Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc2cc3ccccc3nc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([N+](=O)[O-])c2cc3ccccc3nc12
Reaction time: 1 h
Yield: 70 %

Procedure:
4-Methoxyacridine (1.4 g, 6.67 mmole) was dissolved in acetic anhydride (5 ml) and cooled to 0°. Concentrated nitric acid (1 eq, 0.7 ml) was added, followed by concentrated sulphuric acid (1 eq, 0.7 ml). After stirring for 1 hr, the product was filtered and the residue was extracted into methylene chloride and washed with sodium bicarbonate solution. It was then dried and evaporated in vacuo to give 1.2 g (70%) of 4-methoxy-1-nitroacridine. NMR (CDCl3, 90 MHz) δ=4.20, s, 3H; 6.95, d, 9 Hz, 1H; 6.70-8.00, m, 3H; 8.34, d, 9 Hz, 1H; 8.55, d, 9 Hz, 1H; 9.82, s, 1H. The methoxy compound (500 mg) was converted to the 4-hydroxy derivative by heating with KOH (2 ml of an 11M aqueous solution) in DMSO (20 ml). This was tosylated with pyridine and toluenesulfonyl chloride to give the 4-tosyloxy derivative (260 mg, 34%). NMR (CDCl3, 90 MHz) δ 2.2, s, 3H; 7.00, m, 2H, 6.30-6.80, m, 7H; 8.20, d, 9 Hz, 1H; 9.45, s, 1H. The tosyloxy compound (600 mg, 1.5 mmole) was dissolved in acetonitrile (4 ml) and 1,7-diaza-4,10,13-trioxacyclopentadecane (110 mg, 0.5 mmole) were added, followed by 1,8-bis(dimethylamino)naphthalene (290 mg, 2 mmole) and the reaction mixture heated under reflux overnight. The reaction mixture was evaporated in vacuo and the residue taken into chloroform and purified by column chromatography (silica gel, ethyl acetate, hexane 1:1) to give the N,N-bis-(1-nitro-4-acridinyl)-diaza[15]-crown-5 as a yellow gum (180 mg, 27%). NMR (CDCl3, 90 MHz) δ 3.40, s, 4H; 3.82, m, 16H; 6.50, d, 9 Hz, 2H; 6.95, d, 9 Hz, 2H; 7.30, t, 9 Hz, 4H; 7.65, d, 9 Hz, 2H; 8.20, d, 9 Hz, 2H; 9.68, s, 2H.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[S:17])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1.F[C:19](F)(F)S(OC)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[NH2:1][C:2]1[C:3]([C:7]([S:17][CH3:19])=[N:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1
Reactant: Nc1nsnc1C(=S)Nc1ccc(F)c(Br)c1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=Nc1ccc(F)c(Br)c1)c1nsnc1N
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbothioamide (130 mg, 0.4 mmol) in dichloromethane (5.2 mL) was treated with methyl trifluoromethanesulfonate (64 μL, 0.6 mmol) followed by N,N-diisopropylethylamine (102 μL, 0.6 mmol) and stirred for 1 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL) and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (133 mg, 98%). LCMS for C10H9BrFN4S2 (M+H)+: m/z=346.8, 348.8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>O1CCCC1.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>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:3]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)n2)cc1
Temperature: 120 °C
Yield: 42.8 %

Procedure:
tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (100.0 mg, 0.21 mmol); 4-methoxyphenyl boronic acid (128.0 mg, 0.84 mmol), and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.04 mmol) were combined in dry tetrahydrofuran (3 mL) in a sealed tube. The mixture was flushed with nitrogen then 0.75 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:2, 3 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. Concentration and preparative HPLC afforded 41.0 mg (34%) of the desired compound as its TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.99 (d, 2H, J=8.0 Hz), 7.86 (s, 1H), 7.31-7.49 (m, 5H), 7.24 (s, 1H), 7.01 (d, 2H, J=8.0 Hz), 4.61 (s, 2H), 3.84 (s, 3H), 3.34 (s, 2H), 3.32-3.60 (m, 2H), 2.85-2.97 (m, 2H), 2.53-2.57 (m, 2H), 2.20-2.26 (m, 2H). Mass spec.: 457.18 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][C@H:4](CC([O-])=O)[CH2:3]1.CS(C)=[O:22]>P([O-])([O-])([O-])=O>[OH:22][C@@H:4]1[CH2:5][C@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:7][C:2](=[O:1])[CH2:3]1
Reactant: CS(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C[C@@H](CC(=O)[O-])C1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C[C@H](O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
3-Oxo-5-(tert.butyldimethylsilyloxy)-(1S, 5S)-cyclohexylacetate (6, 1.2 parts, 4.2 mmol ) was dissolved in DMSO (10 parts) and 0.1 M phosphate buffer (pH 6.5, 90 parts). To the mixture, PLE (0.1 parts) was added and the reaction mixture was stirred for 48 hr at room temperature. It was filtered through ceilite and filtrate was extracted with ethyl acetate (3×100 parts). Organic extracts were combined and washed with brine. Organic layer was dried on anhydrous sodium sulphate and concentrated under vacuum. Residue was chromatographed on silica gel to afford 3-hydroxy-5-(tertbutyldimethylsilyloxy)-(3R,5S)-cyclohexan-1-one 7 (0.77 parts, 75%).
Reaction SMILES: [CH2:1]([CH:4]([C:19]([O:21]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[C:5]([O:7]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[CH:2]=[CH2:3].C(N(CC)CC)C.[NH2:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=1>CC(C)=O>[CH2:1]([C:4]1[C:5](=[O:7])[N:42]2[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:41]2=[N:40][C:19]=1[OH:21])[CH:2]=[CH2:3]
Reactant: COc1ccnc(N)c1
Reactant: C=CCC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CCc1c(O)nc2cc(OC)ccn2c1=O
Reaction time: 16 h
Yield: 64.8 %

Procedure:
Bis(pentachlorophenyl) allylmalonate (905 mg, 1.412 mmol) and triethylamine (0.359 ml, 2.58 mmol) were added to a slurry of 2-amino-4-methoxypyridine (160 mg, 1.289 mmol) in acetone (6.5 ml). The slurry was stirred for 16 hours, filtered, and washed with acetone to yield the title compound as a white solid (194 mg, 65%). LCMS (ES+) m/z 233.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:50][CH2:49][CH:46]1[CH2:47][O:48][C:43]2[CH:42]=[CH:41][C:40]([OH:39])=[CH:51][C:44]=2[O:45]1
Reactant: NCC1COc2ccc(O)cc2O1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccc(O)cc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
5-Methoxyindole-3-butyric acid (1.5 g, 6.4 mmole), 1-hydroxybenzotriazole hydrate (1.0 g, 7.7 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using first ethyl acetate and then 5% methanol in ethyl acetate as eluants. Evaporation of product-containing fractions gave 1.6 g (63%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-yl)-butanamide, as an oily solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:19])=[CH:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7][CH:6]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:19])=[CH:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:10]=1)=[O:27]
Reactant: CCOC(=O)CC=C(C)c1ccc(CCN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C(C)=CCC(=O)O)cc1

Procedure:
By the reaction of ethyl γ-[4-(2-aminoethyl)-phenyl]-but-2-ene-carboxylate hydrochloride with 5-chloro-2-methoxybenzoyl chloride, there is obtained γ-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-but-2-ene-carboxylic acid; m.p. 180°-183° C., after reprecipitation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]#[N:11])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][NH:26][CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21]>ClC1C=CC=CC=1>[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([C:10](=[NH:11])[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21]
Reactant: COc1ccc(NC#N)cc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Solvent: Clc1ccccc1
Product: COc1ccc(NC(=N)N2CCc3nc(C(=O)Nc4ccccc4N)sc3C2)cc1

Procedure:
A solution of 4-methoxy-phenyl-cyanamide (2 eq) obtained in step I above and N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I (1.0 eq) in chlorobenzene was refluxed for 6 h. Solvent was evaporated and the residue was treated with ethereal HCl at room temperature for 5-15 h. Solvent was evaporated and the residue was dissolved in methanol—DCM system and neutralized. Organic layer was separated, dried on anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which was then purified, by either column chromatography or preparative HPLC to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[CH3:19])[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25]
Reactant: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=O
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Yield: 44.6 %

Procedure:
6′-Bromo-4-methoxy-5′-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 4, 1.38 g, 4.27 mmol) and 2-methylpropane-2-sulfinamide (0.931 g, 7.68 mmol) were dissolved in 2-Me THF (8 mL). Titanium(IV) ethoxide (1.78 mL, 8.53 mmol) was added and the resulting mixture was heated to reflux overnight. 2-Methylpropane-2-sulfinamide (0.259 g, 2.13 mmol) and titanium(IV) ethoxide (0.624 mL, 2.99 mmol) were added and heating was continued. After a total of 4 days, the reaction was allowed to cool to r.t. and diluted with EtOAc (25 mL). Water (12 mL) was added dropwise under vigorous stirring and after stirring for another 10 min, the mixture was allowed to stand without stirring for 1.5 h. The solids were filtered off and the solvent was evaporated. The residue was purified by flash chromatography using a gradient of 0-30% EtOAc in heptane as eluent to afford 812 mg (45% yield) of the title compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (m, 9 H), 1.31 (m, 2 H), 1.58 (m, 4 H), 1.90 (m, 1 H), 2.02 (m, 1 H), 2.42 (s, 3 H), 2.98 (m, 2 H), 3.18 (m, 1 H), 3.25 (m, 3 H), 7.51 (m, 1 H), 8.53 (m, 1 H); MS (ES+) m/z 426, 428 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([C:18]([OH:20])=[O:19])[CH:10]=1.Cl.[CH3:22]O>>[CH3:22][O:19][C:18]([C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)=[O:20]
Reactant: COc1ccccc1-c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(-c2ccccc2OC)cc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2′-Methoxy-5-nitro-biphenyl-3-carboxylic acid (8.62 g, 31.5 mmol) was added to a mixture of MeOH (89 mL) and conc. aqueous HCl (4.9 mL). The reaction mixture was stirred at 80° C. for 24 hours, and then stirred for 18 hours at room temperature. The reaction mixture was filtered, and the resulting solid was washed with MeOH and dried to give 8.2 g of 2′-methoxy-5-nitro-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=288.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cccc(C=O)c1OC
Reactant: C=CCOc1ccc(C(C)=O)cc1
Product: C=CCOc1ccc(C(=O)C=Cc2cccc(OC)c2OC)cc1
Reaction time: 23 h
Yield: 90 %

Procedure:
1.76 g (10 mmol) of 4-allyloxyacetophenone and 1.66 g (10 mmol) of 2,3-dimethoxy-benzaldehyde were under an inert atmosphere (argon) dissolved in 10 ml of dry freshly distilled ethanol, and 100 mg of sodium hydroxide was added to the solution. The mixture was left under stirring for 23 h and concentrated in vacuo. The crystalline residue was recrystallized from methanol-water to give 2.92 g (90%) of 2,3-dimethoxy-4′-prop-2-enyloxychalcone, m.p. 98-99° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([NH2:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C.CN([CH:25]=[O:26])C>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([CH3:11])([CH3:10])[NH:12][C:25]2=[O:26])=[CH:4][CH:5]=1
Reactant: CC(C)(N)c1ccc(F)cc1Br
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)NC(=O)c2cc(F)ccc21
Temperature: 130 °C
Reaction time: 16 h
Yield: 8.6 %

Procedure:
A mixture of 1-(2-bromo-4-fluoro-phenyl)-1-methyl-ethylamine (1.5 g, 6.52 mmol), Pd(dppf)Cl2 (0.15 g), DIPEA (2.52 g, 19.6 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130° C. for 16 hours. After it was cooled to room temperature, the reaction mixture was diluted with EtOAc (300 mL). The organic layer was washed with brine, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to give the title compound (100 mg, yield 8.6%) as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:16][C:15]([CH3:17])=[C:14]([C:18]([OH:20])=O)[C:13]=2[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH2:22][CH2:23][CH:24]([OH:32])[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[OH:32][CH:24]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:23][NH:22][C:18]([C:14]1[C:13]([CH3:21])=[C:12](/[CH:11]=[C:10]2\[C:2](=[O:1])[NH:3][C:4]3[C:9]\2=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:16][C:15]=1[CH3:17])=[O:20]
Reactant: NCC(O)CN1CCOCC1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccccc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (113 mg, 0.4 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (74 mg, 0.48 mmol) to precipitate 2,4-dimethyl-5-[2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (77 mg, 45.3%). 1H NMR (DMSO-d6) δ 2.27 (m, 1H), 2.32 (m, 1H), 2.40 (m, 4H), 2.40, 2.42 (2×s, 6H, 2×CH3), 3.15 (s, 1H), 3.32 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.8 Hz, 1H, OH), 6.86 (d, J=7.6 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.49 (t, J=5.6 Hz, 1H), 7.61 (s, 1H), 7.77 (d, J=8.0 Hz, 1H) (aromatic and vinyl), 10.88 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 425.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:14][CH:15]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[CH:19][CH:18]=1)[CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=1)[CH2:10][N:11]([CH2:14][CH:15]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH2:12][CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCN(CC(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
The product from Example 19A (82 mg, 0.13 mmol) in absolute ethanol (2 mL) was treated with 10% palladium on carbon (25 mg) under a H2 atmosphere (1 atm) for 2 hours at ambient temperature. The mixture was filtered through celite and the solution was concentrated to provide the title compound as a colorless, amorphous solid (64 mg, 91%). 1H NMR (CDCl3) δ 7.00 (d, J=8.5 Hz, 4H), 6.73 (d, J=8.5 Hz, 4H), 4.71 (br s, 1.3H), 4.58 (br s, 0.7H), 3.82-3.71 (m, 2H), 2.82-2.65 (m 4H), 2.59-2.28 (m, 6H), 1.42 (s, 12H), 1.38 (s, 6H), 0.95-0.84 (m, 3H); MS (APCl+) m/z 544 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:8]=1
Reactant: COC(=O)c1ccccc1CCC1CCCCC(=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1CCC1CCCCC(OC)=N1

Procedure:
The product of Example 82 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH:16]([CH2:24][CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:16]([CH2:24][CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(NCC2CC2)cc1Cl
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 1B using 2-chloro-4-[(cyclopropylmethyl)amino]benzonitrile and tert-butyl 2-bromobutanoate: MS (ES) m/z 349 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:4][CH:3]=1.Cl.Cl.[F:30][C:31]([F:41])([F:40])[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14](=[O:15])[NH:16][CH2:17][C:18](=[O:20])[N:37]2[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][C:31]([F:40])([F:41])[F:30])[CH2:39][CH2:38]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)/C=C/c1ccc(Cl)cc1
Reactant: FC(F)(F)CCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of [[(2S)-2-[[(2E)-3-(4-chlorophenyl)-2propenoyl]amino]-3-(2-pyridyl)propanoyl]amino]acetic acid (38.8 g), 1-(3,3,3-trifluoropropyl)piperazine dihydrochloride (25.5 g), 1-hydroxybenzotriazole (14.9 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.1 g) in N,N-dimethylformamide (250 ml) was added dropwise N,N-diisopropylethylamine (38.3 ml) at 10° C. over 50 minutes. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution (750 ml). The mixture was extracted three times with ethyl acetate (total 2500 ml) and washed successively with water (500 ml×3) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; 12% methanol in ethyl acetate) to give the title compound (37.0 g) as a white amorphous solid, which was recrystallized from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][CH:14]2[CH2:17][O:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][CH:14]2[CH2:17][O:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)NC1COC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CC(=O)NC2COC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
2-(3-Nitrophenyl)-N-(oxetan-3-yl)acetamide (0.5 g, 2.11 mmol) was taken in methanol (20 ml) and at 0° C., 10% Pd—C (0.5 g) was added. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.42 gm).