Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.C([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:25]=[N:24][N:23]=2)[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:25]=[N:24][N:23]=2)[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnnn2COCC[Si](C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(O)cc(-c2nnnn2COCC[Si](C)(C)C)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (2.4 g) was added to an EtOH (35 mL)-THF (35 mL) mixed solution of methyl 3-benzyloxy-5-[({[2-(trimethylsilyl)ethyl]oxy}methyl)-tetrazol-5-yl]benzoate (4.02 g), and in a hydrogen atmosphere this was stirred at room temperature for 2 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and dried to obtain the title compound as a white powder. Not purified, this was used in the next step.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](#[N:17])/[CH:14]=[CH:15]/[CH3:16].[H-].[Na+].C(O)(=O)C>C(O)C>[C:13]([CH2:14][CH:15]([P:8]([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:12])[O:9][CH2:10][CH3:11])[CH3:16])#[N:17]
Reactant: CCOC(OCC)P([O-])OCC
Reactant: C/C=C/C#N
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(OCC)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material may be prepared as follows: A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of crotononitrile in 30 ml of dry ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyano-1-methylethyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+42.2 and +42.0 ppm (CDCl3).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][CH:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[OH:1][C@@H:3]1[C@@H:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][C@@:18]2([CH3:20])[CH:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])[CH2:4]1
Reactant: C1CNCCN1
Reactant: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O
Solvent: ClCCl
Product: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 150 °C
Yield: 64.5 %

Procedure:
To compound 22 (202 mg, 0.70 mmol) was added water (1 mL) and piperazine (3.5 g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 0.5% of TEA) to yield compound 23 (169 mg, 65%). 1H NMR (CDCl3) δ: 0.87 (s, 18-CH3 and 19-CH3), 0.73-2.17 (residual CH and CH2), 2.45, 2.64 and 2.91 (3m, 4×CH2N and 2α-CH), 3.85 (m, 3β-CH).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O)([O-:16])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: OCCCNc1nc(Cl)ncc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1OCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1.06 g (4.0 mmol) of 3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propan-1-ol, 0.65 g (4.8 mmol) of 2-nitro-phenol and 1.25 g (4.8 mmol) of triphenylphosphine in 30 ml of THF is mixed under argon at 0° C. with 0.8 ml of DEAD. The reaction mixture is heated to room temperature while being stirred. After 20 hours, the batch is spun in, and the residue is purified by chromatography (hexane/ethyl acetate 3:1, Flashmaster II). 1.15 g (3.0 mmol, corresponding to 74% of theory) of the product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.O[CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH:28]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)C(O)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3cc(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (0.620 g, 1.80 mmol), ethyl 2-hydroxy-3-phenylpropanoate (0.528 g, 2.72 mmol), triphenylphosphine (0.710 g, 2.71 mmol) in benzene (30 mL) was added, dropwise, diisopropyl azodicarboxylate (0.53 mL, 2.7 mmol) in benzene (5 mL). The mixture was stirred at room temperature for 45 minutes, poured into excess water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 100% hexane and 2-3.5% ethyl acetate in hexane as eluants. The title compound was obtained as a thick yellow oil (0.670 g). Mass spectrum (+ESI, [M+H]+) m/z 521.5; 1HNMR (500 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0 (t, 2H, J=7.8 Hz), 7.95 (d, 1H, J=8.6 Hz), 7.8 (dd, 1H, J=8.6 Hz and 1.7 Hz), 7.7 (d, 1H, J=8.1 Hz), 7.25-7.45 (m, 9H), 5.35 (t, 2H, J=6.5 Hz), 4.05-4.15 (m, 3H), 2.7 (t, 2H, J=7.3 Hz), 1.5-1.55 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[Mg].II.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH:27]=[O:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH:27]([C:2]2[C:6]3[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[OH:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)CCC1(C=O)CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc2scc(Br)c2c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)CCC1(C(O)c2csc3ccc(F)cc23)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 21.6 %

Procedure:
A mixture of 3-bromo-5-fluoro-benzothiophene (0.4 g, 1.73 mmoles), magnesium (0.051 g, 2.1 mmoles) and a few particles of iodine in anhydrous tetrahydrofuran (10 nil) was refluxed for 7 hours, and then cooled in an ice bath. To the reaction mixture was slowly added a solution of 3-(3,3-dimethyl-butyl)-3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.39 g, 1.38 mmoles) in anhydrous tetrahydrofuran (9 ml). The reaction mixture was stirred at ice bath temperature for one hour and quenched with saturated aqueous ammonium chloride solution. The aqueous solution was extracted into ethylacetate which was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate in hexane) to yield 3-(3,3-dimethyl-butyl)-3-[(5-fluoro-benzo[b]thiophen-3-yl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert butyl ester as yellow foam (0.13 g, 21%), MS=436 [M+H]+,
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CS(C)=O>[N:10]1([C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)c1ncc(Br)s1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Product: CC(=O)c1ncc(N2CCCCC2)s1
Temperature: 50 °C
Yield: 68 %

Procedure:
To a solution of 1-(5-Bromo-thiazol-2-yl)-ethanone (prepared as described above) (250 mg) in dimethylsulfoxide (3 ml) was added piperidine (0.3 ml). The mixture was heated to 50° C. overnight, concentrated to an oil and the residue was purified by flash chromatography (30% ethylacetate/petroleum ether) to afford the sub-titled compound as an yellow solid (170 mg, 68%); 1H NMR (400 Mhz, CDCl3) δ 1.6-1.8 (6H, m), 2.6 (3H, s), 3.25-3.35 (4H, m), 7.05 (1H, s); MS (ES+) 211.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][C:7]([NH:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:14])[CH2:6]2)[CH3:2].C(NC1CC2C(=CC(CC)=C(CC)C=2)C1)C1C=CC=CC=1>>[CH2:16]([NH:15][C:7]1([CH3:14])[CH2:8][C:9]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[C:11]([CH2:12][CH3:13])[CH:10]=2)[CH2:6]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1cc2c(cc1CC)CC(C)(NC(=O)c1ccccc1)C2
Agent: CCc1cc2c(cc1CC)CC(NCc1ccccc1)C2
Product: CCc1cc2c(cc1CC)CC(C)(NCc1ccccc1)C2

Procedure:
Benzyl-(5,6-diethyl-2-methyl-indan-2-yl)-amine is prepared from N-(5,6-diethyl-2-methyl-indan-2-yl)-benzamide by an analogous procedure to that used to prepare benzyl-(5,6-diethyl-indan-2-yl)-amine in Intermediate 18. ES+ MS m/e 294 (MH+)
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[NH2:29][C@H:30]([C:36]([OH:38])=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].[CH3:39][P:40]([NH2:43])(=[O:42])[O-:41].C([N:47]([CH:50](C)C)CC)(C)C>CN(C=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[NH2:29][C@H:30]([C:36]([OH:38])=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:50]([NH2:47])=[NH:43].[CH3:39][P:40]([NH2:43])(=[O:41])[O-:42]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCC[C@H](N)C(=O)O
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CP(N)(=O)[O-]
Solvent: CN(C)C=O
Product: N=C(N)NCCCC[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of (15) (0.131 g, 0.216 mmol) stirring at room temperature under argon in anhydrous DMF (2.0 ml), 1-H-pyrazole-1-carboxamidine. HCl (32 mg, 0.216 mmol) was added followed by diisopropylethylamine (28 ml, 0.216 mmol). The reaction mixture was stripped slightly on a rotovap then rotated overnight without vacuum at room temperature. After removing DMF in vacuo the reaction residue was dissolved in dichloromethane and applied to a flash silica gel column. An isocratic system of 20% MeOH/dichloromethane, 2% NH4OH followed by treatment with Dowex OH− (300 mg) in MeOH gave 80 mg of desired product (yield, 57%). P NMR (s, 31.99 ppm), mass spec. calcd=648.91, found=649.48.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[S:55]([NH:58][CH2:59][C:60]([NH2:62])=[O:61])(=[O:57])=[O:56])([O-:48])=[O:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:58]([S:55]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[N+:46]([O-:48])=[O:47])(=[O:57])=[O:56])[CH2:59][C:60](=[O:61])[NH2:62])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(CC(N)=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (98 mg) in tetrahydrofuran (2 mL) were added 2-(2-nitrobenzenesulfonylamino)acetoamide (40 mg), triphenylphosphine (45 mg) and diethyl azodicarboxylate (40% toluene solution, 0.1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-[(4-(3-[N-(2-nitrobenzenesulfonyl)-N-(carbamoylmethyl)amino]propoxy)-2-methylphenyl)methyl]-1H-pyrazole (92 mg). This material was dissolved in acetonitrile (1 mL). To the solution were added cesium carbonate (0.14 g) and thiophenol (0.012 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (57 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1F
Reaction time: 0.05 h
Yield: 115.4 %

Procedure:
40% Methanolic Triton B (0.14 mL, 0.31 mM) was added to a solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 5 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (110.5 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 72.8 mg (71%) of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.65 (d, 1H, J=8 Hz), 7.5 (s, 1H), 7.4-7.2 (m, 5H), 7.15 (s, 1H), 7.1 (d, 1H, J=8 Hz), 7.05 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.85 (s, 2H), and 3.7 (s, 3H). IR (CHCl3, cm−1) 3436, 1763, 1675, 1457, 1327, 1208, 1198, 1150, 1102, 772, 756, and 719. MS (FD) m/e 407.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26]CC)=O)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([NH:30][NH2:31])=[O:26])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Solvent: CO
Solvent: O
Product: NNC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of 4-benzyl-1-(2-(3-(ethoxycarbonylmethyl)phenoxy)ethyl)piperidine (0.382 g, 1.00 mmol) in 5 mL of MeOH was added 5 mL of hydrazine hydrate. The resulting solution was allowed to stir at rt for 12 hr. The MeOH was evaporated in vacuo and water (10 mL) was added. A colorless solid precipitated. The solid was collected by filtration and dried in vacuo giving the title product (240 mg, 65%): mp 89-91° C.; 1H NMR (CDCl3) 1.31 (m, 2 H), 1.60 (m, 1 H), 1.62 (m, 2 H), 2.04 (t, J=11.7 Hz, 2 H), 2.52 (d, J=6.9 Hz, 2 H), 2.76 (t, J=6.0 Hz, 2 H), 2.95 (d, J=11.4 Hz, 2 H), 3.53 (s, 2 H), 3.83 (bs, 2 H), 4.08 (t, J=6.3 Hz, 2 H), 6.66 (s, 1 H), 6.79 (m, 3 H), 7.12-7.27 (m, 6 H).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][CH3:27])=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:21][CH:22]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(C1CCOCC1)C2=O
Reactant: COc1ccccc1B(O)O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(C1CCOCC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(tetrahydro-pyran-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate G) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR=7.34 min (HPLC 2); ESI-MS: tR=1.21 min, [M+H]+ 465/467 (LC-MS 1); TLC: Rf=0.40 (EtOAc).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O>>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][N:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:16][CH:15]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Product: O=C1Nc2ccc(F)cc2C1=CN(c1ccccc1)c1ccc(OCCCN2CCCCC2)cc1
Yield: 66.1 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-piperidin-1-yl-propoxy)-phenylamine (0.57 g, 1.3 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.363 g, 2 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (379 mg, 47%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[N:10]1([C:16]2[C:17]3[C:24]([C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=4)[C:28]#[N:29])=[CH:23][N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[OH:3][N:2]=[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:24]2[C:17]3[C:16]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[N:21][CH:20]=[N:19][C:18]=3[N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=2)[CH:26]=1)[NH2:29]
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C(N)=NO)c2)c2c(N3CCOCC3)ncnc21

Procedure:
Hydroxylamine hydrochloride (278 mg, 4.00 mmol) and sodium carbonate (318 mg, 3.00 mmol) were added to a stirred solution of 3-[4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C34) (436 mg, 1.00 mmol) in ethanol (10 mL) and water (5 mL). The reaction mixture was heated at reflux for 2 hours, then concentrated in vacuo, poured into water (25 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated, affording the product as a white solid. Yield: 280 mg, 0.60 mmol, 60%. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.43 (s, 1H), 7.89 (br s, 1H), 7.72 (s, 1H), 7.64 (br d, J=7.8 Hz, 1H), 7.53 (br d, J=7.8 Hz, 1H), 7.46 (dd, J=7.6, 7.6 Hz, 1H), 5.89 (br s, ˜1.6H), 5.61 (s, 2H), 3.53-3.61 (m, 2H), 3.39-3.47 (m, 4H), 3.13-3.21 (m, 4H), 0.81-0.88 (m, 2H), −0.09 (s, 9H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.[I-].C[S+](C)C>CS(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]2([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)[CH2:1][O:13]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Potassium tert-butoxide (18.48 g, 165.0 mmol) was added to a rapidly stirred suspension of 4-chloro-4′-iodobenzophenone (51.38 g, 150.0 mmol) and trimethylsulphonium iodide (33.66 g, 165.0 mmol) in dimethylsulphoxide (200 ml) and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate (500 ml), washed with water (3×500 ml) and then with brine (500 ml). The organic layer was separated and the solvent removed in vacuo to afford (RS)-2-(4-chlorophenyl)-2-(4-iodophenyl)oxirane (53.48 g, 100%) as a pale yellow oil that solidified upon standing to afford an off-white solid. 1H NMR (DMSO-d6) 7.76 (2H, d), 7.45 (2H, d), 7.34 (2H, d), 7.12 (2H, d), 3.32 (2H, m). MS: [M−H]− 355.