Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:28])[C:7]([C:10](=[O:27])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19]CC2C=CC=CC=2)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>CCOC(C)=O.[Pd]>[CH2:1]([C:5]1[N:6]([CH3:28])[C:7]([C:10](=[O:27])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[OH:19])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCc2ccccc2)n1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1ncc(C(=O)c2ccc(OC)cc2O)n1C

Procedure:
2-n-Butyl-1-methyl-5-(2-benzyloxy-4-methoxybenzoyl)-1H-imidazole (1.29 g, 3.41 mmol) dissolved in EtOAc was treated with 10% Pd/C under H2 (1 atm) for 10 h at ambient temperature. The catalyst was removed by filtration and the solvent removed under reduced pressure to afford the title compound as a bright yellow oil which solidified on standing (888 mg, 91%)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].Cl.Cl[CH2:16][C@@H:17]([N:19]([CH3:21])[CH3:20])[CH3:18].[Cl-].[NH4+]>CCOCC>[CH3:16][C@H:17]([N:19]([CH3:21])[CH3:20])[CH2:18][C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1
Reactant: C[C@@H](CCl)N(C)C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: C[C@@H](CC1(c2ccccc2)C=CCC=C1)N(C)C
Temperature: -50 °C

Procedure:
28 g. of biphenyl in 300 ml. of absolute ether are added dropwise at about -33° C. while stirring to 360 ml. of dry, condensed ammonia. The mixture is cooled to about -50° C. and 2.5 g. of lithium wire (about 2 cm long pieces, de-greased with cyclohexane) are added over a period of 10 minutes. Then, the mixture is stirred at boiling temperature (about -33° C.) for 2 hours. 9.4 g. of (S)-2-chloro-N,N,1-trimethylethylamine hydrochloride are added portionwise at about -50° C. within about 3 minutes. The mixture is stirred at about -33° C. for 2 hours and subsequently worked-up. After adding ammonium chloride, distilling off of the ammonia, and aqueous working-up and chromatography in analogy to Example 3, there is obtained (S)-α,N,N-trimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine which is converted in the usual manner into the maleate. After crystallization from ether, the product has a melting point of 87° -90° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[C:32]3[C:27](=[N:28][C:29]([NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:30][CH:31]=3)[N:26](COCC[Si](C)(C)C)[N:25]=2)[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[N:36]1([CH2:35][CH2:34][NH:33][C:29]2[N:28]=[C:27]3[NH:26][N:25]=[C:24]([C:20]4[N:19]=[C:18]([NH:17][CH:10]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:9][CH2:8][NH2:7])[CH:23]=[CH:22][CH:21]=4)[C:32]3=[CH:31][N:30]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCCC(Nc1cccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1

Procedure:
(3-{6-[6-(2-Morpholin-4-yl-ethylamino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester (147 mg, 0.209 mmol) was dissolved in CF3COOH (4 mL). The mixture was heated at reflux for 15 hours. The solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added to the residue, and then extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC, concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give N1-{6-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine; hydrochloride as a yellow solid. (Yield 16 mg, 16.2%).
Reaction SMILES: [F:1][C:2]([F:21])([CH2:18][CH2:19][CH3:20])[CH2:3][CH:4]([NH:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:23][C@@H:24]([CH2:27][CH3:28])[C:25]#[N:26]>>[C:25]([C@@H:24]([NH:23][C:5]([C@@H:4]([NH:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[CH2:3][C:2]([F:1])([F:21])[CH2:18][CH2:19][CH3:20])=[O:7])[CH2:27][CH3:28])#[N:26]
Reactant: CC[C@H](N)C#N
Reactant: CCCC(F)(F)CC(NC(=O)N1CCCOCC1)C(=O)O
Agent: Cl
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCCOCC1)C(=O)N[C@H](C#N)CC

Procedure:
By proceeding in a similar manner to Example 28 above but using 4,4-Difluoro-2-[([1,4]oxazepane-4-carbonyl)-amino]-heptanoic acid and (S)-2-Amino-butyronitrile hydrochloride there is prepared Perhydro-1,4-oxazepine4-carboxylic acid [(S)-1-((S)-1-cyano-propylcarbamoyl)-3,3-fluoro-hexyl]-amide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=1.[Li]CCCC.CON(C)[C:27](=[O:29])[CH3:28]>C(OC)(C)(C)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][CH2:8][C:6]2[CH:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[N:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(COCc2cncc(Br)c2)cc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc(COCc2cncc(C(C)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To a solution of 3-bromo-5-{[(4-methoxybenzyl)oxy]methyl}pyridine (4.4 mmol) in methyl t-butyl ether (20 mL) was added n-BuLi (2.5M in hexane, 1.96 mL) dropwise at −78° C. The reaction mixture was allowed to stir for 15 min and then N-methoxy-N-methylacetamide (6.7 mmol) in methyl t-butyl ether (3 mL) was added dropwise. The reaction mixture was allowed to stir for 30 min at −78° C. and then diluted with water and allowed to warm to rt. After stirring for 30 min, the phases were separated and the aqueous solution was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 1-(5-{[(4-methoxybenzyl)oxy]methyl}pyridin-3-yl)ethanone (3.1 mmol, 70%) as a white solid. LCMS: (FA) ES+ 272.1.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.CO.[C:17](OC(=O)C)(=[O:19])[CH3:18].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:17](=[O:19])[CH3:18])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzonitrile (25.7 g) in tetrahydrofuran (250 ml) was added a 2.0 M tetrahydrofuran solution (59 ml) of a borane-methylsulfide complex and the mixture was refluxed under heating for 4.5 hr. To the reaction mixture was added hydrochloric acid-methanol and the mixture was refluxed under heating for 1.5 hr. The solvent was evaporated under reduced pressure to give a brown oil. The obtained brown oil was crystallized from ethyl acetate to give yellow white crystals. To a mixed solution of the obtained yellow white crystals, acetic anhydride (12.1 ml), water (50 ml) and ethyl acetate (100 ml) was added an aqueous solution (50 ml) of sodium hydroxide (12.8 g) under ice-cooling. This reaction mixture was stirred at room temperature for 2.5 hr and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (21.4 g) as a brown oil.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][C:8]2[CH:9]=[C:10]([F:28])[C:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([CH3:27])[CH2:15]3)=[N:12][CH:13]=2)[CH2:4][O:3]1.Cl.O1CCOCC1.CO>ClCCl.CCOCC>[F:28][C:10]1[CH:9]=[C:8]([CH2:7][C@@H:5]([OH:6])[CH2:4][OH:3])[CH:13]=[N:12][C:11]=1[N:14]1[CH2:19][CH2:18][NH:17][C@H:16]([CH3:27])[CH2:15]1
Reactant: C[C@@H]1CN(c2ncc(C[C@@H]3COC(C)(C)O3)cc2F)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ncc(C[C@@H](O)CO)cc2F)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.6 %

Procedure:
A solution of 48 (2.50 g, 6.10 mmol) in dichloromethane (13.6 mL) was treated at 0° C. with 4 mol/L HCl in 1,4-dioxane (9.2 mL, 36.6 mmol) followed by methanol (2.0 mL). The flask was sealed with a rubber septa and the mixture was then stirred at room temperature for 4 hrs. The reaction mixture was diluted with ether and the precipitate was washed several times with ether and dried under reduced pressure to afford 1.8 g (86%) of 49 which was confirmed by LC/MS and was used directly for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38]>>[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-2-methylbenzene following the procedure of Example 478: MS (ESI) m/z 498.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[Br:20]N1C(=O)CCC1=O.O>O1CCCC1>[Br:20][C:10]1[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[CH:12][CH:11]=1
Reactant: Cc1cnc(-c2cccn2C(=O)OC(C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(Br)n2C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 14 h
Yield: 87.3 %

Procedure:
t-Butyl 2-(5-methylpyrazin-2-yl)-1H-pyrrole-1-carboxylate (373 mg, 1.44 mmol) synthesized in Example (10a) was dissolved in tetrahydrofuran (20 mL), and cooled to 0° C. N-Bromosuccinimide (256 mg, 1.44 mmol) was added, and stirring was carried out at room temperature for 14 hours under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (425 mg, yield 87%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([CH2:24][CH:25]=O)[N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][CH:21]=[C:22]([CH2:24][CH2:25][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CC=O)cs2)c(C(=O)C2CCCC2)c1
Reactant: C1COCCN1
Product: Cc1ccc(NC(=O)Nc2nc(CCN3CCOCC3)cs2)c(C(=O)C2CCCC2)c1
Yield: 30.8 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2-morpholin-4-yl-ethyl)-thiazol-2-yl]-urea (15 mg, 31%) was prepared from 1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[4-(2-oxo-ethyl)-thiazol-2-yl]-urea (0.04 g, 0.11 mmol) and morpholine (0.009 g, 0.11 mmol) following the general procedure O.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24](=[O:26])N)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[C:1]([N:9]1[CH2:10][CH2:11][CH:12]([N:15]2[C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:22][CH2:23][C:24]2=[O:26])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CCc1ccccc1NC1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Product: O=C(c1ccccc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Yield: 43.3 %

Procedure:
To N-(1-benzoyl-4-piperidinyl)-2-(2-carbamoylethyl)aniline (85 g) prepared in Reference Example 4 is added 5% hydrochloric acid (500 ml) and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is extracted with diethyl ether and the aqueous layer is made alkaline with a 50% aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract is dried over sodium carbonate and concentrated. The concentrate is purified by silica gel column chromatography (eluent; n-hexane/ethyl acetate=1/0-10/1) and recrystallized from ethanol/n-hexane to give 1-(1-benzoyl-4-piperidinyl)-3,4-dihydrocarbostyril (35 g) as white powders, m.p. 108°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.100 g, 0.33 mmol), 6-chloropurine (0.051 g, 0.33 mmol, 1 eq) and DIEA (0.07 mL, 0.4 mmol, 1.2 eq) in ethanol (3 mL). N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=68 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (1H, s), 8.11 (1H, s), 8.08 (1H, s), 8.00 (1H, dd, J=8.2, 1.2 Hz), 7.93 (1H, dd, J=7.4, 1.2 Hz), 7.42-7.67 (5H, m) Mass Spectrum (ESI) m/e=421.0 and 423.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][SH:5].Cl[C:11]1[C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=[CH:13][N:12]=1>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][S:5][C:11]1[C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=[CH:13][N:12]=1
Reactant: Cn1cnc2c(Cl)nccc21
Reactant: SCc1ccccc1Cl
Solvent: CCO
Product: Cn1cnc2c(SCc3ccccc3Cl)nccc21
Reaction time: 16 h

Procedure:
2.76 g of Na is dissolved in 180 ml of ethanol; 19.1 g of o-chlorobenzylmercaptan and 16.76 g of 4-chloro-1-methyl-1H-imidazo(4,5-c)pyridine are added; the mixture is boiled for 16 hours and evaporated; and the residue is worked up in the customary manner to give 4-o-chloro-benzylthio-1-methyl-1H-imidazo(4,5-c)pyridine of m.p. 152°-155° (from ethanol).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[Sn:16](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.[NH4+].[Cl-]>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[Sn:16]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of LDA (1.2 eq.) in THF (0.2M) at −78° C. was added 4-chloro-pyridine (1.0 eq.). The mixture was stirred for 1.5 h at −78° C. then Bu3SnCl (1.5 eq.) was added. The final mixture was slowly warmed to rt, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 95:5) afforded the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=3)[C:9]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36]>C(Cl)Cl>[CH2:26]([O:25][C:17]1[CH:16]=[C:15]([CH:10]2[NH:11][C:12](=[O:14])[NH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[CH3:34])=[CH:3][CH:4]=3)=[C:9]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]=1[OH:24])[CH3:27]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(N)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOc1cc(C2NC(=O)NC(c3ccc(NC(C)=O)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.8 %

Procedure:
To a solution of compound 6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one (Compound 84) (100 mg, 0.22 mmol) in DCM (2 mL) was added Ac2O (27 mg, 0.27 mmol) at room temperature, and the mixture was stirred at room temperature for 4 hours. The mixture was evaporated in vacuo and purified by column to give the Compound 73 (32.07 mg, yield 34%). 1H NMR (DMSO-d6 300 MHz): δ 10.28 (brs, 1H), 9.95 (s, 1H), 8.66 (s, 1H), 7.52 (s, 1H), 7.45-7.42 (m, 3H), 7.19 (d, J=1.8 Hz, 1H), 7.13-6.97 (m, 5H), 6.83 (d, J=6.6 Hz, 2H), 5.17 (d, J=2.7 Hz, 1H), 4.10-4.01 (m, 2H), 2.02 (s, 3H), 1.33 (t, J=6.9 Hz, 3H); MS (ESI): m/z 489.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (245 mg, 1.28 mmol) was coupled to aniline (64) (250 mg, 1.28 mmol) using Method C. The residue was purified by column chromatography eluting with 15% EtOAc in heptane to give the title compound.
Reaction SMILES: CCCCCCCC.[F:9][C:10]([F:24])([F:23])[C:11]([F:22])(Br)[C:12](=[O:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].[F:25]C(F)(F)C(=O)C(F)(Br)C(F)(F)C(F)(F)F>>[F:9][C:10]([F:24])([F:23])[C:11]1([F:22])[O:20][C:12]1([F:25])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: O=C(C(F)(F)F)C(F)(Br)C(F)(F)C(F)(F)F
Reactant: O=C(C(F)(F)C(F)(F)F)C(F)(Br)C(F)(F)F
Solvent: CCCCCCCC
Product: FC(F)(F)C(F)(F)C1(F)OC1(F)C(F)(F)F

Procedure:
The distillate was subjected to flash chromatography on silica gel using octane as an eluant. The column effluent containing primarily octane and the mixture of perfluoro-2-bromo-3-pentanone and perfluoro-3-bromo-2-pentanone was then subjected to two vacuum distillations at a pressure of 56 and 100 torr, respectively, to separate the bromoperfluoroketones from the bulk of the octane. The low-boiling fractions from the vacuum distillations were then re-distilled at atmospheric pressure. The fractions collected at a head temperature of 71.2–72.8° C. were combined. The product was a mixture of perfluoro-2-bromo-3-pentanone and perfluoro-3-bromo-2-pentanone in molar ratio of 1.0 to 1.12 with overall purity of >98 GC area %.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:20]([O:24][C:25]([N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:32][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: C1=Cc2ccccc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a solution of indene (5.1 ml, 0.04 mol) in dry tetrahydrofuran (15 ml), cooled in an ice bath and maintained under an atmosphere of nitrogen, was added lithium bis (trimethylsilyl) amide (82 ml of a 1.0M solution in tetrahydrofuran, 0.08 mol), over 15 minutes. The mixture was stirred in the cold for 30 minutes, then added dropwise to a solution of N-tert-butyloxycarbonylbis (2-chloroethyl)amine (9.9 g, 0.04 mol) in tetrahydrofuran (200 ml), at 0° C. The mixture was stirred for 2 hours at this temperature, then allowed to warm to ambient temperature and stirred for a further 30 minutes. The solvent was removed in vacuo to leave a dark oil, which was chromatographed using 5:1 petrol:ether as the eluant, to give 1'-(tert-butyloxycarbonyl)spiro [indene-1,4'-piperidine] (7.1 g, 58%) as a pale yellow solid. N.M.R. (CDCl3) δ 1.28 (2H, d, J=12 Hz), 1.50 (9H, s), 2.00 (2H, t of d, J=12 and 4 Hz), 3.13 (2H, t of d, J=12 and 2 Hz), 4.20 (2H, m), 6.79 (1H, d, J=6 Hz), 6.84 (1H, d, J=6 Hz), 7.30 (4H, m).
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH:4]=[CH2:5].[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[OH:21])([CH3:10])([CH3:9])[CH3:8]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[O:21][CH2:5][CH:4]=[CH2:3])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide pellets (20 g, 0.5 moles), water (25 g), toluene (50 ml) and tetrabutylammonium hydrogen sulphate (1 g) are added in succession into a reactor. They are heated to 50° C. with stirring and under nitrogen and a toluene solution (50 ml) of allyl bromide (16.5 g, 0.134 moles) and of 2,4-di-tert-butylphenol (25 g, 0.12 moles) is added over 45 minutes. The temperature rises progressively to 68° C. The materials are left at this temperature for 3 hours. Cooling is applied, 50 ml of water and 50 ml of toluene are added and the phases are separated. The toluene phase is washed with water and dried over sodium sulphate and the solvent is evaporated off to give an orange-coloured oil which is purified on a bed of silica gel 60 (eluent: heptane). 2,4-Di-tert-butylallyloxybenzene is obtained as a colourless liquid (23 g, yield =78 %).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:14])=[O:12])[C:4]([CH:15]=O)=[CH:3]1.C[C:18]1[NH:19]C2C(C=1C=O)=CC=CC=2>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:14])=[O:12])[C:4]([CH2:15][NH:19][CH3:18])=[CH:3]1
Reactant: COC(=O)c1cccc2c(C=O)cn(C)c12
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: CNCc1cn(C)c2c(C(=O)OC)cccc12
Yield: 92 %

Procedure:
According to the procedure of Preparation 12, except substituting 1-methyl-7-methoxycarbonyl-1H-indole 3-carboxaldehyde for the 2-methylindole-3-carboxaldehyde, the title compound (1.7 g, 92%) was obtained as an oil: MS (ES) m/e 233.2 (M+H)+.