Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]([O:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[C:54](O)=[O:55])(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=3[O:51][C:48](=[O:50])[CH3:49])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-acetyloxybenzoic acid (6.0 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:8]2[CH:13]=[N:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=1)CO>C1COCC1.O>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:7]1[C:8]2[CH:13]=[N:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=[C:5]([CH:2]=[O:1])[CH:6]=1)=[O:18]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C=O)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 6-(1,2-dihydroxyethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide 0.66 g, 1.65 mmol) in 50% THF/Water (12 mL), NaI04 (1.06 g, 4.95 mmol) was added at 0° C. and stirred at room temperature for 1 h. After completion of reaction, solid was filtered and washed with water. Azeotrope with toluene to obtain the desired compound (0.515 g, 84.8%). LCMS: 368.05 (M+1)+; HPLC: 99.53% (@ 254 nm), (Rt; 5.901); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 10.09 (s, 1H), 9.10 (bs, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 5.89 (s, 1H), 5.37-5.31 (m, 1H), 4.37 (d, 2H, J=4.4 Hz), 2.21 (s, 3H), 2.12 (s, 3H), 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.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.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3ccccc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 25.6 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 40 mg, 0.09 mmol), phenylboronic acid (13.2 mg, 0.11 mmol), potassium carbonate (38 mg, 0.272 mmol), tetrakis(triphenylphosphine)palladium (0) (3 mg, 2.7 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (10 mg, 0.023 mmol, 25% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 12.97 (br. s., 1H), 10.16 (t, J=5.56 Hz, 1H), 7.69 (d, J=7.33 Hz, 2H), 7.55 (dd, J=11.62, 1.52 Hz, 1H), 7.51-7.43 (m, 3H), 7.38-7.42 (m, 1H), 7.35 (t, J=7.96 Hz, 1H), 5.34 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.18 (sept, J=6.82 Hz, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 440 [M+H]+.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>[Pd].C(Cl)Cl>[C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cccc(N)c1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To 60 mL anhydrous CH2Cl2 was added O-pivaloyl-3-nitrophenol (5.0 g, 22.4 mmol) and a catalytic amount (50 mg) of 10% Pd on C. The flask was repeatedly evacuated and flushed with N2. The reaction flask was again evacuated and H2 was introduced by balloon. After stirring under an atmosphere of H2 for 3 h, the reaction flask was flushed twice with N2. The suspension was then filtered through a bed of Celite™ and concentrated to give 4.15g (96%) of O-pivaloyl-3-aminophenol as a viscous amber oil. Data for O-pivaloyl-3-aminophenol: Rf 0.21 (silica gel, hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 7.12 (dd, J=8.0, 8.0, 1H), 6.52 (dd, J=7.8, 2.7, 1H), 6.44 (ddd, J=8.0, 2.4, 1.4, 1H), 6.38 (t, J=2.2, 1H), 3.81 (br s, 2H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].[C:28]1([CH2:34]C=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([CH2:15][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2

Procedure:
(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]acrylic acid methyl ester was synthesized starting from Intermediate 4 (350 mg, 1.13 mmol), according to the procedure described in Example 31, Step A, using phenylacetaldehyde (0.25 ml, 2.3 mmol) and NaBH(OAc)3 (360 mg, 1.69 mmol). The product was obtained as a yellow solid (378 mg).
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][P:11](=[O:26])([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[NH2:9][CH2:10][P:11](=[O:26])([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=P(CNCc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCP(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
A mixture of diphenyl N-benzyl-aminomethylphosphonate hydrochloride (185.0 g), 10% palladium on carbon (7.0 g), and ethanol (1500 ml) is hydrogenated at 40 psi until hydrogen absorption ceases. The catalyst is removed by filtration through a pad of super cel and the filtrate is evaporated under reduced pressure to give diphenyl aminomethylphosphonate hydrochloride.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)C(C(O)=O)=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([N:14]1[C:22]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (7.1 mL, 81.4 mmol) was added under nitrogen dropwise over 10 minutes to a suspension of 1-benzyl-1H-indole-3-carboxylic acid (4.10 g, 16.3 mmol) in 200 mL of methylene chloride at room temperature. When the oxalyl chloride was added there was an immediate evolution of gas and within 30 minutes all of the solid had dissolved. After the addition of the oxalyl chloride the reaction was stirred at room temperature for 2 h. The solvent and excess oxalyl chloride were removed under reduced pressure. The residue was taken up in benzene and then concentrated to dryness under reduced pressure to give 1-benzyl-1H-indole-3-carbonyl chloride, which was used in the following reaction without purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1OC2C(Cl)=C(Cl)C(Cl)=C(Cl)C=2O1)=O.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[N:28]/[NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[CH:8]=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(c1ccco1)C1Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2O1
Reactant: NNc1ccccc1
Solvent: CCO
Product: C(=NNc1ccccc1)/C(=N\Nc1ccccc1)c1ccco1
Yield: 86.8 %

Procedure:
A mixture of furan-2-yl(4,5,6,7-tetrachlorobenzo[d][1,3]dioxol-2-yl)methanone (200 mg, 0.568 mmol) and phenylhydrazine (185 mg, 1.704 mmol) in ethanol (3 ml) was heated under reflux for 30 minutes. During the course of the reflux, a yellow solid initially precipitated, but then dissolved upon further heating. The solvent was evaporated to dryness, and the resulting crude material was subjected to flash column chromatography using 7% ethyl acetate/hexane as an eluent to yield (2E)-2,2′-(1-(furan-2-yl)ethane-1,2-diylidene)bis(1-phenylhydrazine) as a yellow solid (150 mg, 87%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:38]([CH3:40])([CH3:39])[C@H:37]2[C@@:5]3([O:33][C:9]4[C:10]5[CH2:11][N:12](C(OC(C)(C)C)=O)[C:13](=[O:25])[C:14]=5[CH:15]=[C:16]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:8]=4[CH2:7][C@:6]3([CH3:42])[C@@H:34]([CH3:41])[CH2:35][CH2:36]2)[CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C@@H:2]1[C:38]([CH3:40])([CH3:39])[C@H:37]2[C@@:5]3([O:33][C:9]4[C:10]5[CH2:11][NH:12][C:13](=[O:25])[C:14]=5[CH:15]=[C:16]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:8]=4[CH2:7][C@:6]3([CH3:42])[C@@H:34]([CH3:41])[CH2:35][CH2:36]2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a solution of Compound (45a) (50 mg, 0.087 mmol) in 5 ml of dry dichloromethane were added 30 μl (0.28 mmol) of anisole and 35 μl (0.45 mmol) of trifluoroacetic acid, and the mixture stirred for 3 hours at room temperature. Under ice-cooling, to the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The extract was washed with water and an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 30 mg (73%) of the crude Compound (46a) as a powdery material.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(CCCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Yield: 63.7 %

Procedure:
A mixture of 7-methyl-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.24 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-methyl-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2,3-dihydro-isoindol-1-one (0.063 g, 64%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.24-2.77 (m, 18H), 4.15 (s, 2H), 4.72 (s, 2H), 7.08 (d, 1H), 7.28 (m, 5H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:12])[CH2:8][C:9](=O)[CH3:10])[CH:2]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=O>C(OCC)(=O)C>[N:13]1([C:9]([CH3:10])=[CH:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCN1
Reactant: CC(=O)CC(=O)c1cccnc1
Solvent: CCOC(C)=O
Product: CC(=CC(=O)c1cccnc1)N1CCCC1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
To a solution of 16.32 g of 1-(3-pyridinyl)butan-1,3-dione in 200 ml of ethyl acetate was added 7.11 g of pyrrolidone. The mixture was stirred at room temperature and then the crystals were collected giving 7.0 g of 3-(1-pyrrolidinyl)-1-(3-pyridinyl)-2-buten-1-one, mp 116°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH2:35][CH3:36])([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:34])[CH:21]=3)[CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH:10]=1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH2:35][CH3:36])([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:34])[CH:21]=3)[CH2:18][CH3:19])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(CCC2(O)CCCC2)c(C)c1
Yield: 79.4 %

Procedure:
10% palladium carbon (16 mg) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 148-(1); 16.4 mg, 0.033 mmol) in methanol (0.2 mL), and the mixture was stirred in a hydrogen atmosphere for 19 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (13.1 mg, 79%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([C:22](=[N:24]O)[NH2:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:24]=[C:12]([C:3]3[CH:2]=[CH:11][C:10]([C:2]4[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=4[CH3:12])=[C:5]([CH2:6][O:8][CH3:9])[CH:4]=3)[O:13][N:23]=2)=[CH:20][N:21]=1
Reactant: NC(=NO)c1ccc(Cl)nc1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Product: COCc1cc(-c2nc(-c3ccc(Cl)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and 6-chloro-N′-hydroxypyridine-3-carboximidamide (J. Med. Chem., 2005, 5215-5223). After purification by flash chromatography (silica, EtOAc/cHex), the title compound was obtained as a colorless oil (661 mg, 70%). HPLC (Method A), Rt: 5.8 min (purity: 99%). UPLC/MS, M+(ESI): 392.2.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH:14]([CH3:18])[C:15](O)=[O:16])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2].C([N:21](CC)CC)C.ClC(OCC)=O.N.Cl>O1CCCC1>[CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH:14]([CH3:18])[C:15]([NH2:21])=[O:16])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCC1CC(=O)c2cc(C(C)C(=O)O)ccc2O1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CCC1CC(=O)c2cc(C(C)C(N)=O)ccc2O1
Yield: 51.6 %

Procedure:
To a stirred solution of 2-(2,3-dihydro-2-ethyl-4-oxo-4H-1-benzopyran-6-yl)propionic acid (10.0 g; 0.04 mol) in dry tetrahydrofuran (100 ml) at -20° C. was added triethylamine (4.05 g; 0.04 mol) followed by ethyl chloroformate (6.0 g; 0.056 mol). After 10 minutes the mixture was saturated with gaseous ammonia. It was then acidified with dilute hydrochloric acid, the organic solvent was removed in vacuo and the product was extracted with chloroform (4×80 ml). The combined extracts were washed with water (2×100 ml), brine (200 ml), and dried over MgSO4. Evaporation of the solvent and recrystallisation of the residue from ethyl acetate gave the title compound (wt=5.1 g). m.p. 148°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][N:5](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:6]2.C1(O)C=CC=CC=1.Br>O.C(O)(=O)CC>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3c(F)ccc(F)c3C2)cc1
Agent: Br
Solvent: O
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: Fc1ccc(F)c2c1CNC2
Yield: 49.4 %

Procedure:
A mixture of 4,7-difluoro-2-(toluene-4-sulphonyl)isoindoline (2.36 g, 7.64 mmol), phenol (2.36 g, 25.11 mmol), 48% hydrogen bromide in water (20 ml) and propionic acid (4 ml) was stirred and held at reflux for 6 hours. Upon cooling to room temperature water (50 ml) was added and the mixture extracted with diethyl ether (2×100 ml). The aqueous layer was basified by the addition of 2M sodium hydroxide and was extracted with diethyl ether (3×100 ml). The combined extracts were evaporated to dryness in vacuo to afford 4,7-difluoroisoindoline (586 mg, 50%) as a brown oil that solidified upon standing. 1H NMR (DMSO-d6) 7.06 (2H, dd), 4.12 (4H, s). MS: [M+H]+ 156.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>ClCCl.CN(C1C=CN=CC=1)C>[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1)=[O:38])([O-:33])=[O:32]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3cccc([N+](=O)[O-])c3)cc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647 μmol) in dichloromethane (15 mL) was added triethylamine (190 μL, 1.43 mmol) and 3-nitrobenzoyl chloride (264 mg, 1.43 mmol). The solution was stirred at room temperature for 96 hours, and DMAP (7.0 mg, 57 μmol) and 3-nitrobenzoyl chloride (120 mg, 647 μmol) was added, and the stirring continued at room temperature for 72 hours. Triethylamine (90 μL, 639 μmol), 3-nitrobenzoyl chloride (120 mg, 647 μmol) and DMAP (7.0 mg, 57 μmol) were then added. The solution was stirred at room temperature for 72 hours, evaporated in vacuo, and the residue purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3), to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=5.52 min, MH+ 459].
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:24][O:25][CH2:26]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.Cl>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:24][O:25][CH3:26])[CH:5]=1)[CH3:14]
Reactant: COCCl
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(C=O)c(OCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
4-Diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol) was placed in a 20 mL reaction vessel, and dissolved in 4.7 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol), 4-dimethylaminopyridine (13 mg, 0.11 mmol), and chloromethyl methyl ether (147 μL, 1.94 mmol). After the reaction mixture was stirred at room temperature overnight, N,N-diisopropylethylamine (0.40 mL, 2.3 mmol), 4-dimethylaminopyridine (13 mg, 0.11 mmol), and chloromethyl methyl ether (147 μL, 1.94 mmol) were added again with additional stirring for 3 h. The resulting mixture was diluted with 100 mL of ethyl acetate and 20 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a pale yellow oil (324.7 mg, 88%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OC1C=C(C=CC=1)C(=O)C=CC1C=CC2OCOC=2C=1>>[OH:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][O:2][C:3]=3[CH:4]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Agent: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1
Product: O=C(CCc1ccc2c(c1)OCO2)c1cccc(O)c1
Yield: 41 %

Procedure:
Prepared in a similar manner as (7) from 3′-Hydroxy-3,4-methylenedioxy chalcone (6). Crystallization of crude material from EtOAc/hexanes afforded 4.10 g (41%) of white solids: 1H NMR (CDCl3, 300 MHz) 9.73 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.347.29 (m, 2H), 7.02 (dd, J=8.0 Hz, 1H), 6.88 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.71 (d, J=7.9 Hz, 1H), 5.96 (s, 2H), 3.26 (t, J=7.6 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H); 13C NMR (CDCl3, 75 MHz) 199.4 158.0, 147.5, 145.7, 138.4, 135.4, 130.1, 121.5, 120.5, 119.3, 114.4, 109.2, 108.4, 101.0, 40.2, 29.7.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:12][N:13]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (150 mg) and ethyl 4-bromobutyrate (44 μl) are dissolved in N,N-dimethylformamide (3 ml) and thereto is added potassium carbonate (42 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (117 mg). MS (m/z): 709 [M+H]+