Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:11]([O:15][C:16](=[O:35])[N:17]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][N:28]=1)[CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)([CH3:14])([CH3:13])[CH3:12].[OH-].[K+].O.[CH3:39]O>>[C:11]([O:15][C:16](=[O:35])[N:17]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][CH:9]=2)[O:34][CH3:39])=[CH:29][N:28]=1)[CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CO
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(OC)c3c[nH]c4ncc(Br)cc34)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-1H-pyrrolo[2,3-b]pyridine (152, 0.622 g, 3.16 mmol) in 50.0 mL of methanol under nitrogen, (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (153, 1.05 g, 3.06 mmol) and potassium hydroxide (1.50 g, 26.7 mmol) were added and the reaction stirred at room temperature overnight. The reaction was poured into water, extracted with ethyl acetate, the organic layer dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (154, 0.35 g). {5-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester was also formed in this procedure and could be isolated and reacted similarly to the following step to form the desired product.
Reaction SMILES: [OH-].[Li+].[OH:3][CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][S:9](=[O:13])(=[O:12])[N:8]1[CH2:14][CH2:15][CH2:16][C:17]1[S:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][CH:18]=1.C(O)(=O)C>O.C1COCC1>[OH:3][CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][S:9](=[O:12])(=[O:13])[N:8]1[CH2:14][CH2:15][CH2:16][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CCCN2[C@@H](/C=C/C(O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCCN2[C@@H](/C=C/C(O)Cc3cccc(C(F)(F)F)c3)CCS2(=O)=O)s1
Reaction time: 16 h
Yield: 41.4 %

Procedure:
Lithium hydroxide (0.25 mL of a 0.5N solution in H2O, 0.125 mmol) was added to a solution of the ester 13 (25 mg, 0.048 mmol) in THF (1.0 mL) at 23° C. The reaction mixture was stirred for 16 h, acidified with acetic acid and extracted with EtOAc. The organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 10% MeOH/CH2Cl2) afforded 10 mg (41%) of pure carboxylic acid 14.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:36]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(OCC4C=CC=CC=4)=C(OCC4C=CC=CC=4)C=3)N=2)CC1)=O)(C)(C)C>>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:36][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c3c2CCNCC3)cc1
Yield: 20 %

Procedure:
The title compound (22 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3,4-bis(benzyloxy)benzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also provided 2-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C34H32ClN3O2, 549.22. found, m/z 550.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.16 (m, 14H), 6.86 (d, J=8.3 Hz, 1H), 6.65 (d, J=1.9 Hz, 1H), 6.56 (dd, J=8.3, 1.9 Hz, 1H), 5.13 (s, 2H), 4.99 (s, 2H), 4.97 (s, 2H), 2.78-2.76 (m, 2H), 2.73-2.71 (m, 2H), 2.65 (m, 4H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.Br[C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37]>C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([C:35]([CH3:41])([CH3:40])[C:36]([NH:38][CH3:39])=[O:37])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CNC(=O)C(C)(C)Br
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(C)(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure of Example 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and 2-bromo-2,N-dimethyl-propionamide in cesium carbonate and DMF were reacted at 80° C. to give 464 isolated as a white solid (33 mg, 17%). LCMS: RT=7.62 min, [M+H]+=467. 1H NMR δ (ppm) (DMSO-d6): 8.27 (1H, d, J=8.17 Hz), 8.06 (1H, s), 7.63 (1H, s), 7.16 (1H, dd, J=8.20, 1.82 Hz), 6.96 (1H, s), 5.83-5.73 (1H, m), 4.32 (2H, t, J=5.01 Hz), 3.53 (2H, s), 3.39 (2H, t, J=5.02 Hz), 2.58 (3H, d, J=4.63 Hz), 1.50 (6H, d, J=6.59 Hz), 1.06 (6H, s). 3 Protons obscured by water peak
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[C:12]([NH:16][C:17]([C:19]1[O:20][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:21]3[O:20][C:19]([C:17]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)(C)NC(=O)c1ccc(CN2CCNCC2)o1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)o1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To a solution of 4-amino-3-fluorobenzoic acid (0.883 g, 5.69 mmol), N-tert-butyl-5-(piperazin-1-ylmethyl)furan-2-carboxamide (1.51 g, 5.69 mmol) and triethyl-amine (0.576 g, 5.69 mmol, 0.791 mL) in dichloromethane was added 1-propanephosphonic acid cyclic anhydride (3.62 g, 5.69 mmol, 3.39 mL, 50% solution in ethyl acetate). The reaction was stirred for 2 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with sodium bicarbonate, water and brine. The organic phase was concentrated under reduced pressure to give the title compound (0.93 g). MS (ESI) m/z 403.6 [M+H]+
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O>[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: NNC(=O)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc(C(=O)NNC(=O)c2ccccc2)c1C
Reaction time: 24 h
Yield: 91 %

Procedure:
First, 9.4 g (69.0 mmol) of benzoylhydrazine and 50 mL of N-methyl-2-pyrrolidinone (NMP) were put into a 300-mL three-neck flask and stiffed under nitrogen flow while being cooled with ice. To this mixed solution, a mixed solution of 13.0 g (77.1 mmol) of 2,3-dimethylbenzoyl chloride and 10 mL of NMP was slowly added dropwise, and the mixture was stiffed at room temperature for 24 hours. After reaction for the predetermined time, this reacted solution was slowly added to 500 mL of water, so that a white solid was precipitated. The precipitated solid was washed by repeating twice ultrasonic cleaning in which water and then 1M hydrochloric acid were used. Then, ultrasonic cleaning using hexane was performed, so that 16.9 g of a white solid of 1-(2,3-dimethylbenzoyl)-2-benzoylhydrazine was obtained in a yield of 91%. A synthesis scheme of Step 1 is shown in (d-1).
Reaction SMILES: BrC1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:8]([OH:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C]=O.CC[O:51][C:52]([CH3:54])=[O:53]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([CH2:18][NH:17][C:15]([C:7]1[C:6](=[O:26])[C:5]2[CH:4]=[CH:3][C:54]([C:52]([OH:51])=[O:53])=[CH:11][C:10]=2[C:9]([CH3:12])([CH3:13])[C:8]=1[OH:14])=[O:16])([OH:21])=[O:20]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2cc(Br)ccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC1(C)C(O)=C(C(=O)NCC(=O)O)C(=O)c2ccc(C(=O)O)cc21

Procedure:
Tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (253 mg, 596 μmol, Example 53A-E), trans-dichlorobis(triphenylphosphine)palladium (II) (21 mg, 30 μmol), and triphenylphosphine (16 mg, 60 μmol) were added to a vial, followed by water (32 μL, 1789 μmol) and n-tributylamine (1491 μL). The reaction mixture was placed under 4 atm of carbon monoxide at 90° C. for 18 hours. The reaction mixture was diluted with 50 mL of EtOAc, washed 3 times with 50 mL of 5 N NaOH (aqueous), and separated. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted 2 times with 50 mL of EtOAc, dried over sodium sulfate, and concentrated via rotovap to give the title compound. MS (ESI) m/z: Calculated; 333.3: Observed; 334.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[O:6].[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]([CH:13]=[CH2:14])[OH:6]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1cc(OC)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,5-dimethoxybenzaldehye (12.0 g, 0.072 mole) in 50 ml of dry THF was added dropwise to 100 ml of 1M solution of vinyl magnesium bromide in THF while keeping the reaction mixture at room temperature with cooling. The mixture was stirred for 4 hours at room temperature and then quenched with saturated NH4Cl solution. The layers were separated and the aqueous portion was extracted with diethyl ether. The combined organic portion was washed with water, dried (MgSO4), and concentrated. The resulting oil, 13.4 g, was sufficiently pure for the next reaction; IR (neat) 3500 cm-1); NMR (CDCl3) δ6.7-7.0 (m,3H); 6.0-6.2 (m, 1H); 5.1-5.3 (m,3H); 3.75 (two singlets, 6H); 3.16 (br,1H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1([C:20]([O:22][CH3:23])=[O:21])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH:5]=C.ClCCl.CSC>CO>[O:1]=[CH:5][CH2:4][C:7]1([C:20]([O:22][CH3:23])=[O:21])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: O=[O+][O-]
Reactant: C=CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: COC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ozone was bubbled through a −78° C. solution of 1-tert-butyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate (4.0 g, 14.1 mmol) in 3:1 dichloromethane:methanol over 30 min to produce a blue solution. Nitrogen was bubbled through the reaction mixture for 30 min, then dimethylsulfide (5.2 mL, 70.6 mmol) was added and the reaction warmed to room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 5 to 50% ethyl acetate:hexane to give the title compound (1.72 g). MS: m/z 230.1 (M−tBu).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[C:17]=1[CH3:32])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Na+].OO.Cl>C1COCC1>[C:11]([O:10][C:9]([N:8]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([OH:33])[C:17]=1[CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:15])([CH3:13])([CH3:14])[CH3:12]
Reactant: [OH-]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(O)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (800 mg, 41.7 mmol, 1.0 eq) in a mixture of THF (10 mL) and NaOH (1M aqueous solution, 5.3 mL, 5.3 mmol, 3.0 eq) at 0° C. was added H2O2 (30% aqueous solution, 603 mg, 5.32 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was acidified to pH 5-7 by addition of diluted HCl, and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography, (EtOAc:petroleum ether, 0:1 to 1:10) to give the title product as an oil (500 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])=[CH:4][CH:3]=1.[C:20]([NH:28][NH2:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:10](=[N:29]/[NH:28][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)cc2)c2ccccc21
Product: O=C(N/N=C1\C(=O)N(Cc2ccc(Cl)cc2)c2ccccc21)c1ccccc1
Yield: 86 %

Procedure:
The title compound was prepared as a yellow solid, using 1-(4-chlorobenzyl)-isatin and benzhydrazide according to the synthetic method D. The resulting solid was purified by crystallization in ethyl alcohol. Yield: 86%. 1H NMR (DMSO-d6): δ 5.03 (s, 2H), 7.08 (d, J=7.8 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 7.39-7.47 (m, 5H), 7.60-7.74 (m, 4H), 7.94 (m, 2H), 13.84 (br s, 1H). 13C NMR (DMSO-d6): δ 42.43 (CH2), 110.97 (CH), 119.87 (C), 121.35 (CH), 123.99 (CH), 127.93 (CH), 129.15 (CH), 129.70 (CH), 129.88 (CH), 132.14 (CH), 132.45 (C), 132.78 (C), 133.44 (CH), 135.15 (C), 143.04 (C═N), 161.74 (C═O). HRMS (ES+) calcd for C22H17N3O2Cl (M+H+), m/e, 390.1018; found, 390.1004.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[N:28]([CH3:29])[CH3:30])[CH:10]=1
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
(Step 3) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-chloro-N,N-dimethylbenzenesulfonamide hydrochloride obtained in Step 2 (0.85 g) and triethylamine (0.58 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.43 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COc1cccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c1

Procedure:
In analogy with Example 44d), 1.315 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3-methoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 49.9 ml of dimethoxyethane and 25.16 ml of water are hydrolysed with 12.36 ml of a 1M lithium hydroxide solution to give the title compound, which is directly subjected to further processing. TLC Rf (C)=0.09. FAB-MS (M+H)+ =444.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH2:32][CH:33]5[CH2:35][CH2:34]5)=[O:30])=[CH:19][N:20](COCC[Si](C)(C)C)[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH2:32][CH:33]5[CH2:34][CH2:35]5)=[O:30])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NCC2CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NCC4CC4)c3n2)c2ccc(Cl)cc21
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(cyclopropylmethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.049 g, 0.096 mmol) in dichloromethane (5 mL) was added TFA (0.55 g, 0.36 mL, 4.78 mmol) at 20° C. After 18 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (5 mL) and ethylenediamine (0.29 g, 0.32 mL, 4.78 mmol) was added. The mixture was stirred for 18 h, then concentrated in vacuo. The residue was triturated with water and collected by filtration, washed with water and dried in a vacuum oven to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(cyclopropylmethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.034 g, 0.089 mmol, 93%) as a yellow solid. MS (M+H)+=381; 1H NMR (DMSO-d6) δ: 9.10 (s, 1H), 8.47 (d, J=8.7 Hz, 2H), 8.44 (s, 1H), 8.21 (t, J=5.4 Hz, 1H), 8.00 (d, J=1.3 Hz, 2H), 7.31 (dd, J=8.6, 1.8 Hz, 2H), 4.18 (s, 3H), 3.33-3.40 (m, 2H), 1.04-1.28 (m, 1H), 0.48-0.65 (m, 2H), 0.27-0.41 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C-:16]#[N:17].[K+]>O>[C:16]([C:9]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)#[N:17]
Reactant: OC1CCNCC1
Reactant: O=C1CCCCC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCC(O)CC2)CCCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-Hydroxypiperidine (Aldrich) (5 g) was dissolved in distilled water (14 ml), cooled to 0° C. and the pH was adjusted to between 4 and 5 by addition of concentrated hydrochloric acid and 4-hydroxypiperidine. After warming to room temperature, 5.2 ml cyclohexanone and 3.3 g potassium cyanide in water (9 ml) were added sequentially. After 18 hours stirring at room temperature, the solid was filtered. The solid was dissolved in 100 ml methylene chloride, dried over Na2SO4, filtered and the solvent was removed in vacuo to yield pure 1-(1-cyanocyclohexyl)-4-hydroxypiperidine.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:32][C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([O:43]CC)=[O:42])[CH2:37][CH2:36]2)=[O:34])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O>[OH-].[Na+]>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:32][C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]2)=[O:34])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)N1CCC(C(=O)OCC)CC1)Cc1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)N1CCC(C(=O)O)CC1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70 mg (0.1 mmol) of ethyl 1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-4-piperidinecarboxylate were suspended in 1N sodium hydroxide solution in a 9:1 mixture of methanol and water and stirred at room temperature for 3 hours. Thereafter, the solvent was evaporated and the residue was recrystallized from methanol/methylene chloride/hexane, to obtain 1-[(R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyryl]-4-piperidinecarboxylic acid as white crystals, melting point 169°.