Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:29])[N:4]([CH2:24][CH2:25][C:26]([OH:28])=O)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH:6]=2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:52]([CH2:54][NH2:55])[OH:53]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:53][CH2:52][CH2:54][NH:55][C:26](=[O:28])[CH2:25][CH2:24][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:6]=2)[N:11]=[C:2]([CH3:1])[C:3]1=[O:29]
Reactant: NCCO
Reactant: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCC(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCC(=O)NCCO)c1=O
Reaction time: 8 h

Procedure:
In this example 3-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)-quinoxalin-I (2H)-yl)propanoic acid (50 mg) was dissolved in chloroform (1 mL). HOBt (20 mg), EDC hydrochloride (29 mg), triethylamine (75 μL), and ethanolamine (9 μL) were added sequentially to the reaction flask and stirred overnight. Concentrated and residue chromatographed on silica gel using 5% MeOH in dichloromethane as eluent. Product N-(2-hydroxyethyl)-3-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)-quinoxalin-1(2H)-yl)propanamide is isolated as yellow solid.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:14][CH3:15])[NH:8][C:7]2=O.[N+:17]([C:20]1[N:24]=[CH:23][NH:22][N:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:14][CH3:15])[N:8]=[C:7]2[N:22]1[CH:23]=[N:24][C:20]([N+:17]([O-:19])=[O:18])=[N:21]1
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(-n2cnc([N+](=O)[O-])n2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 89 %

Procedure:
Iodine (16.5 g, 65.1 mmol) was added to a suspension of compound 5a (8.03 g, 29.6 mmol), 3-nitro-1H-1,2,4-triazole (11.8 g, 103.6 mmol), triphenylphosphine (18.1 g, 69.1 mmol) in 630 mL of toluene. The reaction mixture was rapidly heated to 95° C. for 15 minutes after which 25 mL of N,N-diisopropylethylamine was added and the mixture was stirred for another 50 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was precipitated from ethanol, to give 6 as a yellow solid (9.67 g, 89%). mp: 204° C.,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]([NH2:17])=[S:16])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15]2[S:16][C:27]3[CH2:28][CH2:29][CH2:30][CH:25]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=4)[C:26]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: COc1cc(NC(N)=S)ccc1-c1cnco1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1cnco1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A suspension of (3-methoxy-4-oxazol-5-yl-phenyl)-thiourea (74.8 mg, 0.3 mmol) and of 2-bromo-6-phenyl-cyclohexanone (75.9 mg, 0.3 mmol, preparation: WO9404487) in ethanol (4 mL) was heated over night to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (101 mg, 83%) as an off-white foam. MS ISP (m/e): 404.5 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.29 (s, 1H), 8.31 (s, 1H), 7.66 (s, 1H), 7.50 (d, 1H), 7.46-7.51 (m, 3H), 7.09-7.31 (m, 3H), 6.83 (s, 1H), 4.00 (m, 1H), 3.46 (s, 3H), 2.73 (m, 2H), 2.12 (m, 1H), 1.70-1.94 (m, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1.[NH3:18]>CO>[CH:12]1([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[N:7]=2)[C:3]([NH2:18])=[O:2])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1cc(OC)nc(C2CCCC2)c1
Reactant: N
Solvent: CO
Product: COc1cc(C(N)=O)cc(C2CCCC2)n1

Procedure:
A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (3.19 g, 13.6 mmol) in 7 N NH3 in methanol (50 mL) is stirred at 60° C. for 18 h. The solvent is removed in vacuo and the residue is dried under HV to give crude 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g) as a pale yellow solid; LC-MS**: tR=0.57 min, [M+1]+=221.38.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1.C(=O)([O-])O.[Na+].Cl>C(OCC)C>[CH2:5]([O:4][C:2]([N:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 72 %

Procedure:
A diethyl ether (50 ml) solution of benzyl chloroformate (36 g, 0.21 mols) was dropwise added to an aqueous solution (200 ml) of isonipecotic acid (25 g, 0.19 mols) and sodium hydrogencarbonate (49 g, 0.58 mols) with stirring at room temperature. After the addition, this was further stirred at room temperature for 15 hours. The reaction mixture was acidified with concentrated hydrochloric acid added thereto, and then extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether/hexane, and taken out through filtration. A colorless crystal of N-benzyloxycarbonylisonipecotic acid (36 g, 71%) was obtained.
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([CH3:27])[NH:21][C:20]3=[O:28])[CH2:13][C:14]#[CH:15])=[CH:8][CH:7]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([O:1][CH:2]([C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)[CH2:3][NH:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([CH3:27])[NH:21][C:20]3=[O:28])[CH2:13][C:14]#[CH:15])=[CH:8][CH:7]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(OC(C)=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 88 %

Procedure:
Using an analogous procedure to that described in Example 4, N-[2-hydroxy-2-(4-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide was reacted with acetic anhydride to give N-[2-acetoxy-2-(4-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide (containing 2.3 equivalents of water) in 88% yield, m.p. 198°-203° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[Si:22](OS(C(F)(F)F)(=O)=O)([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>C(Cl)Cl>[CH:23]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)([CH3:25])[CH3:24]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)Cc1ccc(CO)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To methyl 2-(4-(hydroxymethyl)phenyl)acetate (E132) in CH2Cl2 at 0° C. was added 2,6-lutidine and TIPS-OTf. The ice bath was removed and the solution was allowed to warm to room temperature and stir. After 4 h the solution was poured into NH4Cl(sat) and CH2Cl2 and the organic layer was further extracted with NH4Cl(sat). The organics were dried (MgSO4) filtered and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 2-(4-((triisopropylsilyloxy)methyl)phenyl)acetate (E133).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](OCC)=[O:15])=[C:10]([OH:19])[C:9]3[CH2:20][O:21][CH2:22][C:8]2=3)=[CH:4][CH:3]=1.C([NH:29][CH2:30][C:31]([OH:33])=[O:32])(C)(C)C.C(Cl)Cl>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:29][CH2:30][C:31]([O:33][CH2:24][CH2:2][CH2:3][CH3:4])=[O:32])=[O:15])=[C:10]([OH:19])[C:9]3[CH2:20][O:21][CH2:22][C:8]2=3)=[CH:23][CH:24]=1
Reactant: CC(C)(C)NCC(=O)O
Reactant: CCOC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)COC2
Solvent: ClCCl
Solvent: COCCOC
Product: CCCCOC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)COC2
Temperature: 120 °C

Procedure:
To a solution of the ester from Step C (563 mg, 1.43 mmol) in 1,2-dimethoxyethane (12 mL) was added tert-butyl glycine (0.390 mL, 2.86 mmol). The mixture was heated in the microwave at 120° C. for 1.5 h. The mixture was concentrated in vacuo to give a yellow oil which was taken up in the minimum amount of CH2Cl2 and chromatographed on a Biotage 40S+ column with a 10, 20, 30, EtOAc/hexanes gradient elution to give compound, 28-4, as a white solid, 494 mg: 1H NMR (500 MHz, CDCl3): δ 1.49 (s, 9 H), 4.09 (d, 2 H, J=5.2 Hz), 4.91 (t, 2 H, J=3.2 Hz), 5.01 (s, 2 H), 5.05 (t, 2 H, J=3.2 Hz), 7.09 (d, 2 H, 8.3 Hz), 7.46 (d, 2 H, J=8.2 Hz), 10.44 (m, 1 H); HPLC/MS: 1.28 min, 480.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH3:24])[CH:14]=2)[C:5]([N+]([O-])=O)=[N:4]1)[CH3:2].[O-:28][CH2:29][CH3:30].[Na+]>C(O)C>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH3:24])[CH:14]=2)[C:5]([O:28][CH2:29][CH3:30])=[N:4]1)[CH3:2]
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])nn(CC)c(=O)c2Cl)ccc1OC
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1cc(CNc2c(OCC)nn(CC)c(=O)c2Cl)ccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
300 mg of 2-ethyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 24) prepared in Example 4, was dissolved in 6 ml of dried ethanol, and 160 mg of sodium ethoxide was added thereto. The mixture was gently refluxed under stirring for 10 minutes. After cooling, ice water was poured into the reaction solution, and then most ethanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and a saturated sodium chloride aqueous solution in this order and dried over sodium sulfate. The solvent was distilled off and the residual oily substance thereby obtained was purified by silica gel thin layer chromatography by using benzene:ethyl acetate (7:3 v/v) as the developer, to obtain 300 mg of the above identified compound. The physical properties and the spectrum data of NMR, IR and MS of the compound completely agreed to those of the compound prepared by the above method (1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:40]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH2:40])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](N)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of compound A (46.2 mmol) in EtOAc (175 mL) at room temperature was added piperidine (4.57 mL, 46.2 mmol) and the reaction mixture was stirred for 18 h at room temperature. Next the solvent was removed in vacuo and the resulting residue dissolved in minimum amount of EtOAc (˜50 mL) and hexane (˜1 L) was added. The precipitated crude product was filtered off and recrystallised again with EtOAc (˜30 mL) and hexane (˜750 mL). The precipitate was filtered off, washed with hexane and dried in vacuo to afford compound B (28.0 g, 46.2 mmol). LC-MS [M+H] 595.4 (C28H46N6O6S+H, calc: 595.3). Compound B was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O[CH2:10][C:11]1[CH:16]([C:17]([OH:19])=[O:18])[N:15]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]2[S:13][CH:12]=1)(=O)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[C:25]1([CH2:24][C:23]([NH:22][CH:21]2[C:20](=[O:32])[N:15]3[CH:16]([C:17]([OH:19])=[O:18])[C:11]([CH2:10][C:5]4[S:1][CH:2]=[CH:3][CH:4]=4)=[CH:12][S:13][C@H:14]23)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccsc1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 3.4 g of thiophene in 200 ml of trifluoroacetic acid is mixed with 4 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature and then mixed with an equal quantity of toluene, and the mixture is evaporated under reduced pressure. The residue is triturated with acetic acid ethyl ester and the solid material is twice crystallised from a mixture of methanol and acetic acid ethyl ester. 7-(N-Phenylacetyl-amino)-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid is thus obtained as colourless crystals, melting point 189°C; thin layer chromatogram (silica gel): Rf = 0.72 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.81 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.50 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol):λmax = 233 mμ (ε = 15400); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.73μ, 5.82μ and 6.05μ. A further quantity of the desired product can be obtained by concentrating the mother liquor and recrystallising the crystalline material.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[O:12][CH2:13][C:14](=[O:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCCCC1>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]4[N:1]=[CH:2][NH:3][C:4]=4[CH:9]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc3nc[nH]c3c2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc3nc[nH]c3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 3.6 %

Procedure:
To a solution of ethyl 2-[(5-benzimidazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0 mL), piperidine (0.20 mL, 3.1 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.015 g, y. 4%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.OS(O)(=O)=O.[NH3:17]>C(O)CCC.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:17])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: N
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCO
Product: NC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 μL, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R.T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield). 1H NMR (CDCl3) δ 12.15 (s, 1 H), 7.54 (m, 2 H), 6.97 (d, J=12 Hz, 1 H), 6.00 (broad, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C1CCCCN1
Reactant: Nc1ccccc1CN1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(N=C2CCCCN2)c(CN2CCOCC2)c1

Procedure:
A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4-(2-aminobenzyl)morpholine (5.7 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65°-70° C. for 48 hours to yield 4-[2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 108°-110° C.) which was recrystallised from hexane.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:8][C:9](=[O:38])[C@H:10]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:11][C:12]([C:14]1([NH:19][C:20](=[O:29])[C@H:21](Br)[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:7]>O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:8][C:9](=[O:38])[C@H:10]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:11][C:12]([C:14]1([NH:19][C:20](=[O:29])[C@@H:21]([S:3][C:1](=[O:4])[CH3:2])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:7]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)NC(=O)C1(NC(=O)[C@H](Br)C2CCOCC2)CCCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCc1ccccc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C2CCOCC2)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of potassium thioacetate (1.66 g, 14.6 mmol) and N-[1-[(R)-2-bromo-2-(4-tetrahydropyranyl)acetylamino]-cyclopentanecarbonyl]-L-homophenylalanine ethyl ester (1.84 g, 3.52 mmol) in 50 mL of tetrahydrofuran is stirred at room temperature for 4 hours. The mixture is diluted with ethyl acetate, washed with water, with saturated sodium bicarbonate solution, with brine and then dried over magnesium sulfate. The mixture is filtered and concentrated to dryness in vacuo. The residual oil is chromatographed on silica gel with hexane:ethyl acetate (50:50) to yield the title compound, m.p. 107–111° C.; [αD]−56.27° (c=0.994, methanol).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.Cl[CH2:13][CH2:14][C:15]([NH:17][C:18]1[S:22][C:21]2[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=2[C:19]=1[C:27]([NH:29][CH3:30])=[O:28])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[I-].[K+]>[CH:8]([C:7]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][N:5]([CH2:13][CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[CH:6]=1)=[O:9]
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Reactant: CNC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(NC(=O)CCn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Reaction time: 168 h
Yield: 85 %

Procedure:
3-(Trifluoromethyl)-1H-pyrazole-4-carbaldehyde (437 mg, 2.66 mmol) and 2-(3-chloropropanamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (801 mg, 2.66 mmol) were dissolved in DMF (15 mL). Potassium carbonate (368 mg, 2.66 mmol) was added followed by potassium iodide (10 mg, 0.06 mmol). The reaction mixture was left to stand for 7 days. Water was added and the reaction mixture extracted into EtOAc (×3). The EtOAc layers were combined and washed with water (×5), brine, dried over MgSO4, filtered and the solvent removed in vacuo to give desired product as a yellow solid (970 mg, 2.26 mmol, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29](O)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:27])[CH3:28])[C:21]([C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a yellow solid (91%).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].FC(F)(F)S([O-])(=O)=O.[F:40][C:41]1([F:54])[CH2:44][N:43]([S:45](N2C=C[N+](C)=C2)(=[O:47])=[O:46])[CH2:42]1>CC#N>[F:40][C:41]1([F:54])[CH2:44][N:43]([S:45]([NH:31][C:26]23[CH2:29][CH2:30][C:23]([C:20]4[N:19]5[C:14]6[CH:13]=[CH:12][N:11]([S:1]([C:4]7[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=7)(=[O:3])=[O:2])[C:15]=6[N:16]=[CH:17][C:18]5=[N:22][N:21]=4)([CH2:28][CH2:27]2)[CH2:24][CH2:25]3)(=[O:47])=[O:46])[CH2:42]1
Reactant: C[n+]1ccn(S(=O)(=O)N2CC(F)(F)C2)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)N6CC(F)(F)C6)(CC4)CC5)n23)cc1
Temperature: 70 °C
Yield: 43.7 %

Procedure:
To a solution of 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amine (0.20 g, 0.46 mmol, Example #9, Step F) in MeCN (5 mL) was added 1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (0.19 g, 0.50 mmol). The reaction mixture was heated to about 70° C. for about 24 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (10 mL). The layers were separated and the organic layer was washed with water (10 mL) and brine (2×10 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM to give 3,3-difluoro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)azetidine-1-sulfonamide (0.119 g, 38%): LC/MS (Table 1, Method a) Rt=2.32 min; MS m/z 592 (M+H)+.