Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[H][H]>CC(O)C>[OH:1][C@@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)CCCCCC(=O)c1ccccc1
Solvent: CC(C)O
Product: COC(=O)CCCCC[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 98 %

Procedure:
Chiral hydrogenation of methyl 7-oxo-7-phenylheptanoate was carried out (see formula (11) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S, SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using methyl 7-oxo-7-phenylheptanoate (587 mg; 2.5 mmol) as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 12 hours. As a result, methyl (R)-7-hydroxy-7-phenylheptanoate was obtained at a conversion rate of 100%, isolation yield of 98% (588 mg; 2.48 mmol), and enantiomeric excess of 95%. The enantiomeric excess was determined by HPLC analysis of the corresponding benzoic acid ester. HPLC (column: CHIRALPAC AD: size: 4.6 mm×250 mm; made by Daicel Chemical Industries Ltd.; solvent: hexane/2-propanol=19:1; temperature: 30° C.; UV wavelength: 254 nm; flow rate: 0.5 ml/minute; tR of methyl (R)-7-benzoyloxy-7-phenylheptanoate: 20.8 minutes (97.6%); tR of the Sisomer:25.9 minutes(2.4%)); [α]28D+29.1° (c:1.09;CHCl3); absolute structure: R. The absolute structure was determined from the value of the angle of rotation of 1-phenylheptanol obtained by conversion.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]1[C:19]2[CH:18]=[C:17]3[C:20]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]4[C:26]([C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:6].[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:5][CH3:6])[C:19]1[CH:18]=[C:17]3[C:20]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:21]4[C:26]([C:16]3=[CH:15][C:14]2=1)=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:41])[CH3:40]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c4ccccc4n(CC)c3cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c4cc(C(C)=O)ccc4n(CC)c3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (80 mL) in which were dissolved 10-ethyl-12,12-dihexyl-10,12-dihydro-10-aza-indeno[2,1-b]fluorene (5.95 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. The dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: [C:1]([CH:3]([NH:9][CH:10]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:12](#[N:15])[CH:13]=[CH2:14].FC(F)(F)C(O)=O>ClCCCl>[NH2:2][C:1]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:9][CH:10]=[CH:14][C:13]=1[C:12]#[N:15]
Reactant: CCOC(=O)C(C#N)NC=O
Reactant: C=CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1nccc(C#N)c1N
Yield: 20.9 %

Procedure:
A stirred solution of ethyl 2-cyano-2-(formyl-amino)acetate (J. Org. Chem., 1979, 44, 3835; 0.47 g, 0.003 mol), acrylonitrile (1.2 ml, 0.018 mol) and tri-fluoroacetic acid (0.02 ml, 0.0003 mol) in 1,2-dichloroethane (4 ml) was heated under reflux for 3 days. The solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (30 ml) and the resulting solution washed with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous phase was washed with dichloromethane (30 ml) and the organic solutions then combined, dried (MgSO4) and evaporated under vacuum. Chromatography of the residue on silica gel (12 g), eluting with dichloromethane:methanol (100:1), followed by crystallization from acetone:hexane, gave the title compound as a colourless solid (0.12 g, 21%), m.p. 114-116° C.
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH:20]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH2:21]C#N)=[N:8]2)=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:37](=[O:40])(O)[O-:38].[Na+].[CH3:42]O>>[CH3:42][O:38][C:37](=[O:40])[CH2:21][CH:20]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)[CH2:19][C:9]1[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:31])=[CH:2][CH:3]=2)[N:8]=1
Reactant: CO
Reactant: O=C([O-])O
Reactant: Cc1ccc(-c2cc(CC(CC#N)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)CC(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a flask were added 4-(1,5-di-p-tolyl-1H-pyrazol-3-yl)-3-m-tolyl-butyronitrile (100 mg, 0.24 mmol), concd sulfuric acid (1.5 mL) and methanol (1.5 mL). The mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature, poured into ice (20 g) and neutralized with satd sodium bicarbonate. The resulting solution was extracted with diethyl ether (3×10 mL), and the combined organic extracts were washed with water (10 mL) then brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC yielding the desired ester (86 mg, 82%). HPLC: Rt=3.43 (Method B). MS (ESI): mass calculated for C29H30N2O2, 438.23; m/z found, 439.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.19 (t, J=7.4 Hz, 1H), 7.01-7.13 (m, 11H), 6.15 (s, 1H), 3.56 (s, 3H), 3.54-3.52 (m, 1H), 3.11-3.08 (m, 2H), 2.77-2.75 (m, 2H), 2.36 (s, 3H), 2.32 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[CH2:41](O)[CH2:42][CH3:43].[ClH:45].O1CCOCC1>>[ClH:45].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:41][CH2:42][CH3:43])=[O:11])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:39])([F:40])[F:38]
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Reactant: CCCO
Agent: Cl
Solvent: C1COCCO1
Product: CCCOC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 45 °C
Reaction time: 4.5 h

Procedure:
703 mg (1.24 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoro ethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 1.86 mL (24.8 mmol) of 1-propyl alcohol were mixed, 12.4 mL (49.6 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 45° C. for 4.5 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:30]1([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([NH:42][CH2:41][C:39]2[CH:38]=[C:37]([C:43]3[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=3)[N:36]=[C:35]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:40]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (1.1 equiv., 353.47 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 140 mg of a pale yellow solid. Yield=23.6% 1HNMR (DMSO, 200 MHz) δ 1.09 (3H, t), 1.91 (4H, m), 3.38 (6H, m), 4.40 (2H, d), 5.17 (1H, s), 6.11 (1H, d), 6.34 (1H, s), 7.19 (1H, s), 7.78 (6H, m), 8.28 (2H, d), 8.80 (1H, bt) [M+1] 593.9 (C28H28ClF3N4O3S requires 593.06).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][S-:15].[Na+].C[OH:18].ClCCl>CC(C)=O.O>[CH3:14][S:15][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]([NH2:6])=[O:18]
Reactant: C[S-]
Reactant: CO
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CSc1cc(C(N)=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 500-mL, 3-neck round-bottomed flask equipped with an 100-mL pressure-equalizing addition funnel fitted with an nitrogen inlet, and a rubber septum, 3-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 1.0 eq.), in acetone (40 mL). Sodiumthiomethoxide (3.42 g, 1.15 eq) was dissolved in water to make 21% aqueous solution and was added dropwise in 30 min at 5° C. temperature. The temperature of the reaction was slowly raised to RT and stirred for 3 h. Then temperature was raised to 50-60° C. and maintained for further 4-6 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% MeOH-dichloromethane as mobile phase and visualization with UV, SM Rf=0.40 and Product Rf=0.25. Reaction was stirred for 3 hr at 25° C. and 4-6 hrs at 50-60° C. and reaction mixture was transparent. The reaction mass was quench by water and extracted by ethyl acetate (3×100 mL). The combined organic layer was washed with brine 50 mL and dried over sodium sulphate and evaporated on buchi rotaevaporator. The resulting crude compound (8 g) was subjected to further stage Yield (80.9%); Mass: (ES+) 235.94 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a mixture of 2-Amino-benzoic acid methyl ester (900 g, 6 mol) in pyridine (6 L) was added p-Toluenesulfonyl chloride (1500 g, 7.5 mol). The mixture was stirred overnight at room temperature. The mixture was poured into ice water, and the resultant precipitates were collected by filtration. The filtrates were dissolved in CH2Cl2, and the solution washed with diluted HCl, H2O, and dried over MgSO4. The residue thus obtained was crystallized from ethanol to give 2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester (1454 g, 80%).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[CH:9]=[CH:8]1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:40]([C:42]1[C:50]([O:51][CH3:52])=[CH:49][C:48]([CH3:53])=[C:47]2[C:43]=1[CH:44]=[CH:45][N:46]2[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[O:41]>C1COCC1.[Li+].CC([N-]C(C)C)C>[C:57]([O:56][C:54]([N:46]1[C:47]2[C:43](=[C:42]([CH:40]([C:8]3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=4)[OH:41])[C:50]([O:51][CH3:52])=[CH:49][C:48]=2[CH3:53])[CH:44]=[CH:45]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: C[Si](C)(C)CCOCn1ccc2ccc(C#N)cc21
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1cc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (424 mg, 1.55 mmol) in THF (0.7 mL), 1.8 M LDA in heptane/THF/ethylbenzene (139 mg, 1.29 mmol) was added at −78° C. The reaction was stirred at −78° C. for 30 minutes. tert-Butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (250 mg, 0.86 mmol) in THF (0.7 mL) was added at −78° C. The reaction was quenched with MeOH and then a saturated aq. ammonium chloride solution. The mixture was then diluted with EtOAc and the organic layer was removed, dried over MgSO4, filtered and concentrated. The resulting residue was purified via flash chromatography (0-40% EtOAc:heptanes) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 8.06 (s, 1H) 7.61 (d, J=8.34 Hz, 1H) 7.51 (d, J=3.79 Hz, 1H) 7.34 (dd, J=8.21, 1.39 Hz, 1H) 6.91 (s, 1H) 6.79 (d, J=3.79 Hz, 1H) 6.63-6.71 (m, 1H) 6.20 (s, 1H) 6.09 (d, J=4.80 Hz, 1H) 5.57-5.74 (m, 2H) 3.81 (s, 3H) 3.40 (ddd, J=9.22, 6.82, 2.15 Hz, 2H) 2.55 (s, 3H) 1.50-1.63 (m, 9H) 0.78 (td, J=9.28, 6.95 Hz, 2H) −0.13-−0.09 (m, 9H).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:14][O:15][CH3:16])[NH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].[CH3:17]C(C)([O-])C.[K+].[C:23]([O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:43]=[CH:42][C:39](CBr)=[CH:38][CH:37]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:43]=[CH:42][C:39]([N:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[NH:6][C:7]2([CH3:17])[CH2:14][O:15][CH3:16])=[CH:38][CH:37]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)[nH]1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: COCC1(C)NC(C(C)(C)O)=C(C(=O)OC)N1c1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 93.5 %

Procedure:
Following a procedure similar to that described in Example82(a), but using 230 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethylimidazole-5-carboxylate [prepared as described in Preparation 42(v)], 119 mg of potassium t-butoxide and 420 mg of 4-[2-(t-butoxycarbonyl)phenyl]benzyl bromide and then purifying the product by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, 468 mg of the title compound were obtained as a syrup.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CN(C)C=O>O.CO>[CH3:1][C:2]1([CH3:10])[C:3](=[O:9])[CH:4]=[C:5]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)[CH2:6][CH2:7]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)CCC(=O)CC1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(Nc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C

Procedure:
A mixture of 4,4-dimethylcyclohexane-1,3-dione (563 mg, 4.02 mmol), 3-(trifluoromethyl)aniline (500 μL, 645 mg, 4.02 mmol), Ytterbium(III) trifluormethanesulfonate (12.5 mg, 20 μmol, 0.5 mol %) and N,N-dimethylformamide (2.5 mL) is stirred at room temperature over night. Methanol and water are added and the mixture is filtered. The precipitate is washed with water and dried under reduced pressure. Yield: 654 mg; ESI mass spectrum [M+H]+=284, Retention time HPLC: 1.18 min (Z005—001).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[Br:12][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([CH:20]=1)[CH:18]=O.[C:25](#[N:29])[CH2:26][C:27]#[N:28].N1CCCCC1>C(O)C>[NH2:29][C:25]1[O:1][C:2]2[C:10]([CH:18]([C:17]3[CH:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[C:13]([Br:12])[CH:20]=3)[C:26]=1[C:27]#[N:28])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: N#CCC#N
Reactant: Cn1ccc2c(O)cccc21
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a solution of 4-hydroxy-1-methyl-indole (132 mg, 0.90 mmol), 5-bromoveratraldehyde (220 mg, 0.90 mmol) and malononitrile (59.3 mg, 0.90 mmol) in ethanol (3 mL) was added piperidine (0.05 mL, 0.45 mmol). The solution was stirred at room temperature for 2 h and precipitates were observed. The precipitates were collected by filtration and dried to yield 260 mg (66%) of title compound as a white solid. 1H NMR (CDCl3): 7.07-7.02 (m, 2H), 6.91(d, J=2.1 Hz, 1H), 6.77-6.75 (m, 2H), 6.57 (dd, J=0.9 Hz, 1H), 4.78 (s, 1H), 4.70 (brs, 2H), 3.82 (s, 6H), 3.78 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:18].O.[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:13])([CH3:3])/[C:4](/[OH:12])=[CH:5]/[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11].[CH3:1][C:2]([CH3:13])([CH3:3])/[C:4](/[OH:12])=[CH:5]/[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11].[CH3:1][C:2]([CH3:13])([CH3:3])/[C:4](/[OH:12])=[CH:5]/[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11].[CH3:1][C:2]([CH3:13])([CH3:3])/[C:4](/[OH:12])=[CH:5]/[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11].[Zr:18]
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Reactant: [Zr+4]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)/C=C(\O)C(C)(C)C
Product: [Zr]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To 177 g of methanol, 43.7 g (0.216 mol) of 2,2,6,6-tetramethyl-3,5-heptanedione of 91% purity was dropwise added with stirring. To the resulting solution, a solution, which had been obtained by dissolving 12.7 g (0.054 mol) of ZrCl4 of 99% purity in 218 g of methanol and cooled to room temperature, was added over a period of about 5 minutes. The reaction was conducted for 1 hour with stirring, and 590 g of water was added over a period of 50 minutes. Then, stirring was performed for 1 hour. The resulting solution was adjusted to pH 6.6 with a 20% NaOH solution. The resulting crystals were collected by centrifugation and then dried. Thus, 43.9 g (yield: 98.2%) of tetrakis(2,2,6,6-tetramethyl-3,5-heptanedionato)zirconium was obtained.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate were coupled under Suzuki conditions to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:1].[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1Nc1nc(Cl)c2ccccc2n1
Product: Cc1ccccc1Nc1nc(Nc2ccccc2)c2ccccc2n1
Product: Cl
Yield: 17.2 %

Procedure:
4-Chloro-2-(2-methylphenylamino)quinazoline (1.5 g, 0.0048 mol) was dissolved in aniline (1.5 ml, 0.016 mol) and heated at 170° for 1 hour. After cooling and evaporation of excess solvent the residue was crystallised from ethanolic hydrogen chloride to give 2-(2-methylphenylamino)-4-phenylaminoquinazoline hydrochloride (0.30 g, 17%) m.p. 239°-240°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[C:12](O)(=O)CC(O)=O.N1CCCCC1.O>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:12])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: C=Cc1ccc(O)c(OC)c1
Yield: 51 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (3.42 mmol), malonic acid (13.68 mmol), piperidine (15.58 mmol) in DMF (20 ml) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the monomode microwave oven and irradiated (250 W, 160° C.) for 15 minutes in parts. After completion, the reaction mixture was poured in ice cooled water and extracted with ethyl acetate. The organic layer was washed with dil. HCl, brine and water and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel by column chromatography using a mixture of hexane and ethyl acetate (9:1 to 6:4), provided 4-hydroxy-3-methoxystyrene, a sweet and pleasant smelling liquid, in 51% yield; 1H NMR (CDCl3) 7.36 (21-1, d), 6.94 (2H, m), 6.83 (5H, m), 5.59 (1H, s), 3.86 (3H, s), 3.75 (3H, s); 13C NMR (CDCl3) 159.0, 146.7, 145.2, 130.3, 127.4, 126.6, 126.1, 120.1, 114.5, 114.1, 108.0, 55.9 and 55.3.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:19])[CH3:18])=[CH:11][C:10]=1[O:20][CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30](Cl)(=[O:32])[CH3:31].C(OCC)C.CCCCCC>C1COCC1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:19])[CH2:18][C:30](=[O:32])[CH3:31])=[CH:11][C:10]=1[O:20][CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: COc1cc(C=CC(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C=CC(=O)CC(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A solution of 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-butene-3-one (12.8 g, 41.8 mmol) in THF (50 mL) is cooled to -78° C. under an argon atmosphere. Lithium di-isopropyl amide (83.5 mmol, in 50 mL THF) is slowly added to the reaction mixture. The reaction is stirred at -78° C. for 30 minutes. Acetyl chloride (16.4 g, 209 mmol) dissolved in THF (20 mL) is then added to the reaction over a 30 minute period. The reaction is quenched with aqueous HCl. The layers are separated, and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and evaporated to give a red oil. Flash chromatography (ethyl ether/hexane 2:8) afford 5.0 g (34%) of 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-hexene-3,5-dione, mp=81°-85° C.