Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:29][CH2:30][CH2:31][CH3:32])[C:10]3[N:15]=[C:14]([C:16]4[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.[C:36]([O:40][C:41](=[O:44])[CH2:42][NH2:43])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>ClCCl>[C:36]([O:40][C:41](=[O:44])[CH2:42][NH:43][C:22](=[O:23])[CH2:21][O:20][C:19]1[C:18]([CH3:28])=[CH:17][C:16]([C:14]2[O:13][C:11]3[N:12]=[C:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]=[C:9]([O:29][CH2:30][CH2:31][CH3:32])[C:10]=3[N:15]=2)=[CH:26][C:25]=1[CH3:27])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)Cl)c(C)c3)nc12
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)NCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.3 %

Procedure:
200 mg of {4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetyl chloride were dissolved in 2 ml of dichloromethane, and the solution was slowly added to a solution of 67 mg of glycine tert-butyl ester hydrochloride and 121 mg of triethylamine in 3 ml of dichloromethane. The mixture was stirred for 18 h at room temperature. Then the solvent was distilled off in vacuo and the product was isolated via preparative HPLC (method HPLC2) to yield 53 mg of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=O.OC(C(F)(F)F)=O.[NH2:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33].C[O-].[Na+]>CCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])=[O:2]
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1ncc2cc(-c3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1ncc2cc(-c3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 47.4 %

Procedure:
A mixture of 4-hydroxy-7-phenyl-isoquinoline-3-carboxylic acid methyl ester (60 mg, 0.22 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (200 mg, 0.86 mmol) and NaOMe (93 mg, 1.72 mmol) in EtOH (2.2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 38 mg of the title compound. MS: (+) m/z 365.11 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[NH:11][CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[N:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[CH:18]([N:14]([CH:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][NH:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][N:6]=1)=[O:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(C(=O)NCCN(C(C)C)C(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(CCNC(=O)c1ccc(C(=O)O)cn1)C(C)C
Yield: 88.9 %

Procedure:
To a solution of 1100 mg (3.6 mmol) 6-(2-diisopropylamino-ethylcarbamoyl)-nicotinic acid methyl ester in 10 ml THF and 3.0 ml MeOH was added 3.6 ml of an 2N aqueous NaOH solution. After 4 h at rt the solvent was evaporated. The residue was acidified with 1N HCl, filtered off and washed with water to give 936 mg (3.2 mmol) 6-(2-diisopropylamino-ethylcarbamoyl)-nicotinic acid; exact MW [M+H] calc'd: 294.18; MW .found [M+H]: 209.15.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:18])=[CH:15][C:14]=2[O:29][CH3:30])[N:3]=1.[C:31]1([OH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CO>[CH3:30][O:29][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([O:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[C:17]([NH:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]
Reactant: Oc1ccccc1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (50 mg) and phenol (21.3 mg) are dissolved in dioxane (0.3 mL). Pyridine (36.4 μL) and Cs2CO3 (235 mg) are added and the suspension is stirred overnight at 80° C. Then the reaction mixture is diluted with methanol (5 mL) and mixed with isolute. The solvent is eliminated in vacuo and then the mixture is purified by preparative HPLC. (PTK2 IC50=35 nmol)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:19]=1>CN1C(=O)CCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:20]1[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
436 mg (2.00 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 200 mg (0.652 mmol) (4-chloro-6-methoxy-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone were stirred in 2 mL NMP overnight at 120° C. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:18][CH:19]=[CH:20][CH2:21][CH:22]([OH:30])[C:23]1([CH2:27][CH2:28][CH3:29])[CH2:26][CH2:25][CH2:24]1)[S:14]([CH3:17])(=[O:16])=[O:15])C.Cl>O.C1COCC1>[OH:30][CH:22]([C:23]1([CH2:27][CH2:28][CH3:29])[CH2:26][CH2:25][CH2:24]1)[CH2:21][CH:20]=[CH:19][CH2:18][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:31])=[O:5]
Reactant: CCCC1(C(O)CC=CCN(CCCCCCC(=O)OCC)S(C)(=O)=O)CCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1(C(O)CC=CCN(CCCCCCC(=O)O)S(C)(=O)=O)CCC1
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Lithium hydroxide (0.50 mL of a 0.5N solution in H2O, 0.122 mmol) was added to a solution of the ester 11 (45 mg, 0.122 mmol) in THF (1.0 mL) at 23° C. The reaction mixture was stirred for 16 h, acidified with 1 N HCl and extracted with EtOAc. The organic portion was washed with brine (2×), dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 100% EtOAc) gave 36.2 mg (72%) of the free acid 12 as a light yellow, viscous oil.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:35][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc(N)c1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3cccc(OC)c3)ccc12
Reaction time: 48 h
Yield: 104.9 %

Procedure:
87 mg (0.708 mmol, 1.0 equiv) DMAP were added to a room temperature solution of 196 mg (0.708 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride, 99μL (0.708 mmol, 1.0 equiv) triethylamine and 80 μL (0.708 mmol, 1.0 equiv) m-anisidine in 5 mL CH2Cl2. After 48 hours, the reaction mixture was diluted with 75 mL ethyl acetate, washed 2×15 mL 1N HCl, 1×15 mL H2O, 1×15 mL brine, and dried over MgSO4. Filtration, concentration of filtrate and drying gave 0.27 g of an amber solid, which was purified by silica gel chromatography (ethyl acetate/hexanes gradient 10% (20%) to give 118 mg of a clear oil. Crystallization from petroleum ether gave 75 mg (29%) of a white powder: mp 91-93° C.; Anal. calcd for C22H25N3O2: C, 72.71; H, 6.95; N, 11.56. Found: C, 72.35; H, 7.15; N, 11.47.
Reaction SMILES: C(O[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:25][O:26][C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[NH:28]1.CCOC(C)=O.[C:43]1([CH3:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:49]([CH:9]1[CH:14]([N+:15]([O-:17])=[O:16])[C:13]([C:30]2[C:29]([CH3:33])=[N:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)=[CH:12][CH:11]=[N:10]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1ccccc1
Reactant: COC1(B(O)O)C=CC=C(C)N1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=CC=NC(Cc3ccccc3)C2[N+](=O)[O-])c(C)n1
Yield: 96 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (1.95 g, 7.4 mmol) in ethanol (10 mL) and toluene (40 mL), was added Na2CO3 (9.2 mL, 2M), 2-methoxy-6-methyl pyridine boronic acid (Wilde, et al. WO99/01454) (1.85 g, 11.1 mmol), and Pd(PPh3)2Cl2 (0.31 g, 4.44 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H2O (500 mL). The EtOAc layer was washed with H2O, brine, dried Na2SO4, filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc/hexane) gave 2.5 g (96%) of 2′-benzyl-6-methoxy-2-methyl-3′-nitro-2′,3′-dihydro-[3,4′]bipyridinyl as a viscous oil: MS (AP) m/z 352.5 [(M+H)+, 100], 392.9 [(M+H+CH3CN)+, 65]. The purified intermediate was used in the following step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH2:10].C(N(C(C)C)CC)(C)C.[C:20]1([CH:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][NH:10][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:30][CH3:31]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: Cc1ccc(F)c(CN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C(=O)NCc1cc(C)ccc1F)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2-fluoro-5-methylphenyl)methanamine (1-f, 50 mg, 0.26 mmol, Oakwood Products, Inc., West Columbia, S.C.) and diisopropylethylamine (88 uL, 0.52 mmol) in dichloromethane (1 mL) was treated at room temperature with 2-phenylbutanoyl chloride (1-a, 47 mg, 0.26 mmol). The reaction mixture was stirred for 30 min, partitioned between dichloromethane and 0.1N—NaOH. The aqueous layer was removed and the organic layer washed with 0.1N-HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (1-2); HRMS (M+1)=286.1586.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([NH2:23])=[N:17][C:18]([NH2:22])=[N:19][C:20]=3[CH3:21])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#N.S(=O)(=O)(O)[OH:25].[CH2:29]([OH:31])[CH3:30]>>[NH2:22][C:18]1[N:17]=[C:16]([NH2:23])[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([O:31][CH2:29][CH3:30])=[O:25])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)=[C:20]([CH3:21])[N:19]=1
Reactant: O=S(=O)(O)O
Reactant: CCO
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C#N)cc2)CC1
Product: CCOC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1
Temperature: 130 °C

Procedure:
A mixture of 5.0 g (0.016 mole) of 5-[4-(4-cyanophenyl)-1-piperazinyl]-6-methyl-2,4-pyrimidinediamine, 30 ml of 95% ethanol and 30 ml of sulfuric acid was heated under reflux at 130° C. for four hours and cooled. The solution was poured into 400 g of ice. The solid was collected, washed first with 5N aqueous sodium carbonate solution and then with 50 ml of water. Recrystallization from N,N-dimethylformamide gave 1.72 g of the product as an off-white solid, mp 281°-285° C.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:31]([Si:35]([CH3:52])([CH3:51])[O:36][CH:37]([C:39]1[O:40][C:41]([CH2:44][N:45]2[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]2)=[CH:42][N:43]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl.O>[C:31]([Si:35]([CH3:52])([CH3:51])[O:36][CH:37]([C:39]1[O:40][C:41]([CH2:44][N:45]2[CH:49]=[CH:48][C:47]([NH:50][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])=[N:46]2)=[CH:42][N:43]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc(N)n2)o1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid (114 mg, 0.60 mmol) in CH2Cl2 (3.0 mL) was treated at rt with HOBt (98 mg, 0.72 mmol), EDC (289 mg, 1.51 mmol) DMAP (18 mg, 0.15 mmol) and the resulting mixture was stirred at rt for 30 min. 1-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-1H-pyrazol-3-ylamine (297 mg, 0.60 mmol) in CH2Cl2 (3.0 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=1.17 min, [M+H]+=494.56.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)=[O:9])[CH:5]=C[CH:7]=1.C(N(CCCC)CCCC)CCC.[C]=O.[C:39]([O:42][CH2:43]C)(=[O:41])[CH3:40]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:16]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:22])([CH3:23])[C:12]2[CH:11]=[C:10]([C:8]([C:4]3[CH:5]=[C:40]([CH:7]=[CH:2][CH:3]=3)[C:39]([O:42][CH3:43])=[O:41])=[O:9])[CH:19]=[CH:18][C:17]1=2
Reactant: CCOC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3cccc(I)c3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1cccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of 3-iodophenyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)methanone (10.5 g, 25.1 mmol), palladium diacetate (564 mg, 2.5 mmol) and tributylamine (12 ml, 50.5 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH2:32])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[N:12][N:11]=2)[CH2:3]1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>N1C=CC=CC=1>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:43]([CH3:42])(=[O:45])=[O:44])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:34])=[O:35])=[N:12][N:11]=2)[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O

Procedure:
To a solution of 5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinamine (200 mg, 0.347 mmol) in pyridine (1 ml) was added, dropwise, methanesulphonyl chloride (0.054 ml, 0.695 mmol) and the mixture stirred at 20° C. for 18 hr. Water (10 ml) was added and the title compound was collected by filtration as a brown solid (106 mg).
Reaction SMILES: C12([OH:11])CC3CC(CC(C3)C1)C2.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[C:26]12([OH:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[OH:36])[CH2:33]2>ClC1C=CC=CC=1.C(O)(=O)C>[C:26]12([OH:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[C:27]1([OH:11])[OH:36])[CH2:33]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: OC1C2CC3CC(C2)CC1(O)C3
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: OC12CC3CC(CC(C3)C1(O)O)C2
Temperature: 85 °C
Reaction time: 20 h
Yield: 50.5 %

Procedure:
A mixture of 25 g (164 mmol) of adamantanol, 5.36 g (32.8 mmol) of N-hydroxyphthalimide, 0.11 g (0.328 mmol) of vanadiumacetylacetonato [V(acac)3], 150 mL of acetic acid and 150 mL of chlorobenzene was stirred for 20 hours at 85° C. and 1 atm (0.101 MPa) in an atmosphere of oxygen. After completion of reaction, the reaction mixture was analyzed by gas chromatography and high performance liquid chromatography, and, as a result, the conversion of adamantanol was 95.6%, adamantanediol and adamantanetriol were formed in yield 50.5% (selectivity 52.8%) and yield 40.7% (selectivity 42.6%), respectively. Moreover, in the reaction mixture, 1.85 g of N-hydroxyphthalimide used as a catalyst, 1.51 g of phthalimide, and 0.40 g of phthalic anhydride were contained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(OCCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
A solution [2-(4-Hydroxy-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid methyl ester (0.1 mmol) in DMF (1 mL) is added phenethyl bromide (0.2 mmol) followed by K2CO3 (80 mg, 578 μmol). The mixture is heated without agitation overnight at 60° C. and monitored by TLC. The mixtures are cooled, water (2 mL) and CH2Cl2 (2 mL) are added, vortexed, centrifuged and the organics separated. The process is repeated with solely CH2Cl2 (1 mL). The organics are combined and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=O)O1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:50]([C:53]1[CH:60]=[CH:59][C:56](C=O)=[CH:55][CH:54]=1)([OH:52])=[O:51]>N1CCCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])/[C:21](/[C:22]([O:24][CH2:17][CH3:25])=[O:23])=[CH:19]/[C:56]2[CH:59]=[CH:60][C:53]([C:50]([OH:52])=[O:51])=[CH:54][CH:55]=2)[CH2:11][O:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1COC[C@H]1C(=O)O
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C(=C\c1ccc(C(=O)O)cc1)C(=O)[C@@H]1COCN1C(=O)OC(C)(C)C
Yield: 84.6 %

Procedure:
To (4S)-3-(tert-butoxycarbonyl)-1,3-oxazolidine-4-carboxylic acid (11.15 g, 0.051 mol), Meldrum's acid (7.33 g, 0.051 mol), dimethylaminopyridine (12.44 g, 0.102 mol) and DCM (200 ml) was added 1,3-dicyclohexylcarbodiimide (10.52 g, 0.051 mol). After 24 h the reaction was filtered, extracted twice with 1N HCl (200 ml) once with water, dried (Na2SO4), filtered, concentrated, then warmed to reflux in 100% ethanol for 2 h. The reaction was concentrated to a pale yellow oil (14.3 g). A portion of this material (5.88 g, 0.02 mol) was refluxed 2 h using Dean Stark trap with 4-carboxybenzaldehyde (3.0 g, 0.02 mol), piperidine (110 mg, 0.0012 mol) and toluene (100 ml). The reaction was filtered, concentrated to give A as a yellow gum (7.1 g, 85%). LCMS m/z 420 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[C@@H:12]([CH3:16])[C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccco1
Reactant: C[C@@H]1NCCN(CCCc2ccccc2)[C@H]1C
Solvent: c1ccccc1
Product: C[C@H]1[C@H](C)N(C(=O)c2ccco2)CCN1CCCc1ccccc1

Procedure:
The compound was obtained by following the same process as in Example 3 from a mixture of trans-1-(3-phenylpropyl)-2,3-dimethylpiperazine [b.p. 130° - 132°C (2 mmHg), dipicrate, m.p. 195° - 196°C], 2-furoyl chloride and benzene.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[C:25]2[CH2:30][CH2:29][O:28][C:26]2=[O:27])[N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(C=C2CCOC2=O)nc(C(C)(C)C)c1O
Yield: 62.6 %

Procedure:
A solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidine-2-carboxaldehyde (0.5 g, 2.1 mmol) and α-triphenylphosphoranylidene-γ-butyrolactone (Katsumi, et al. Chem. Pharm. Bull. [Japan]1986, 34, 619) (0.95 g, 2.8 mmol) in 50 mL of toluene is warmed to 60° C. overnight. The toluene is evaporated and the residue purified by flash chromatography (silica, 20% EtOAc/hexane). Recrystallization from hexane gives 0.4 g (62%) of α-[[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]methylene]-γ-butyrolactone, mp 158°-160° C.
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)[Cl:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl-:2].[Ti+4:1].[Cl-:2].[Cl-:2].[Cl-:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: [Cl-]
Product: [Ti+4]

Procedure:
To the above described solid component were added 40 ml of toluene and titanium tetrachloride so as to give a titanium chloride/toluene volume ratio of 3/2, the temperature being then raised to 80° C. While stirring, a mixed solution of 2 ml of di-n-butyl phthalate and 5 ml of toluene was dropwise added thereto and stirred at 80° C. for 2 hours. The resulting solid material was separated by filtration and washed with 100 ml of toluene 2 times at 75° C. Furthermore, titanium tetrachloride was added thereto so as to give a titanium tetrachloride/toluene volume ratio of 3/2 and stirred at 80° C. for 2 hours. The resulting solid material was separated by filtration at 80° C. and then washed with 100 ml of n-hexane at room temperature 7 times, thus obtaining 3.4 g of a catalyst component.