Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[O:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([CH3:20])[CH:13]=2)=[O:8])C.[OH-].[Na+]>O1CCCC1.CO.O>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:20])=[CH:15][CH:16]=2)[O:11][C:10](=[O:21])[C:9]=1[C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:8]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccc(C)cc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of [(4-hydroxy-7-methyl-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid ethyl ester (106 mg, 0.347 mmol) and NaOH solution (0.70 mL, 1.38 mmol) in tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL) was stirred at rt overnight; the solvents were evaporated and the resulting residue was dissolved in water, acidified with 2 M HCl solution, the precipitates were then dried to give the desired product (80 mg). ESI (m/z): 278 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[C:15](#[N:18])[CH2:16][CH3:17].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].Cl>C(OCC)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:15]([NH2:18])[CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: CCC#N
Reactant: COc1ccc(Br)cn1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCOCC
Solvent: O
Product: CCC(N)c1ccc(OC)nc1
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
3 ml (23.2 mmol) of 5-bromo-2-methoxypyridine were added at −70° C. to a solution of 10.2 ml of butyllithium (2.5 M solution in hexane; 25.5 mmol) in 50 ml of diethyl ether. After 10 min, 1.4 ml (19.5 mmol) of propionitrile were added. After 2 hours at −70° C., the reaction mixture was slowly allowed to come to room temperature. 2.2 g of sodium sulfate decahydrate were then added and allowed to stir for 1 hour. After subsequent addition of 5 g of magnesium sulfate, the salts were filtered off after stirring briefly and the filtrate was concentrated. The residue was dissolved in 70 ml of methanol and 1.1 g (28 mmol) of sodium borohydride were added at 0° C. After stirring overnight, the reaction mixture was adjusted to pH 2 using concentrated hydrochloric acid and concentrated on a rotary evaporator. The residue was treated with 10 ml of water, and extracted once with diethyl ether. The aqueous phase was then saturated with sodium hydrogencarbonate, concentrated in vacuo and the residue was extracted with ethyl acetate. After drying and concentrating the ethyl acetate extracts, 1.4 g of racemic 1-(6-methoxypyridin-3-yl)propylamine were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[N:4](C2CCCCO2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[CH:32]=[C:33]([CH:48]=[CH:49][C:50]=1[N:51]1[CH2:55][CH2:54][C@@H:53]([OH:56])[CH2:52]1)[C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([Cl:47])([F:46])[F:45])=[CH:39][CH:38]=1)=[O:35].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:47][C:44]([F:45])([F:46])[O:43][C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:50]([N:51]3[CH2:55][CH2:54][C@@H:53]([OH:56])[CH2:52]3)=[C:49]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[CH:48]=2)=[CH:42][CH:41]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)ccc2N2CC[C@@H](O)C2)[nH]n1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Stage 23.1, 128 mg, 0.329 mmol), K3PO4 (140 mg, 0.658 mmol) and Pd(PPh3)4 (15.22 mg, 0.013 mmol) were added to a solution of (R)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide (Stage 20.1, 80 mg, 0.165 mmol) in toluene (1.5 mL) under an argon atmosphere. and the RM was heated at 110° C. for 2 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (4 mL) and treated with TFA (0.507 mL, 6.58 mmol) and stirred at RT for 2 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative HPLC (Condition 10-20% to 80% B in 20 min). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue which was crystallized from DCM/n-hexane to give the title product as a white solid. HPLC (Condition 5) tR=6.41 min, UPLC-MS (Condition 3) tR=1.03 min, m/z=463 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.84 (s, 1H) 2.16-2.30 (m, 3H) 2.74 (d, J=10.56 Hz, 1H) 3.04-3.33 (m, 3H) 4.14-4.23 (m, 1H) 4.76-4.87 (m, 1H) 6.07 (s, 1H) 6.73-6.86 (m, 1H) 7.29 (d, J=8.21 Hz, 2H) 7.78-7.90 (m, J=8.99 Hz, 4H) 10.07 (s, 1H) 12.34-12.56 (m, 1H).
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([O:8][C:9](=[O:13])[CH2:10][N+:11]#[C-:12])[CH3:7]>>[CH2:6]([O:8][C:9]([CH:10]1[CH:1]([CH:2]=[CH:3][CH3:4])[O:5][CH:12]=[N:11]1)=[O:13])[CH3:7]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C/C=C/C=O
Product: CC=CC1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acidethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 (12 hours) yields E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:28][CH:29]([N-]C(C)C)C.ICC>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH2:28][CH3:29])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CC[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (165 mg, intermediate E1) in THF (3.0 ml) was added at −78° C. a solution of LDA (3 eq., 2.8 ml) and stirring was continued for 1 h. The mixture was treated at −78° C. with a solution of iodoethane (67 μl) in THF (2.0 ml) and stirring was continued at the same temperature for 1.5 h and at −20° C. for 16 hours. The mixture was quenched with saturated aqueous NH4Cl, extracted with diethyl ether, the organic layer was dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (4:1) to give [(4S,5R)-5-ethyl-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (96 mg) as a colorless foam. MS (ESI): m/z=391.3 [ M+H]+. The hydrogenation of the nitro group to give the aniline (intermediate F) was carried out as described in Scheme 1.
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[N:19]=[C:18]4[NH:20][C:21]([C:23]5[N:28]=[C:27]([C:29](OC)=[O:30])[CH:26]=[CH:25][CH:24]=5)=[N:22][C:17]4=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:33].C[Al](C)C>C1(C)C=CC=CC=1.O1CCOCC1>[N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[N:19]=[C:18]4[NH:20][C:21]([C:23]5[N:28]=[C:27]([C:29]([NH2:33])=[O:30])[CH:26]=[CH:25][CH:24]=5)=[N:22][C:17]4=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1
Reactant: N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)n1
Temperature: 100 °C

Procedure:
To (R)-methyl 6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)picolinate (200 mg, 0.460 mmol) in toluene (5 mL) were added sequentially a freshly prepared saturated solution of ammonia in dioxane (10 mL) at −20° C., and trimethylaluminum (0.099 g, 1.348 mmol). The reaction vessel was sealed and was heated at 100° C. for 16 h. The mixture was cooled to room temperature and was partitioned between ethyl acetate, and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated twice with methanol:diethyl ether (1:10) to afford the title compound (40 mg). MS (ES+) (M+H) 420.2892; LCMS retention time 3.71 min (Method I1).
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl.C(OCC)(=O)C>[C:46]([N:11]1[CH2:12][CH2:13][C@@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C@@:9]([CH3:38])([C:7]([NH:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:8])[CH2:10]1)(=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@](C)(C(=O)NOC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (323 mg, 0.597 mmol) was dissolved in CH2Cl2 (5 mL). The solution was cooled to 0° C., then triethylamine (100 μL) and acetylchloride (50 μL) were added. The reaction was stirred for 1 h, then diluted with ethyl acetate and washed with saturated aqueous Na2CO3 (2×) and brine (2×). The organic layer was isolated, dried over Na2SO4, concentrated, and then purified via column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give (3S,4R)-1-acetyl-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (341 mg, 0.585 mmol, quant) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.09 (s, 3H) 1.22-1.28 (m, 9H) 1.55 (qd, J=12.93, 4.67 Hz, 1H) 1.88 (ddd, J=13.52, 2.78, 2.65 Hz, 1H) 2.07-2.10 (m, 3H) 2.33-2.39 (m, 1H) 2.75 (s, 3H) 3.09-3.18 (m, 1H) 3.24 (ddd, J=12.19, 8.53, 3.79 Hz, 1H) 3.78 (dt, J=13.58, 2.18 Hz, 1H) 4.76 (dd, J=14.91, 2.53 Hz, 1H) 5.55 (s, 2H) 7.08-7.14 (m, 2H) 7.42 (s, 1H) 7.53-7.58 (m, 1H) 7.70-7.75 (m, 1H) 7.83-7.87 (m, 2H) 7.89-7.93 (m, 1H) 8.07-8.11 (m, 1H) 9.93 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.[Pd]>[CH2:19]([O:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(CCOCCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(OCCOCCc2ccccc2)cc1
Yield: 91 %

Procedure:
The 1-benzyloxy-4-(2-phenethyloxyethoxy)benzene obtained according to the preceding paragraph was dissolved in 200 ml of ethanol and 200 ml of ethyl acetate and hydrogenated overnight at atmospheric pressure and room temperature in the presence of 0.4 g of 10% palladium/carbon. The catalyst was removed by filtration and the filtrate was evaporated to give 10.8 g (91%) of 4-(2-phenethyloxyethoxy)phenol in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:27])[CH:33]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccc(Cl)c1
Yield: 21.6 %

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.335 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.03 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3-chlorophenylboronic acid (0.240 g) in ethanol (1 ml). The mixture was heated under reflux for 4 hours, cooled and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, washed with water (25 ml), brine (25 ml) and then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave a white solid (70 mg) which was further purified by HPLC. Combination and processing of suitable fractions gave the title compound as a white crystalline solid, m.p. 161-2° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Product: COC(=O)c1nc(C)sc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. 1H-NMR (CDCl3): δ=2.75 (s, 3H); 3.84 (s, 3H); 7.10 (m, 2H); 7.47 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:22][CH:18]4[CH2:19][NH:20][CH2:21][CH:17]4[CH2:16]3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].[OH:27][C@H:28]([CH3:32])[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:22][CH:18]4[CH2:19][N:20]([C:29](=[O:30])[C@H:28]([OH:27])[CH3:32])[CH2:21][CH:17]4[CH2:16]3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CN1c2nc(C3CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CC2CC(c3ccc4c(n3)N(C)S(=O)(=O)N4CC3CC3(F)F)CC2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-3-methyl-5-(octahydrocyclopenta[c]-pyrrol-5-yl)-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (25-1, 20 mg, 0.052 mmol, 1.0 equiv), (2R)-2-hydroxypropanoic acid (25-2, 7.0 mg, 0.078 mmol, 1.5 equiv), DIPEA (27 μL, 0.16 mmol, 3.0 equiv) and HATU (29.7 mg, 0.078 mmol, 1.5 equiv) were added to anhydrous acetonitrile (520 μL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 25-3 as a white solid. MS m/z (M+H): calculated=457.1716; observed=457.1726.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>CO.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccccn1
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)CC1CCCCN1
Reaction time: 18 h
Yield: 97.3 %

Procedure:
At rt a mixture of ethyl 2-(pyridin-2-yl)acetate (3.0 g, 18 mmol) and platinum (IV) oxide (0.825 g, 3.63 mmol) in methanol (25 mL) was subject to hydrogenation at 50 psi for 18 h. After filtration, the filtrate was concentrated to afford Intermediate 22A (3.0 g, 96%) as a clear oil. HPLC/MS (Method L) RT=0.99 min, [M+1]+ 172.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[NH:19][C:18]3=[O:27])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:28])[CH3:2].C(O)(=O)C.[Br:35]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:35][CH:10]1[CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:29][CH3:30])[C:7](=[O:28])[C:8]2[C:14]([CH3:15])=[C:13]([CH:16]=[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[NH:19][C:18]3=[O:27])[NH:12][C:9]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC)CCN1CC(Br)c2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 21.5 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (82 mg, 0.2 mmol) prepared from Example 1 in 2 ml of tetrachloromethane was added with acetic acid (20 ml), N-bromosuccinimide (43 mg, 0.24 mmol) and azobisisobutyronitrile (2 mg, 0.012 mmol). The mixture was heated to reflux for 45 minutes, cooled down to room temperature filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give the mixture (21 mg) of 7-bromo-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one and 3-bromomethyl-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one which was used as such.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26]([N:4]3[CH2:5][CH2:6][N:1]([CH2:7][C:8]#[N:9])[CH2:2][CH2:3]3)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1
Reactant: N#CCN1CCNCC1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of piperazin-1-yl-acetonitrile (0.32 g, 2.3 mmol) and Et3N (350 mg, 3.4 mmol) is added 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (615 mg, 2.3 mmol) at 0° C. The reaction is warmed to room temperature and stirred 4 h. The reaction is diluted with CH2Cl2, washed with 1 N HCl, NaHCO3 and dried over MgSO4. The solution is concentrated and the residue is triturated with PE, triturated with Et2O, and pumped to yield [4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-acetonitrile which can be used without further purification. 1H NMR (300 MHz, CDCl3) δ7.89-7.84 (m, 3H), 7.48 (dd, 1H), 4.36 (s, 2H), 3.92 (s, 2H), 3.64-3.61 (m, 2H), 3.57-3.54 (m, 2H); MS (Ion Spray) 444 (M+H)+.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([CH:11]([N:10]2[CH:3]=[CH:7][CH:6]=[CH:5]2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:21][CH:20]=1
Reactant: COC1CCC(OC)O1
Reactant: NC(CC(=O)O)c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccc(O)cc1)n1cccc1
Reaction time: 1 h

Procedure:
At 100° C., 2,5-dimethoxytetrahydrofuran (8.5 mmol) was added to a mixture of 3-amino-3-(4-hydroxyphenyl) propanoic acid (7.7 mmol) and sodium acetate (46 mmol) in acetic acid (34 mL). After stirring for 1 h, acetic acid was removed under reduced pressure. The residue was extracted with ethyl acetate (300 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4 and concentrated. The residue was purified via column chromatography (10% methanol in dichloromethane) to compound 55.1. LC-MS (neg.) m/e: 230.2 (M−H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=O.O.[NH2:18][NH2:19]>O1CCCC1>[F:1][C:2]([F:16])([F:15])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[N:18][NH2:19]
Reactant: NN
Reactant: O=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O
Product: NN=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone (Sov. Prog. Chem. (Engl.Transi.), 1966, 32, 745, 1.8 g, 7.72 mmol) was dissolved in tetrahydrofuran (10 ml) and hydrazine monohydrate (0.56 ml, 11.58 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature then heated under reflux for 40 min. The reaction mixture was concentrated in vacui and the residue treated with water (10 ml) and extracted with dichloromethane (4×10 ml). The organic extracts were concentrated in vacuo and the residue was purified by chromatography on silica gel (100 g), eluting with diciforomethane: hexane (1:1 and then 2:1). The product was obtained as an amber gum (159 mg, 8%).
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:3](C=O)[CH:2]=1.S([O-])([O-])(=O)=O.[Mg+2].Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1cc(C=O)c2cccccc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: c1ccc2cccc-2cc1
Temperature: 95 °C
Yield: 225.1 %

Procedure:
1,3-Azulenedicarboxaldehyde (600 mg) is dissolved in 6.5 ml of pyridine. Magnesium sulfate (1200 mg) and N-tert-butylhydroxylammne hydrochloride (1638 mg,) is added to the solution,. The mixture is heated wit stirring to 95° C. under nitrogen and is stirred for 13 hours. Upon cooling to rt, the reaction mixture is poured into a separator flinnel containing 60 ml of CHCl3 and 60 ml of sat aq. NaHCO3. The aqueous layer is separated and washed with three 30 ml portions of CHCl3. The combined organc layers are dried over anhydrous MgSO4, filtered, and evaporated to give the bis-nitrone 34 (940 mg, 89% yield) as dark green crystals. Oxidation potential equals 0.72 V vs SCE. 1H NMR (CDCl3): 10.35 (s, 1H), 8.65 (d, 2H, J=10 Hz) 8.11 (s, 2H), 7.68 (t, 1H, J=10 Hz), 7.32 (t, 2H, J=10 Hz), 1.67 (s, 18H). 13C NMR (CDCl3): 139.9, 135.0, 134.2, 125.8, 125.6, 123.2, 120.5, 69.8, 28.4. IR (thin film): 3052, 2972, 1644, 1564, 1452, 1404, 1356, 1261, 1196, 1124, 1052, and 892 cm-1.