Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:23]([NH:30][C:31]1[N:36]=[C:35](Cl)[CH:34]=[C:33]([Cl:38])[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:35]2[CH:34]=[C:33]([Cl:38])[N:32]=[C:31]([NH:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:36]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Clc1cc(Cl)nc(NCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(Cl)nc(NCc3ccccc3)n2)cc1)Oc1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (60 mg, 0.2 mmol), benzyl-(4,6-dichloro-pyrimidin-2-yl)-amine (50 mg, 0.2 mmol) and Cs2CO3 (76 mg, 0.22 mmol) were combined in anhydrous N,N-dimethylformamide (DMF) (5 mL) and stirred at 90° C. in dry atmosphere for 5 h. The DMF was removed in vacuo, the residue was purified in silica to provide a white oil.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)[N:4]2[N:3]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([CH:65]2[CH2:70][CH2:69][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]2)=[CH:61][CH:60]=1>>[CH3:21][S:18]([N:17]([CH3:22])[C:12]1[C:11]([C:10]2[N:4]3[C:5]([CH:6]=[N:7][C:2]([NH:58][C:59]4[CH:64]=[CH:63][C:62]([CH:65]5[CH2:66][CH2:67][N:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:69][CH2:70]5)=[CH:61][CH:60]=4)=[N:3]3)=[CH:8][CH:9]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:20])=[O:19]
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(c1ncccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1-c1ccc2cnc(Nc3ccc(C4CCN(CC(N)=O)CC4)cc3)nn12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Into a 8-dram vial, N-[3-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyridin-2-yl]-N-methyl-methanesulfonamide (56 mg, 0.18 mmol), N,N-Dimethylformamide (0.50 mL, 6.4 mmol), N,N-Diisopropylethylamine (0.0672 mL, 0.386 mmol) and N-Phenylbis(trifluoromethanesulphonimide) (2.77 g, 7.75 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (90.0 mg, 0.386 mmol) was added. The reaction was heated at 110° C. for 3 hours. The solvent was removed under vacuum overnight The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were combined and neutralized via polymer bound sulfonic acid column with 2N NH3 in methanol. The filtrate was concentrated to afford 2-[4-(4-{7-[2-(Methanesulfonyl-methyl-amino)-pyridin-3-yl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperidin-1-yl]-acetamide as a yellow solid (50 mg, 50%). LCMS (E/I+) 535.16 (M+H). NMR 1H (DMSO-d6)-9.42 (s, 1H), 9.01 (s, 1H), 8.56-8.61 (m, 2H), 7.64-7.69 (m, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.19 (s, 1H), 7.07-7.14 (m, 2H), 6.98 (d, 2H, J=4.63 Hz), 3.13 (s, 3H), 3.00 (s, 3H), 2.84-2.96 (m, 4H), 2.32-2.44 (m, 1H), 2.08-2.19 (m, 2H), 1.64-176 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]1[OH:34].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:24][C@@H:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@@H:26]2[OH:34])=[O:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1Cc2ccccc2[C@@H]1O
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)N[C@@H]1Cc2ccccc2[C@@H]1O
Reaction time: 17 h
Yield: 73 %

Procedure:
A suspension of 2,2,2-trichloroethyl 5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenylcarbamate (1.50 g, 3.90 mmol), (1S,2R)-2-amino-2,3-dihydro-1H-indene-1-ol.L-tartaric acid salt (1.28 g, 4.29 mmol) and N,N-diisopropylethylamine (2.37 mL, 13.6 mmol) in acetonitrile (19.5 mL) was heated to reflux. After 17 hours, the mixture was allowed to cool and the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50-0/100) to obtain 1.09 g of the captioned compound (73% yield).
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]1[O:26][CH2:25]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]([OH:26])[CH2:25][S:4][CH:1]([CH3:3])[CH3:2])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)S
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)SCC(O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Isopropylmercaptan (0.93 ml) and triethylamine (1.39 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (2.11 g) as obtained in Example 1-A) in methanol (100 ml), and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give 1.66 g of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6].[CH3:9][N:10]([S:14][C:15]([CH2:18][Cl:19])([CH3:17])[CH3:16])[C:11](Cl)=[O:12]>C(N(CC)CC)C>[CH3:9][N:10]([S:14][C:15]([CH2:18][Cl:19])([CH3:17])[CH3:16])[C:11]([O:6][N:5]=[CH:4][C:3]([S:2][CH3:1])([CH3:8])[CH3:7])=[O:12]
Reactant: CN(SC(C)(C)CCl)C(=O)Cl
Reactant: CSC(C)(C)C=NO
Solvent: CCN(CC)CC
Product: CSC(C)(C)C=NOC(=O)N(C)SC(C)(C)CCl

Procedure:
Prepared as in Example I by reacting 2-methylthio-2-methylpropionaldoxime with N-methyl-N-(2-chloromethyl-2-propanesulfenyl)carbamoyl chloride in the presence of triethylamine as an acid acceptor. The product was isolated as an oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][N:30]([S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N1CCC(n2c(=O)n(-c3cccc(Cl)c3)c(=O)c3cnc4c(OC)cccc4c32)CC1

Procedure:
3-(3-Chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (32 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (40 mg) and ethanesulfonyl chloride. LCMS: m/z 529 [M+1]+.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([O:17][CH3:18])[CH:8]=1.[C:19](=[O:21])=[O:20].O>C1COCC1>[CH:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:19]([OH:21])=[O:20])=[CH:8][C:9]=1[O:17][CH3:18])([CH3:16])[CH3:15]
Reactant: COc1cc(Br)ccc1OC(C)C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Under an atmosphere of nitrogen, tert-butyllithium (2.14 mL of 1.6 M in toluene, 3.42 mmol) was added dropwise to a solution of 4-bromo-1-isopropoxy-2-methoxy-benzene (400 mg, 1.63 mmol) in THF (6 mL) at −78° C. The reaction mixture was allowed to stir for 1 hour at −78° C., then added dropwise to a flask containing CO2 (1.8 g, 40.8 mmol) (solid, dry ice) in THF (2 mL). The reaction mixture was allowed to stir for 30 minutes warming to room temperature. Water (20 mL) was added to the reaction mixture and the volatiles were removed in vacuo. The resultant aqueous layer was acidified with 1N HCl solution to pH 1 and was extracted with ethyl acetate (3×15 mL). The organics were separated and the combined organics were washed with brine solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 4-isopropoxy-3-methoxy-benzoic acid (310 mg, 85%) as a white solid. ESI-MS m/z calc. 210.1. found 211.1 (M+1)+; Retention time: 1.23 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 4.67 (dt, J=12.1, 6.0 Hz, 1H), 3.78 (s, 3H), 1.28 (d, J=6.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.CN(C(ON1N=[N:37][C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC[C@@H]1C#N.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:36]3[CH2:35][CH2:34][CH2:33][C@@H:31]3[C:32]#[N:37])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#C[C@H]1CCCN1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1CCC[C@@H]1C#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol), HATU (15 mg, 0.039 mmol), (R)-pyrrolidine-2-carbonitrile hydrochloride (4 mg, 0.032 mmol), and N-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL). The reaction mixture was stirred under nitrogen at 40° C. for 10 min and then at room temperature for 30 min. The solution was concentrated and purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA) to afford the title compound as a white solid (2 mg, 18%). 1H NMR (500 MHz, CD3OD) δ 0.94 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.03-1.12 (m, 1H), 2.12-2.17 (m, 2H), 2.25-2.27 (m, 2H), 2.59-2.63 (m, 1H), 3.72-3.74 (m, 1H), 3.83-3.86 (m, 1H), 4.92 (d, J=5.9 Hz, 1H), 5.06 (d, J=13.2 Hz, 1H), 5.46 (d, J=11.8 Hz, 1H), 7.86 (s, 1H), 8.25 (s, 1H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[N:30]([Si](C)(C)C)=[N+:31]=[N-:32].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]4[N:30]=[N:31][NH:32][N:29]=4)=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(Nc3ccc(Cc4nn[nH]n4)cc3)c21
Temperature: 110 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetonitrile (17 mg, 0.04 mmol, 1 eq.), azido(trimethyl)silane (0.2 ml, excess) and tetrabutylammonium fluoride hydrate (50 mg, 0.19 mmol, 4.6 eq.). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was partitioned between dichloromethane (8 ml) and 2N HCl (4 ml). The organic layer was separated and washed with sodium bicarbonate solution (5 ml) and dried over Na2SO4. Removal of solvent under reduced pressure gave a residue, which was purified using a preparation TLC plate and 3% of methanol in dichloromethane as mobile to give the title compound as white solid (13 mg, 70% yield). MW=467.93. 1H NMR (400 MHz, methanol-d4) δ 8.32 (s, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.46 (m, 2H), 7.38 (d, J=8.4 Hz, 2H), 4.38 (s, 2H), 3.63 (d, J=5.6 Hz, 2H), 3.14 (d, J=6.4 Hz, 2H), 2.54 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.C(O[C:11](=[O:14])[CH:12]=[CH2:13])C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][C:17]=1[CH3:24].[H-].[Na+]>CCO>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:11](=[O:14])[CH2:12][CH2:13][NH:23]2)=[CH:18][C:17]=1[CH3:24]
Reactant: Cc1cc(NN)ccc1Br
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N2NCCC2=O)ccc1Br
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Triethylamine (625 μL, 13.1 mmol) and acrylic acid ethyl ester (1.82 mL, 5.74 mmol) were added to a solution of (4-bromo-3-methyl-phenyl)-hydrazine (1.05 g, 5.22 mmol) in EtOH (26.1 mL) at room temperature in a nitrogen atmosphere, and the mixture was stirred at 80° C. for 18 hours. The reaction solution was cooled, and 50% NaH (501 mg, 10.4 mmol) was then added to the reaction solution at 0° C. The mixture was stirred at 0° C. for 30 minutes, and 50% NaH (251 mg, 5.20 mmol) was then further added, followed by further stirring for 30 minutes. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate three times. The organic layers were combined and washed with a mixed solution of water:saturated brine (1:1). After separation, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-(4-bromo-3-methyl-phenyl)-pyrazolidin-3-one as a brown form (684 mg, 60%).
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCCC2)cc1
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (15 mL) at ambient temperature under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 1.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 4-methoxybenzenesulphonyl chloride (2.95 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the organic phase was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (2.771 g, 79%) as an oil. H1-NMR (chloroform-D3): 1.61 (m, 8H), 3.87 (s, 3H), 4.57 (m, 1H), 6.67 (s, 1H), 6.99 (m, 2H), 7.83 (m, 2H). MS(ESI): 294 (M+Na).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N-:33]([C:36]#[N:37])[C:34]#[N:35].[Na+]>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:21]=4)[CH2:16][CH2:15][N:14]3[C:36](=[NH:37])[NH:33][C:34]#[N:35])[CH2:10][CH2:11][CH2:12]2)=[CH:5][CH:4]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)N(C(=N)NC#N)CC2
Reaction time: 4 h
Yield: 31.6 %

Procedure:
Propane-1-sulfonic acid (2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-amide hydrochloride (example 4, 95.0 mg, 0.19 mmol) was dissolved in 1-butanol (10 ml) and sodium dicyanamide (42.3 mg, 0.48 mmol) was added. The reaction mixture was stirred under reflux. After 4 h, the solvent was removed and dichloromethane was added. The resulting precipitate was removed by filtration and purified by flash column chromatography on silica with dichloromethane/methanol 10:0→94:6. The product was obtained as a solid (30.0 mg, 0.06 mmol, 30.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C(Cl)Cl>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:18]\[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CF)c1cccc(Br)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a round-bottomed flask charged with 1-(3-bromophenyl)-2-fluoroethanone (11.42 g, 52.6 mmol) in THF (100 ml), was added (R)-2-methylpropane-2-sulfinamide (12.75 g, 105 mmol). Then tetraisopropoxytitanium (31.2 ml, 105 mmol) was added into the reaction mixture. The reaction mixture was stirred at ambient temperature under inert atmosphere overnight. The material was poured slowly into a vigourously stirring solution of ice water. The resulting suspension was stirred vigourously for 20 min. Then methylene chloride was added into the mixture and the overall mixture was allowed to stir an additional 30 min. The mixture was filtered through a pad of celite and the filter cake was washed with methylene chloride. The organic layer was separated and the remaining aqueous layer was extracted with methylene chloride three times. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in-vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column, eluting with a gradient of 0-15% EtOAc/hexane to give (R,E)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (9.69 g, 57.5% yield).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:92]=[C:93]1[CH:97]=[CH:96][C:95](=[O:98])[N:94]1[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][C:104]([NH:106][NH2:107])=[O:105]>CN(C=O)C>[O:98]=[C:95]1[CH:96]=[CH:97][C:93](=[O:92])[N:94]1[CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][C:104]([NH:106][NH:107][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][CH2:38][CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:105]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
38 mg (47 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(1H-indol-3-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 37 ml of DMF and then admixed with 71 mg (187 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 33 μl of N,N-diisopropylethylamine and with 37 mg (140 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT for 1 h. This was followed by concentration under high vacuum and purification of the remaining residue by means of preparative HPLC. Thus, 12.2 mg (26% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[CH2:40][C:41]([NH2:43])=[O:42])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].I([O-])(=O)(=O)=[O:45].[Na+].OS([O-])=O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@H:21]([C:31]([OH:45])=[O:32])[CH:20]=[C:19]1[CH2:40][C:41]([NH2:43])=[O:42])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
To the solution of (25)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(2-amino-2-oxoethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 174, 2.61 g, 4.96 mmol) in acetonitrile (50 mL) was added sodium periodate (4.66 g, 21.81 mmol) and catalytic solution of NaCr2O7/HNO3 solution (6.0 mL) at room temperature and stirred for 15 h. The mixture was diluted with 100 mL ethyl acetate, 25 mL 1M pH 7 buffer, 25 mL 2M NaHSO3. The aqueous solution was extracted with 50 mL ethyl acetate. The ethyl acetate layer was then washed with brine and dried over MgSO4, filtered and concentrated to afford (2S)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(2-amino-2-oxoethyl)-1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine-2-carboxylic acid, which was used directly in the next step without further purification. Pale yellow solid, crude, 2.79 g, 104%.