at 150 W, 90° C. for 30 minutes with 5 min ramp time. EtOAc was added and the reaction mixture filtered through celite. The celite pad was washed with DCM and the combined organic fractions removed to give a yellow solid. The solid was redissolved in DCM and extracted into saturated sodium hydrogen carbonate. The aqueous layer was washed with DCM and diethyl ether. The aqueous basic layer was acidified with 2M HCl (pH=5) and the product extracted into EtOAc. The solvent was removed to give the required product (370 mg, 86% yield). LCMS purity 86%, m/z 260 [M++H]+
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])=[O:8].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.Br[C:56]1[CH:61]=[CH:60][C:59]([C:62]([OH:68])([CH3:67])[C:63]([F:66])([F:65])[F:64])=[CH:58][CH:57]=1>C1(C)C=CC=CC=1.CO.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]>[F:64][C:63]([F:65])([F:66])[C:62]([C:59]1[CH:58]=[CH:57][C:56]([N:13]2[CH2:12][CH2:11][N:10]([S:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH2:15][CH2:14]2)=[CH:61][CH:60]=1)([OH:68])[CH3:67]
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: O=S(=O)(c1cccs1)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)cc1)C(F)(F)F
Temperature: 100 °C

Procedure:
A 20 ml, vial was charged with 4-(2-thiophenylsulfonyl)piperazine hydrochloride (70 mg, 0.260 mmol), sodium tert-butoxide (45.7 mg, 0.476 mmol), tris(dibenzylideneacetone)dipalladium (0) (1.1 mg, 1.13 μmol, Strem Chemical Inc, Newburyport, Mass.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.6 mg, 3.40 μmol, Strem Chemical Inc, Newburyport, Mass.) and 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (60.9 mg, 0.226 mmol, Example 27, step 1) in toluene (906 μL) was heated to 100° C. for 20 h. The reaction was then cooled to ambient temperature and additional tris(dibenzylideneacetone)dipalladium (0) (1.1 mg, 1.13 μmol, Strem Chemical Inc, Newburyport, Mass.) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (1.6 mg, 3.40 μmol, Strem Chemical Inc, Newburyport, Mass.) were added. The reaction was then heated to 100° C. for an additional 20 h. The reaction was cooled to ambient temperature and diluted with MeOH (2 mL). The reaction was loaded onto a 1 g AccuBOND II SCX cartridge, which was washed with MeOH (5 mL) and eluted with 2 N ammonia in MeOH (5 mL) to give the crude reaction mixture. The crude material was absorbed onto a plug of silica gel and purified by column chromatography (10 g of silica gel, 5%-45% EtOAc in hexanes) to provide 1,1,1-trifluoro-2-(4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two enantiomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C([O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:56][C:53]3[CH:52]=[CH:51][C:50]([CH2:49][CH2:48][NH:47][C:46](=[O:57])[OH:45])=[CH:55][CH:54]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CCNC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h

Procedure:
To a solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (51.1 mg, 0.11 mmol) in dichloromethane (3 mL) were added DIPEA (71.2 mg, 0.55 mmol), [2-(4-AMINO-PHENYL)-ETHYL]-CARBAMIC ACID TERT-BUTYL ESTER (52.3 mg., 0.22 mmol, Chem-Impex) and HATU (77.8 mg, 0.20 mmol) (The acid, DIPEA, and HATU were added in thirds at 20 min intervals). After 90 mins, the reaction was diluted with dichloromethane, washed with water and saturated sodium chloride and purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral [2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-ethyl]-carbamic acid tent-butyl ester (40.6 mg., 54.2%) as a white lyophilized solid. HRMS (ES+) m/z Calcd C36H40Cl2F2N4O3+H [(M+H): 685.2519. Found: 685.2517.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[F:27][C:28]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([CH3:39])[C:29]=1[C:30](Cl)=[O:31].Cl>C1COCC1>[F:27][C:28]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([CH3:39])[C:29]=1[C:30]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:31]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)Cl
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
A solution of 8.0 g (60.5 mmol) of malonic acid monoethylester, bipyridyl (catalytic) and 200 mL of dry THF was cooled to -35° C. under argon, treated with 32 mL of 1.9M n-butyllithium (60.8 mmol), and warmed to -5° C. To this suspension was added another 32 mL of 1.9M n-butyllithium until a pale pink color persisted for 10 minutes. The mixture was cooled to -78° C. To this mixture was added a solution of 6.3 g (30.2 mmol) of 2,4,5-trifluoro-6-methylbenzoyl chloride in 75 mL of dry THF, and the reaction mixture was stirred at -78° C. for 1 hour. The solution was then warmed to -35° C., poured onto a mixture of ice and 1N hydrochloric acid (70 mL), and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, 3M hydrochloric acid, and water, and was stirred over magnesium sulfate. Concentration gave an orange oil which was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate, to give 7.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12](C(OC(C)(C)C)=O)[N:11]=3)[N:7]=[N:8][C:4]=2[C:3]=1[O:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([C:36]#[N:37])[C:30]=1[Cl:38]>C(O)(C(F)(F)F)=O>[Cl:38][C:30]1[C:29]([O:28][C:3]2[C:4]3[N:8]=[N:7][N:6]([CH2:9][C:10]4[C:18]5[C:13](=[N:14][CH:15]=[CH:16][CH:17]=5)[NH:12][N:11]=4)[C:5]=3[CH:26]=[CH:27][C:2]=2[Cl:1])=[CH:34][C:33]([Cl:35])=[CH:32][C:31]=1[C:36]#[N:37]
Reactant: CC(C)(C)OC(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4Cl)c(Cl)ccc32)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1Cl
Reaction time: 0.33 h

Procedure:
tert-Butyl 3-{[5-chloro-4-(2,5-dichloro-3-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (569 mg, 0.997 mmol) was dissolved in TFA (5 mL). After 20 minutes, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions concentrated under reduced pressure to yield the title compound. 1H NMR (DMSO-d6) δ 8.53 (dd, J=4.4 Hz, J=1.6 Hz, 1H), 8.14 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 8.04 (d, J=0.6 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.21 (dd, J=8.0 Hz, J=4.5 Hz, 1H), 6.38 (d, 2H). HRMS (M+1)=470.0076
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:17]([C:19]2[N:20]([S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:28])=[CH:23][CH:22]=3)[OH:18])([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:17]([C:19]2[N:20]([S:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:31])=[O:30])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([F:28])=[CH:23][CH:22]=3)=[O:18])([CH2:14][CH2:15][CH3:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC1(C(O)c2cc3cc(F)ccc3n2S(=O)(=O)c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCC1(C(=O)c2cc3cc(F)ccc3n2S(=O)(=O)c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 4-[(1-benzenesulfonyl-5-fluoro-1H-indol-2-yl)-hydroxy-methyl]-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (319 mg, 0.6 mmol) in 20 mL of dichloromethane was added Dess-Martin periodinane (255 mg, 0.6 mmol). The reaction was stirred for 30 minutes at room temperature, and then quenched with a 1:1 mixture of 5% aqueous Na2S2O3: saturated aqueous NaHCO3. The mixture was stirred until all solids were dissolved, then extracted with diethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered and concentrated in vacuo to afford crude 4-(1-benzenesulfonyl-5-fluoro-1H-indole-2-carbonyl)-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.57 mmol) as a beige solid in a 95% yield.
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[CH:36]=[CH:35][C:15]([O:16][C:17]([C:19]2([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1>[Pd].CO.C(OCC)C>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]([C:19]2([C:25]3[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])=[CH:35][CH:36]=1)=[O:11]
Reactant: COC(=O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NOCc4ccccc4)cc3)CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Reaction time: 0.83 h
Yield: 64.4 %

Procedure:
A mixture of methyl 4-{1-[(4-{[(benzyloxy)amino]carbonyl}phenoxy)carbonyl] cyclohexyl)-benzoate (E23) (0.063 g, 0.129 mmol) and 5% palladium on activated carbon (0.026 g) in methanol (1 ml) was hydrogenated at room temperature for 50 minutes. The black suspension was filtered, the catalyst was washed with methanol (3×1 ml), and the filtrate was evaporated to give a viscous oil. The oil was converted to white crystals by stirring in diethyl ether (3 ml) overnight. The solid was filtered, washed with diethyl ether (0.5 ml), and dried in vacuum to give the title compound (0.033 g, 64%) as white crystals, m.p. 129-131° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.13-1.99 (8H, m); 2.35-2.58 (2H, m, overlapped with a signal of DMSO); 3.86 (3H, s); 7.05 (2H, d, J=8.6 Hz); 7.65 (2H, d, J=8.4 Hz); 7.77 (2H, d, J=8.6 Hz); 8.01 (2H, d, J=8.4 Hz); 9.07 (1H, s); 11.25 (1H, s). HPLC analysis on Symmetry C8 column: impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.0 ml/min). Anal. Calcd for C22H23NO6*0.35H2O, %: C, 65.45; H, 5.92; N, 3.47. Found, %: C, 65.17; H, 5.76; N, 3.49.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:12])[F:11])=[N:6][C:5]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>CO.O>[F:12][CH:10]([F:11])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[C:5]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[N:6]=1
Reactant: COCCCc1nc(C(F)F)ccc1C(=O)OC
Solvent: CO
Solvent: O
Product: COCCCc1nc(C(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A solution of 181 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid methyl ester in 750 ml of a 2:1 methanol/water mixture is treated with 43.9 g of lithium-hydroxide monohydrate, and the mixture stirred at ambient temperature for 1 hour. Then the methanol is removed by distillation in vacuo, and the reaction mixture then diluted with crushed ice and acidified with aqueous 6N hydrochloric acid. The product is filtered and washed thoroughly with water. Crystallisation from n-hexane:methylene chloride gives 138.3 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid as white crystals (melting point 86-87° C.). A solution of 101.2 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid in 1250 ml of dichloromethane is charged initially, 1 ml of dimethylformamide are added and the mixture is subsequently treated with 38.4 ml of oxalyl chloride. After the intensive evolution of gas has ceased, the mixture is stirred at room temperature for 1 hour and then cooled to 0° C. and treated with 57 g of bicyclo[3.2.1]octane-2,4-dione and 87 ml of triethylamine and the mixture then stirred for 2 hours at ambient temperature. The mixture is then diluted with methylene chloride, and washed with cold 1N hydrochloric acid, dried over magnesium sulphate and concentrated in vacuo to give 150.9 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid 4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester as an oil which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=O)[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.Cl.[OH:23][NH2:24].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:12]=[N:24][OH:23])[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1
Reactant: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C=NO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of (69) (11.66 g, 35.8 mmol), hydroxyamine hydrochloride (2.98 g, 42.96 mmol), and triethyl amine (7.48 ml, 53.7 mmol) in ethanol (100 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 4.5 g (37%) of a white solid. m.p. 185-187° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.40 (3H, s), 3.58 (1H, m), 6.94 (1H, s), 7.16 (1H, s), 7.28 (1H, s), 7.51 (1H, s), 8.10 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH3:38])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH3:38])[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:11]1)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2N)C1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
To an ice-cooled mixture of 2,2-dimethylpropionic acid 2-[(R)-3-(2-amino-5-fluorophenylamino)piperidin-1-yl]ethyl ester (500 mg, 1.48 mmol), (S)-2-tert-butoxycarbonylaminobutyric acid (331 mg, 1.63 mmol) and HOAt (202 mg, 1.48 mmol) in DCM (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (341 mg, 1.78 mmol). The reaction mixture was stirred in the ice bath for 1 h, then diluted with DCM, washed with 2M Na2CO3, then water. The organic fraction was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 50-80% EtOAc in cyclohexane) affording the title compound as a pink gum (0.734 g, 95%). LCMS (Method B): RT 2.56 min [M+H]+ 523.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH2:24]>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CN(C)CCCN
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Product: CN(C)CCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
0.16 g (0.00041 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 6 ml of dioxane and treated with 0.52 ml of 3-dimethylamino-1propylamine. The mixture was stirred at 60° C. for 24 hrs., the solvent was removed and the residue was chromatographed on silica gel firstly with 5% methanol in dichloromethane and then with 10% methanol in dichloromethane. The product-containing fractions were freed from solvent, the residue was dissolved in 1N HCl, filtered and the filtrate was adjusted to pH 9 with 1N NaOH. The precipitate which thereby resulted was filtered off under suction and dried in a high vacuum. There was obtained 0.072 g (43%) of N-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-N',N'-dimethylpropane-1,3-diamine as pink coloured crystals; m.p.: >250° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[C:8]([O:17]CC2C=CC=CC=2)=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[C:8]([OH:17])=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: [H][H]
Reactant: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1O
Yield: 80.6 %

Procedure:
Methyl 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoate (343 mg, 0.7360 mmol) was dissolved in methanol (10 ml), added to a methanolic suspension (40 ml) of 10% palladium-carbon (100 mg) and stirred for 16 hours at room temperature in a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (223 mg, 0.5930 mmol, 81%).