Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+:17].P([O-])([O-])(O)=O.[NH4+].[NH4+].O>S1(CCCC1)(=O)=O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:17])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: O=P([O-])([O-])O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
Ammonium picrate (0.18 g, 0.75 mmol) and diammonium hydrogen phosphate (0.99 g, 7.5 mmol) are suspended in dry sulfolane (3 ml) and stirred in a Teflon® capped glass pressure tube (8 ml) for 2 hr with the application of heat, which raises the temperature of the reaction from 25° C. to 177° C. The reaction is continued an additional 5 hr at 177° C. and cooled to ambient temperature. Water (30 ml) is added to the slurry and the product is collected and washed with water. Vacuum drying yields 0.13 g (76%) of picramide (Table 1, entry 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=1[CH2:32][CH3:33])=[O:13])[CH:6]=[CH:5]2.[CH3:34][N:35](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:34]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:31])([C:23]([F:26])([F:25])[F:24])[C:27]([F:30])([F:28])[F:29])=[CH:17][C:16]=1[CH2:32][CH3:33])=[O:13])[CH:6]=[CH:5]2)#[N:35]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2cc(C#N)ccc2c1
Temperature: 80 °C
Yield: 9 %

Procedure:
6-Bromo-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-2-naphthamide (0.49 g) was dissolved in N,N-dimethylformamide (4 ml), and deaeration was carried out three times under argon atmosphere (i.e., the reaction solution was de-pressurized to 20 mmHg and brought back to atmospheric pressure under argon atmosphere). Zinc cyanide (0.07 g) and tetrakis (triphenylphosphine) palladium(0) (0.11 g) were added thereto and stirred with heating at 80° C. for 7 hours under argon atmosphere. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and washed with water and saturated brine. The organic phase was dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by silica gel chromatography to obtain 6-cyano-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-2-naphthamide (0.04 g, yield 9%).
Reaction SMILES: [CH2:1]([O:8][C:9]([P:11](=[O:16])([O:14]C)[O:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+:18]>O1CCCC1>[CH2:1]([O:8][C:9]([P:11](=[O:14])([O-:16])[O:12][CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:18]
Reactant: COP(=O)(OC)C(=O)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COP(=O)([O-])C(=O)OCc1ccccc1

Procedure:
3.66 g of dimethyl benzyloxycarbonylphosphonate and 2.25 g of sodium iodide were stirred in 25 ml of dry tetrahydrofuran for 3 days. The precipitate was filtered, washed with ether and dried in a desiccator. Colourless, hygroscopic crystals of the title compound were obtained (3.15 g, 82%). By t.l.c. (polyethyleneimine, 1M LiCl, molybdate spray) the compound was estimated to contain <0.4% of trisodium oxycarbonylphosphonate.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-].[Na+]>CO>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][O:16][CH2:15][CH2:14][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=[CH:8]1
Reactant: COCCOCOCCn1ccc2c(C(=O)OC)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOCOCCn1ccc2c(C(=O)O)cccc21
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
To a solution of 1-[2-(2-Methoxy-ethoxymethoxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester (69 mg, 0.225 mmol) in MeOH (2 ml) is added 2 M NaOH (1 ml) and the reaction is stirred at room temperature for 19.5 hours, then for 2 hours at 50° C. The reaction is allowed to cool to room temperature and the solvent removed in vacuo. To the residue is added sat. NH4Cl (10 ml), and the product is extracted with EtOAc (5×25 ml), washed with brine (10 ml), dried over Na2SO4, and the solvent is removed in vacuo, to give the title compound 1-[2-(2-Methoxy-ethoxymethoxy)-ethyl]-1H-indole-4-carboxylic acid; [M+H]+ 294
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[O:40][C:39]=2[CH3:47])O1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[K+]>C(#N)C.O.CCOC(C)=O>[CH3:22][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:38]4[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[O:40][C:39]=4[CH3:47])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)([CH3:23])[C:19]([NH2:21])=[O:20]
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Temperature: 140 °C
Yield: 30.7 %

Procedure:
To a degassed suspension of 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (90.0 mg 0.205 mmol), 4,4,5,5-tetramethyl-2-(2-methylbenzofuran-3-yl)-1,3,2-dioxaborolane (120 mg, 0.46 mmol) in acetonitrile (2 mL) was added 2 M aqueous solution of sodium carbonate (0.20 mL) and 1M aqueous solution of potassium acetate (0.2 mL). The mixture was then heated in a microwave at 140° C. for 30 minutes. The reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by RP-HPLC to give 140 (33.6 mg, 30.6%). LCMS: M+H+=535.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.45 (m, 1H), 7.55 (m, 1H), 7.42 (s, 1H), 7.31 (m, 2H), 7.05 (s, 1H), 6.93 (s, 1H), 3.95 (m, 4H), 3.86 (s, 2H), 3.83 (m, 4H), 2.84 (s, 3H), 2.42-2.63 (m, 8H), 1.08 (s, 6H)
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([CH3:18])[C:15]([CH2:19]O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>CN(C)C=O>[Cl:3][CH2:19][C:15]1[C:16]([CH3:18])=[N:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
10.1 g (6.2 ml, 85 mmol) thionyl chloride is added drop by drop within 15 min. at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 9.24 g (42.5 mmol) [6-(4-Fluor-phenyl)-2-methyl-pyridin-3-yl]-methanol, and stirred for 3 h at room temperature (r.t.) The mixture is poured on ice/sodium bicarbonate solution, the organic phase separated, washed with water, dried (sodium sulphate), and evaporated. 9.78 g (97%) of the title compound were obtained.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH3:17])([CH2:14][C:15]#[N:16])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=O)C.C([O-])([O-])=O.[K+].[K+].CCOCC>CO.O>[OH:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH3:17])([CH2:14][C:15]#[N:16])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC#N)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2
Temperature: 25 °C
Reaction time: 64 h
Yield: 96.9 %

Procedure:
A mixture of 581 mg (2.02 mmoles) of rac.-6-acetyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile and 418 mg (3.03 mmoles) of K2CO3 in 17 ml of methanol and 3 ml of water was stirred at room temperature for 64 hr. The resulting mixture was poured into water and worked-up with ether in the usual manner giving 480 mg of a tan solid. This material was triturated with cold ether to give 340 mg (69%) of a tan solid. A sample of this material was recrystallized from toluene yielding pure rac. 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile as a tan solid mp 162-163°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][C:7](/[CH:8]=[C:9]2/[C:10](=[O:23])[N:11]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].NCCN1C(=O)C(CC2C=CC(OCC)=CC=2)SC1=O>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][C:7](/[CH:8]=[C:9]2/[C:10](=[O:23])[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CC(=O)OC(C)(C)C)C2=O)cc1
Agent: CCOc1ccc(CC2SC(=O)N(CCN)C2=O)cc1
Product: CCOc1ccc(/C=C2\SC(=O)N(CC(=O)O)C2=O)cc1
Yield: 93.3 %

Procedure:
The title compound 28h was prepared by deprotection of tert-butyl group of compound 28g (300 mg, 0.82 mmol). Deprotection following the procedure of compound 6 gave the title compound 28h as a yellow solid (93.4%, 235 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]([Cl:18])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([O:19][CH3:20])[C:5]=2[Cl:18])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCc1ccc(C(=O)c2cc(Br)cc(OC)c2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.1 %

Procedure:
To a solution of compound 61 (4.45 g, 12.6 mmol) in CH2Cl2 (80 mL) was added dropwise triethylsilane (6.00 mL, 37.8 mmol) and boron trifluoride diethyl etherate (4.67 mL, 37.8 mmol) at 0° C. under an atmosphere of nitrogen. After being stirred for 5 hours at room temperature, the mixture was quenched with aq. saturated K2CO3 solution (30 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 62 (2.40 g, 56%) as colorless oil.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@@H:10]1[CH2:15][C@@H:14]([N:16]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=2)C(=O)C(F)(F)F)[CH2:13][CH2:12][N:11]1[C:34]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(C)=O>CO>[CH2:3]([C@@H:10]1[CH2:15][C@@H:14]([NH:16][CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=2)[CH2:13][CH2:12][N:11]1[C:34]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1ccc2ccccc2c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(c1ccc2ccccc2c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1
Reaction time: 3 h

Procedure:
28 mg (0.73 mmol) of sodium borohydride are added in three portions over the course of 20 minutes to a solution of 106 mg (0.182 mmol) of (2R*,4S*)-2-benzyl-1-(2-naphthoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 1.5 ml of methanol at 0°, and the mixture is subsequently stirred at 0° for 3 hours. 0.06 ml (0.81 mmol) of acetone is then added to the reaction mixture, and the stirring is completed for 10 minutes. The methanol is removed in a rotary evaporator, and the solid white residue is partitioned between ethyl acetate and water. The organic phases are washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting white foam is chromatographed with methylene chloride/methanol/conc. ammonia (1500:50:1) on silica gel. The title compound of the formula ##STR28## as white foam is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.34, FD-MS: M+ =485.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([C:15]4[S:14][CH:18]=[CH:17][CH:16]=4)[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cccc(-c2cccs2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(-c4cccs4)c3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-thiophen-2-yl-benzylamine (121 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-thiophen-2-yl-benzylamino)-2H-phthalazin-1-one: 69 mg (32.3%): m/z (M+H)=368. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.93 (d, 1H), 7.70 (m, 2H), 7.54 (m, 2H), 7.48 (dd, 1H), 7.39 (m, 1H), 7.32 (m, 1H), 7.18 (dd, 1H), 7.13 (m, 1H), 6.86 (s, 1H), 4.47 (d, 2H).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[S:42][CH:43]=[CH:44][CH:45]=3)[CH:36]=2)=[N:32][C:31]=1[CH2:46][CH2:47][O:48]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:8]=[CH:9][C:10]([O:48][CH2:47][CH2:46][C:31]4[N:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]6[S:42][CH:43]=[CH:44][CH:45]=6)[CH:36]=5)[O:34][C:30]=4[CH3:29])=[CH:11][CH:12]=3)[C:4]([OH:28])=[O:3])=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3cccs3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C3CCCCC3)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-cyclohexylphenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030 mmol) (see Ex. 5, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(4-cyclohexyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.88 (d, 1H, J=7.82 Hz), 7.64 (d, 1H, J=7.82 Hz), 7.43 (d, 1H, J=7.82 Hz), 7.41 (dd, 1H, J=3.52 Hz, 1.17 Hz), 7.31 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.19 (d, 2H, J=8.60 Hz), 7.10–7.06 (m, 3H), 6.84 (d, 2H, J=7.04 Hz), 6.82 (d, 2H, J=8.21 Hz), 4.23 (t, 2H, J=6.65 Hz), 3.22 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 2.99 (t, 2H, J=6.65 Hz), 2.39 (s, 3H), 1.81 (d, 5H, J=8.60 Hz), 1.40 (s, 3H), 1.38–1.32 (m, 5H). MS (ES+) m/z mass calcd C38H40NO5S 622.26, found 622.3.
Reaction SMILES: [C:1]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=O)CCCCCCCCC(=O)CCCCCC1>>[C:1]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCC=CCCCCCCCC1
Agent: O=C1CCCCCCCCC(=O)CCCCCC1
Product: O=C1CCCCCCC=CCCCCCCC1

Procedure:
7-Cyclohexadecen-1-one can be advantageously prepared from the known 1,8-cyclo-hexadecanedione by partial reduction and subsequent acid dehydration (a mixture of 7-cyclohexadecen-1-one and 8-cyclohexadecen-1-one is obtained). 8-Cyclohexadecen-1-one can be similarly obtained from the known 1,9-cyclohexadecanedione. A mixture of 1,8/1,9-cyclohexadecanediones can also be used and this is advantageous particularly for the preparation of the (E,Z)-7,8-cyclohexaden-1-one mixture. 1,8/1,9-cyclohexadecanediones are known for example from J. Org. Chem. 1968, 33, 4541 and U.S. Pat. No. 3,935,270.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)=[CH:10][N:9]=1.[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40].C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>C(Cl)Cl>[CH3:23][N:24]1[C:32](=[O:33])[C:31]2[N:30]([C@@H:34]([CH3:38])[C:35]([NH:20][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:11]4[CH:10]=[N:9][C:8]([N:4]5[CH2:5][CH2:6][CH2:7][C@H:3]5[C:2]([F:1])([F:21])[F:22])=[N:13][CH:12]=4)[N:19]=3)=[O:36])[CH:29]=[N:28][C:27]=2[N:26]([CH3:39])[C:25]1=[O:40]
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: Nc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](C(=O)Nc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1)n1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 3, 5.44 g, 17.59 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoic acid (Intermediate 8, 5.10 g, 20.23 mmol, ee: 99%), CH2Cl2 (58.6 mL) and the resulting mixture was stirred at 25° C. for 5 minutes. To the resulting yellow heterogeneous mixture was added HOAt (2.394 g, 17.59 mmol) and DCC (6.90 g, 33.4 mmol). The reaction mixture was cooled to 0° C. and pyridine (2.85 mL, 35.2 mmol) was added slowly around the edges of the flask. The reaction mixture was kept at 0° C. for 5 minutes before it was removed from the ice bath, and was then stirred at 25° C. for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite® to remove urea byproduct. The filtrate was then quickly concentrated to an oil, taken up in minimal CH2Cl2 and added dropwise to stirring hexanes to precipitate out crude (S,S)-product which was dried overnight. The product was recrystallized from CH2Cl2:MeOH (4:1) to obtain the title product (4.78 g, 8.79 mmol, 50%, de>99%); 1H NMR; 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.12 (s, 2H), 8.34 (s, 1H), 7.88 (dt, J=15.7, 8.1 Hz, 2H), 7.68 (d, J=8.2 Hz, 1H), 5.84 (d, J=6.7 Hz, 1H), 5.11 (p, J=7.4, 7.0 Hz, 1H), 3.83-3.61 (m, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.33-1.96 (m, 4H), 1.87 (d, J=7.3 Hz, 3H); m/z [M+H]+=544.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2.Cl[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[C:34]([CH2:33][CH:14]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26]([CH3:31])=[CH:25]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1])#[N:35]
Reactant: N#CCCl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC(CC#N)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A mixture of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (419 mg, 1 mmol), (prepared as described in Example 70), in DMF (6 ml) containing chloroacetonitrile (114 mg, 1.5 mmol), potassium carbonate (346 mg, 2.5 mmol) and potassium iodide (50 mg, 0.3 mmol) was stirred at ambient temperature overnight. The mixture was poured into water and the precipitate was filtered, washed with water and dried under vacuum. The residue was purified by column chromatography, eluting with methylene chloride, followed by methylene chloride/methanol (98/2 and 95/5). After removal of the solvent under vacuum, the residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (304 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[C:7]2[CH3:24].[Si]([O:40][C:41]([O:43][CH3:44])=[CH2:42])(C(C)(C)C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:44][O:43][C:41](=[O:40])[CH2:42][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:9](=[O:12])[NH:10]2
Reactant: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(=O)[nH]c2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-3-(4-methanesulfonylbenzyl)-4-methyl-2-oxo-1,2-dihydroquinolin-5-yl ester (0.042 g), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.10 mL), sodium acetate (0.008 g), bis(dibenzylideneacetone) palladium (0.002 g) and 1,1′-bis(diphenylphospino) ferrocene (0) (0.002 g) in N,N-dimethylformamide (0.8 mL) was heated by microwave irradiation at 120° C. for 15 minutes. The mixture was diluted with ethyl acetate and this solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 1:1 by volume) gave title compound as an off-white solid, 0.053 g.