Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.O.NN>CO.[Ni]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Yield: 81.2 %

Procedure:
A solution of compound 141 (0.12 g, 0.423 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g), hydrazine hydrate (0.13 mL, 4.235 mmol) at room temperature. The resulting mixture was refluxed for 2 min, in pre-heated oil bath. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2×20 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5) to obtain 3-(1,2,3,5,8,8a-Hexahydroindolizin-7-yl)-1H-indol-5-amine, (0.087 g, 81%) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.33-1.48 (m, 1H), 1.67-1.79 (m, 2H), 1.94-2.13 (m, 2H), 2.16-2.26 (m, 2H), 2.58-2.65 (m, 1H), 2.85 (d, 1H, J=15.6 Hz), 3.08-3.17 (m, 1H), 3.59 (dd, 1H, J=4.5, 15.7 Hz), 4.49 (s, 2H), 6.01 (d, 1H, J=4.5 Hz), 6.48 (dd, 1H, J=1.8, 9.1 Hz), 7.01 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS (m/z, %) 254 (MH+, 62), 185 (100). A solution of the amine (0.053 g, 0.209 mmol) in dry ethanol (3 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.12 g, 0.418 mmol) at room temperature and the solution was stirred for 24 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) to obtain compound 142 (0.06 g, 79%) as a solid. mp 122-124° C.; 1H NMR (DMSO-d6) δ 1.38-1.46 (m, 1H), 1.70-1.78 (m, 2H), 1.93-2.12 (m, 2H), 2.20-2.28 (m, 2H), 2.62-2.72 (m, 1H), 2.83 (d, 1H, J=15.9 Hz), 3.07-3.13 (m, 1H), 3.59 (dd, 1H, J=4.5, 16.0 Hz), 6.07 (d, 1H, J=3.9 Hz), 6.22 (brs, 2H), 6.66 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H, J=3.9, 4.9 Hz), 7.22 (s, 1H), 7.30-7.32 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.92 (s, 1H); ESI-MS (m/z, %) 363 (MH+, 20), 294 (100), 182 (15); ESI-HRMS calculated for C21H23N4S (MH+), calculated: 363.1655; observed: 363.1637.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)=[N:11][CH:12]=1
Reactant: C#Cc1cccnc1N
Reactant: Cc1ccc(OCc2ccc(CC(Cl)=NO)cc2)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (4-(5-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (246 mg, 0.846 mmol) described in Manufacturing Example 44-1-5 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (189 μL, 1.36 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→1:2) to obtain the title compound (21.3 mg, 16.9%).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.[C:19]1([CH2:25][C:26]2[O:30][N:29]=[C:28]([CH2:31][CH2:32][CH2:33]O)[N:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:33][CH2:32][CH2:31][C:28]3[N:27]=[C:26]([CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:30][N:29]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Reactant: OCCCc1noc(Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.74 mmol) in THF (4 ml) was treated with 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (195 mg, 0.89 mmol) and PPh3 (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol) was added in one portion and the mixture was left to stir at rt under nitrogen for 18 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified on a silica SPE column using a 0-70% cyclohexane/EtOAc gradient. The product fractions were combined, concentrated by high vacuum and purified on a silica SPE column using a 0-60% cyclohexane/EtOAc gradient. The product fractions were combined and concentrated then dissolved in anhydrous THF (4 ml). The solution was degassed by high vacuum then Pd(PPh3)4 (61 mg, 0.053 mmol) and morpholine (460 μl, 5.3 mmol) were added and the mixture left to stir at rt under nitrogen for 1 day. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 2-4% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated to leave the title compound as a white solid (36 mg, 11%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=3.[Cu](C#N)[C:26]#[N:27]>CN1CCCC1=O>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]1[C:5]2[N:6]([C:2]([C:26]#[N:27])=[CH:3][N:4]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=2
Reactant: N#C[Cu]C#N
Reactant: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(Br)cnc12
Solvent: CN1CCCC1=O
Product: N#Cc1cnc2c(NCCCO)nc3cc(OC(F)(F)F)ccc3n12
Temperature: 160 °C

Procedure:
To a stirred solution of 3-(1-Bromo-7-trifluoromethoxy-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (1.00 g; 2.47 mmol; 1 eq) prepared as in example 51 step 2 in degassed N-methylpyrrolidone (10 mL) are successively added under argon tetrakis-triphenylphosphine palladium (570 mg; 0.49 mmol; 0.2 eq) and copper cyanide (885 mg; 9.90 mmol; 4 eq). The resulting solution is then heated at 160° C. for 3 hours until reaction is complete on TLC. The mixture is then quenched with an aqueous solution saturated with sodium hydrogenocarbonate (50 mL) and the resulting basic solution (pH>8) is extracted with ethyl acetate (100 mL). The organic layer is separated, washed with an aqueous solution saturated with sodium hydrogenocarbonate (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford a brown oil. Chromatography of this crude oil on silica gel (gradient of ethyl acetate/cyclohexane from 1:9 to 5:5) afforded the title compound contaminated by 21% of residual triphenylphosphine oxide. Therefore, the mixture was further purified by a second column chromatography (chloroform/ethyl acetate 7:3) yielding the pure title compound (424 mg; 1.21 mmol; 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].O>C1COCC1>[CH2:29]([O:28][C:26]([NH:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc([N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 0° C. solution of methyl 5-amino-2-methyl-3-nitrobenzoate (1 g, 4.76 mmol, prepared according to the procedure described in J.Med.Chem. 1984, 27, 386) and diisopropylethylamine (0.91 mL, 5.24 mmol) in THF (24 mL) was treated with benzyl chloroformate (0.65 mL, 5.34 mmol), stirred at 0° C. for 30 minutes, warmed to room temperature for 2 hours, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give 1.7 g of the desired product. MS (ESI(−)) m/e 343 (M−H)−.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:13])=[C:9]([O:11]C)[CH:10]=1)[C:6]#[N:7])=[O:2].B(Br)(Br)Br>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:13])=[C:9]([OH:11])[CH:10]=1)[C:6]#[N:7])=[O:2]
Reactant: COc1cc(C=O)cc(C#N)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(C=O)cc(O)c1O
Temperature: 0 °C
Yield: 72.4 %

Procedure:
18 g of the product of Step A and 400 ml of dichloromethane were mixed together under nitrogen and the mixture was cooled to 0° C. 150 ml of a molar solution of boron tribromide in dichloromethane were added and the mixture stood for one night at ambient temperature. It was concentrated, cooled again to 0° C. and 250 ml of a normal solution of hydrochloric acid were added. The crystallized product was separated out, washed with water, dried then crystallized from an isopropanol--water mixture (1-2) to obtain 12 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]3=[O:22])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[N:13]([CH3:23])[C:12]3=[O:22])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc2snc(Cl)c2c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(Cl)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(3-chloro-1,2-benzisothiazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.06 g), potassium carbonate (0.470 g) and iodomethane (0.500 mL) in N,N-dimethylformamide is stirred at room temperature for 90 minutes, treated with additional iodomethane (0.500 mL), stirred at room temperature for 15 minutes, and diluted with water. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven at room temperature to give the title product as a solid which is identified by NMR spectral analysis.
Reaction SMILES: CCCCCC.[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10].[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][C:22]#[N:23])[CH3:17].O>O1CCCC1>[CH2:25]([O:24][CH:19]([O:18][CH2:16][CH3:17])[CH2:20][CH:21]([C:9](=[O:10])[C:8]([F:15])([F:14])[F:7])[C:22]#[N:23])[CH3:26]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(CCC#N)OCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC
Yield: 32.3 %

Procedure:
To a 40°-45° C. stirring suspension of hexane-washed sodium hydride (5.5 g of a 60% dispersion, 0.14 mol) in 200 mL of dried tetrahydrofuran is added dropwise a solution of ethyl trifluoroacetate (15 g, 0.11 mol) and 3-cyanopropionaldehyde diethyl acetal (17 g, 0.11 mol) in 100 mL of dry tetrahydrofuran. The previously gray suspension slowly turns light brown in color. The reaction mixture is stirred at 50°-55° C. overnight before being quenched by slow addition of 2-propanol (15 mL). Rotary evaporation of the volatiles yields a dark oil, to which is added 150 mL of pH 7 water. Unreacted starting materials are conveniently removed by washing the aqueous layer with diethyl ether (3×30 mL). The basic aqueous phase is then acidified with 12N hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed once with saturated sodium bicarbonate (40 mL) and once with brine (15 mL) before being dried over magnesium sulfate. Rotary evaporation yields a reddish oil which is flash chromatographed over silica gel using 4:1 hexane-ethyl acetate as eluent to provide the desired product (9 g, 32%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]/[CH3:22].C(O)C.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.O>[CH:20](/[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:21]/[CH3:22]
Reactant: C/C=C\B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C/C=C\c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 95 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.61 mmol), cis-1-propen-1-ylboronic acid (78.5 mg, 0.910 mmol), ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (170 mg, 97.1%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.CN(C)C=O.[CH3:19][N:20]=[C:21]=[S:22].C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]([C:21]([NH:20][CH3:19])=[S:22])[N:4]=[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: Nc1n[nH]c(Nc2ccccc2)n1
Reactant: CN=C=S
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CNC(=S)n1nc(Nc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 144 h
Yield: 18 %

Procedure:
The synthesis method of Example 1-(3) was applied. The compound (3.86 g) obtained in (2) above, dimethylformamide (50 ml) and methyl isothiocyanate (1.81 g) were used as reagents and the mixture was stirred at room temperature for 6 days. After the reaction, silica gel column chromatography (chloroform-methanol) and recrystallization from chloroform gave 961 mg of white crystals (yield 18%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][CH2:14][C:15]([C:17]4[CH:21]=[CH:20][N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][CH2:14][C:15]([C:17]4[CH:21]=[CH:20][NH:19][CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cc(F)ccc2/C1=C1/C=C(c2cc[nH]c2)CO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of (3E)-6-fluoro-3-{4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]furan-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one (Example 33; 90 mg) in a mixture of trifluoroacetic acid (7 mL) and CH2Cl2 (7 mL) was stirred at room temperature for 3 days. The mixture was evaporated to dryness, and re-dissolved in 1:1 THF/MeOH (6 mL). The solution was slowly added into diluted NaHCO3 solution (100 mL) with stirring. The precipitates were filtered, washed with water, and dried in vacuum to give (3E)-6-fluoro-3-[4-(1H-pyrrol-3-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as brown solid. Yield: 40 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([CH:33]([CH3:37])[C:34]([OH:36])=[O:35])[CH:26]=1)[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][CH2:39]O>S(=O)(=O)(O)O>[CH2:38]([O:35][C:34](=[O:36])[CH:33]([C:27]1[CH:26]=[C:25]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:24])[F:22])=[CH:20][C:15]=2[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH3:13])[C:30]([O:31][CH3:32])=[CH:29][CH:28]=1)[CH3:37])[CH3:39]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)O)ccc1OC)C(=O)OCc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
2-{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-propionic acid (0.058 g, 0.11 mmol) in EtOH (3 mL) was treated with sulfuric acid (2 drops) at 70° C. for 1.5 hours to give the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12]([NH:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)=[S:13])[O:4][CH2:3][CH2:2]1.CI.[C:23](OCC)(=O)C>O1CCCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11][C:12](=[N:14][C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)[S:13][CH3:23])[O:4][CH2:3][CH2:2]1
Reactant: Cc1cscc1NC(=S)NC1CCCCC12OCCO2
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CSC(=Nc1cscc1C)NC1CCCCC12OCCO2
Temperature: 70 °C
Reaction time: 48 h

Procedure:
1-(1,4-Dioxaspiro[4.5]dec-6-yl)-3-(4-methylthiophen-3-yl)thiourea (393 mg) was dissolved in absolute tetrahydrofuran (8.5 ml), and a solution of methyl iodide (179 mg) in absolute tetrahydrofuran (0.5 ml) was added. The mixture was then stirred at 70° C. in sand bath for 2 days. Ethyl acetate was then added to the reaction mixture, and the mixture was washed twice with water. The organic phase was dried over magnesium sulfate and the solvent was removed after filtration. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. This gave 59 mg of the desired product which was used directly for the next step.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[O:6]=[C:7]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]2[S:19][C:20]([C:28](O)=[O:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH:9]=[CH:8]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:28]([C:20]1[S:19][C:11]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:6])[CH:8]=[CH:9][C:10]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:29]
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (31 mg, 0.32 mmol) was added to a mixture of the compound of Example 59 (101 mg, 0.29 mmol), HOBT (55 mg, 0.41 mmol), EDC (78 mg, 0.41 mmol) and NMM (0.090 mL, 0.81 mmol) in DCM (3 mL). The mixture was stirred for 6 h at room temperature. DCM was added and the mixture washed with 2M HCl(aq). The organic phase was re-extracted with DCM. The combined organics were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (3.5% MeOH in DCM) to give the title compound as a white solid (95 mg, 84%). δH (DMSO-d6) 7.48–7.35 (3H, m), 7.34–7.30 (3H, m), 7.29–7.23 (3H, m), 7.16–7.13 (2H, m), 6.33 (1H, d, J 9.6 Hz), 3.26 (3H, s), 2.79 (3H, s). LCMS (ES+) RT 3.27 minutes, 391.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(O)(=O)C.N1CCCCC1>>[CH3:19][O:18][C:12](=[O:17])[CH2:13][C:14]([CH:16]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:15]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)CC(=O)C=Cc1ccccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
In the first step of the synthesis 2-nitro-benzaldehyde is reacted with methyl acetoacetate in the presence of a catalytic amount (0.01-0.7 mole, related to 1 mole of methyl acetoacetate) of piperidine acetate to give methyl-2-nitro-benzylidene-acetoacetate with a high yield of about 97%. This product is reacted after or without isolation with methyl-3-amino-crotonate. The yield of the second step is 87%, the total yield of both steps amounts to 84.4%. According to the disclosure of the cited Hungarian patent the thin layer chromatogram of the nifedipine thus obtained shows no by-products (Merck-type plate coated with kieselgel; developped with a 3:2:5 mixture of chloroform, acetone and petrolether).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[F:23])[C:17](O)=[O:18])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:24][C:25]1([CH3:33])[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH2:31][NH2:32].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:32][CH2:31][CH2:30][N:26]4[CH2:27][CH2:28][CH2:29][C:25]4([CH3:33])[CH3:24])[CH:20]=[CH:21][C:22]=3[F:23])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)CCCN1CCN
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(7-Bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoic acid (prepared by hydrolysis of methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A) using NaOH) (700 mg, 1.851 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (290 mg, 2.036 mmol) and triethylamine (0.774 ml, 5.55 mmol) were dissolved in EtOAc (7.284 ml) and DMF (1.28 ml) to give a yellow solution. ®T3P (propylphosphonic anhydride) (1.620 ml, 2.036 mmol) was added and the mixture was stirred at room temperature for 90 mins. The reaction mixture was diluted with EtOAc and washed with 0.5M LiCl in H2O and sat NaHCO3. The organic portion was dried MgSO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc/iso-hexane to afford the title compound as a white solid;