Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10]C(=O)OCC2C=CC=CC=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[O:9][C:8]([NH2:10])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(NC(=O)OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cnc(N)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a solution of benzyl (5-tert-butyl-1,3-oxazol-2-yl)carbamate (5.0 g, 18.2 mmol) in methanol (100 mL) is added 10% palladium on carbon (500 mg, 0.5 mmol). The reaction is stirred at room temperature for 3 h under hydrogen atmosphere. The reaction mixture is filtered through Celite and the filtrate is concentrated. The residue is purified by flash column chromatography to afford the title compound (1.7 g, 68%) as a light brown solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCCCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:28][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: C1CCNCC1
Product: CC(C)(C)c1nc(N2CCCCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and piperidine and isolated as light-yellow solid (10.0 mg, 55%). MS (m/e): 385.4 (MH+).
Reaction SMILES: [P:1]([CH2:5][C:6]([OH:8])=[O:7])([OH:4])([OH:3])=[O:2].Cl.[CH2:10](O)[CH3:11]>>[P:1]([CH2:5][C:6]([O:8][CH2:10][CH3:11])=[O:7])([OH:4])([OH:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)CP(=O)(O)O
Agent: Cl
Product: CCOC(=O)CP(=O)(O)O
Reaction time: 8 h

Procedure:
Into 100 ml. of absolute ethanol was placed 28 g. (0.2 mole) of phosphonoacetic acid. The solution was treated with a stream of dry hydrogen chloride at 0° C. for 45 minutes. After refluxing for 3 hours the solution was allowed to stand overnight at room temperature. Evaporation of the solvent yielded a viscous oil, which was dried in vacuo over P2O5 and NaOH.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1F)[C:13]([O:15]C)=[O:14])#[N:9].[Li+].[OH-]>CN(C=O)C.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:13]([OH:15])=[O:14])#[N:9]
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Reactant: CC1CCCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
2-Methylpiperidine (744 mg; 7.5 mmol; 5 eq.) was added to a solution of methyl 3-cyano-4-fluorobenzoate (269 mg; 1.5 mmol; 1 eq.) in DMF (2 mL) and the resulting mixture was stirred at room temperature for 2 days. The solution was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with HCl 0.1M then brine, dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in THF (5 mL) and LiOH (126 mg; 3 mmol; 2 eq.) then water (5 mL) were added and the reaction mixture was stirred at room temperature for 5 hours. The resulting solution was diluted with water and washed with Et2O. The aqueous layer was acidified to pH 2 with HCl 0.1M and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (294 mg, 80%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]([CH3:9])[C:4](=O)[N:5]([CH3:7])[CH3:6])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:3]([CH3:9])[C:4]([N:5]([CH3:7])[CH3:6])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:2]
Reactant: CCN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-ethyl-1,1,3-trimethylurea (6.57 g) in benzene (70 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) for 45 hours at 65°-70° C. gave 1-ethyl-2-(2-morpholinophenyl)-1,3,3-trimethylguanidine (bp. 140° C. at 0.2 mm Hg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[C:7]2[OH:12])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: Oc1cccc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2c(O)cccc12
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 20.0 g of 1,5-dihydroxynaphthalene (Sigma-Aldrich), 51.81 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the reaction temperature was set to 80° C., and homogeneous mixture was refluxed (hereinafter, the temperature written during the synthesis represents the set temperature of the refluxing apparatus and was higher than about 10° C. to 15° C. than true reaction temperature of reaction medium). During the refluxing, 13.5 ml of allyl bromide (Sigma-Aldrich) was added in a dropwise manner and allowed to react overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and was filtered using Celite. The solvent was evaporated to obtain a coarse product. A reaction product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvents were removed by using an evaporator to obtain an intermediate product (11), 5-(allyloxy)naphthalene-1-ol. The reaction scheme in the 1st step and the NMR data of the intermediate product (11) thus obtained are as follows.
Reaction SMILES: [F:1][CH:2]([F:47])[O:3][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+].CO>C(O)C.[C].[Pd]>[F:47][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)(=[O:33])=[O:34])=[O:11])=[CH:45][CH:46]=1
Reactant: O=C(NCc1ccc(OC(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: O=C(NCc1ccc(OC(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of the compound (1.09 g) obtained in Step 9 and ammonium formate (895 mg) in ethanol (15 ml)-methanol (5 ml) was added 10% palladium carbon (1.0 g). After stirring at 85° C. for 1 hr, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (596 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:24]=[CH:23][S:22][CH:21]=1>CN(C)C=O>[S:22]1[CH:23]=[CH:24][C:20]([CH2:19][O:1][C:2]2[CH:11]=[CH:10][C:5]3[S:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)=[CH:21]1
Reactant: O=c1oc2cc(O)ccc2s1
Reactant: ClCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(OCc3ccsc3)ccc2s1
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
A mixture of 6-hydroxy-1,3-benzoxathiol-2-one (15 g) and potassium carbonate (13.8 g) in dimethylformamide (200 mL) is stirred for 20 minutes, and is then treated, dropwise, with 3-chloromethylthiophene (11.8 g). The mixture is stirred at 60° C. for 16 hours. The reaction mixture is then concentrated in vacuo, and partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer is extracted with ethyl acetate (100 mL) and with diethyl ether (100 mL), and the combined aqueous layers are washed with brine, dried over magnesium sulphate, and evaporated to give a yellow solid, which is recrystallised from ethanol (200 mL) to give 6-(3-thienylmethoxy)-1,3-benzoxathiol-2-one (8.9 g), in the form of pale yellow crystals.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccccc12
Product: Clc1ncnc2ccccc12
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
A mixture of 4-hydroxyquinazoline (2.56 g, 17.5 mmol) and POCl3 (8.0 mL, 88 mmol) was stirred at 140° C. (oil bath) for 10 min. The homogeneous light amber solution was then allowed to cool to rt before concentrating under reduced pressure at 70° C. The translucent residue was dissolved in DCM (25 mL), and the homogeneous yellow solution was partitioned with ice and 1 M NaHCO3 to pH ˜6 (paper) (˜20 mL aq layer). The organic layer was dried twice (Na2SO4), filtered through a 0.22 micron filter, and concentrated under reduced pressure (bath <40° C.) to provide the title compound as a yellow solid (2.53 g, 88%). 1H-NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.30 (ddd, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[CH2:14][OH:15].CCN(CC)CC.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>ClCCl.CN(C1C=CN=CC=1)C>[Si:27]([O:15][CH2:14][C@@H:3]1[C@@H:2]([OH:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a 0° C. solution of (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 equiv) and Et3N (1.05 equiv) in dichloromethane (0.5 M) was added TBSCl (1.05 equiv), followed by a few crystals of DMAP. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane, and washed with sat'd. aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (99%), which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].I[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>C(N(CC)CC)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>[NH2:9][C:8]1[C:3]([C:1]#[C:2][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[N:4][C:5]([CH3:10])=[CH:6][CH:7]=1
Reactant: C#Cc1nc(C)ccc1N
Reactant: N#Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cccc(C#N)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.6 %

Procedure:
To a solution of Cul (2.4 mg, 12 μmol) in triethylamine (4 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (33 mg, 0.33 mmol described in Example 7), (PPh3)2PdCl2 (8.8 mg, 12 μmol), and 3-iodobenzonitrile (57 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated and the crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 1:1) to yield 16 mg (69 μmol, 21%) of 3-(3-amino-6-methyl-pyridin-2-ylethynyl)-benzonitrile as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3ncccc23)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4ncccc34)cc2=O)n1
Yield: 59 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(quinolin-5-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 57) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(quinolin-5-yloxy)-6H-pyridazin-1-yl]-propionamide as a white solid (0.69 g, 59%); ES+-HRMS m/e calcd for C28H32N6O4 [M+H+] 517.2558 found 517.2557. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.05 (s, 3H), 1.10 (m, 1H), 1.21-1.77 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=4.4, J=10.7 Hz, 1H), 5.78 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.57 (d, Jo=7.8 Hz, 1H), 7.62 (dd, Jo=8.5, 4.0 Hz, 1H), 7.86 (t, Jo=8.2 Hz, 1H), 8.04 (d, Jo=8.5 Hz, 1H), 8.29 (d, J=2.7 Hz, 1H), 8.39 (d, Jo=8.5 Hz, 1H), 9.01 (dd, Jo=4.0, Jm=1.5 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH2:3][C:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:13]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1NC(N)=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g (0.03 mol) of sodium cyanate were added to a solution of 7.91 g (0.02 mol) of N-[(2-aminophenyl)methyl]-N-(1,1-dimethylethoxycarbonyl)-1-(phenylmethyl)-4-piperidineamine in a mixture of 5.5 ml glacial acetic acid and 80 ml of water and the mixture was stirred overnight at ambient temperature. The mixture was made slightly alkaline by the addition of saturated sodium hydrogen carbonate solution, then extracted exhaustively with EE. The combined ethyl acetate extracts were washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 8.7 g (99% of theoretical) of colourless crystals were obtained, Rf 0.71 (El D), which were further processed without any additional purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=1>>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][C:24]=1[CH3:29]
Reactant: Cc1cc(I)ccc1O
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: Cc1cc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)ccc1O
Yield: 73 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodo-2-methylphenol were reacted to give the title compound as a light yellow solid (43 mg, 73%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=3)C3C=CC=CC=3C(=O)O2)=[CH:4][CH:3]=1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>>[C:5]1([C:8]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:29][C:28]=2[C:27]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:25]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: ClCC1CO1
Product: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
(A-2) 159 g of 3,3-bis (4-hydroxyphenyl)-2-benzofuran-1-on, 426.6 g of epichlorohydrin, and 160 g of a 50% alkali aqueous solution are mixed in a 1 L flask and reacted together at 95° C. for 1 hour to form a bisphenylbenzofuran-type epoxy resin. 215 g of the bisphenylbenzofuran-type epoxy resin is mixed with 450 mg of triethylbenzylammoniumchloride, 100 mg of 2,6-diisobutylphenol, and 72 g of acrylic acid. The mixture is heated up to 90 to 120° C. and completely dissolved, while air is blown therein at a speed of 25 Ml. Then, the dissolved product is cooled down to room temperature to form a non-colored transparent solid bisphenylbenzofuran-type epoxy acrylate. 287 g of the synthesized bisphenylbenzofuran-type epoxy acrylate is dissolved in 2 kg of cellosolveacetate. The solution is mixed with 10 g of 1,2,3,6-tetrahydrophthacid anhydride, 108.5 g of benzophenonetetracarboxylic acid dianhydride, and 1 g of tetraethylammonium bromide. The mixture is slowly heated up to 110 to 115° C. for 2 hours to form a cardo-based binder resin with a weight average molecular weight of 30,000 g/mol.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[C:13]([Cl:26])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[Cl:26][C:13]1[C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[CH:15][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[C:9]=2[CH:12]=1
Reactant: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 139.8 %

Procedure:
The above prepared 5-chloro-6-(1-isopropyl-piperidin-4-yloxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.897 g, 2.36 mmol) was dissolved in 4.8 mL of THF/ethanol=1/1 and treated with 1.18 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 3 h at ambient temperature and was then neutralized by adding 1.77 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents and drying afforded finally 1.161 g of the title compound as off-white solid, contaminated with innocuous inorganic salts.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7](OC)=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[NH2:13][OH:14]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([NH:13][OH:14])=[O:8]
Reactant: NO
Reactant: COC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: C1COCCO1
Product: O=C(NO)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 5-bromosalicylate (5 g, 21.6 mmol) was dissolved in 90 mL 1,4-dioxane and 10 mL water. 10 mL 50% aqueous hydroxylamine solution was added and the mixture was stirred at ambient temperature for 24 hours. After concentrating the mixture under vacuum, water was added. The formed precipitate was filtered, washed with water and dried yielding 5-bromo-N,2-dihydroxybenzamide (4.12 g, 17.76 mmol) as off-white solid.
Reaction SMILES: S(NN=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:30]([CH2:31][CH2:32][C@:14]12[CH3:15])[C@:27]1([CH2:28][OH:29])[C:22](=[CH:23][CH:24]([OH:33])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)(C1C=CC(C)=CC=1)(=O)=O.C([Li])CCC>O1CCCC1.CCCCCC>[OH:33][CH:24]1[CH2:25][CH2:26][C@@:27]2([CH2:28][OH:29])[C:22]([CH2:21][CH2:20][C@@H:19]3[C@@H:30]2[CH2:31][CH2:32][C@@:14]2([CH3:15])[C@H:16]3[CH2:17][CH:18]=[CH:13]2)=[CH:23]1
Reactant: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CCC5=CC(O)CC[C@]5(CO)[C@H]4CC[C@]23C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(O)CC[C@]3(CO)[C@H]1CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The tosylhydrazone (20) in tetrahydrofuran is treated with n-butyl lithium (BuLi, b) in hexane and the mixture is stirred at room temperature for 16 hours. Aqueous work up is followed by extraction and purification to yield the diene (21) .
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:11]([S-:14])[CH2:12][CH3:13].[Na+]>>[Br:8][C:6]1[CH:7]=[C:2]([S:14][CH2:11][CH2:12][CH3:13])[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=1
Reactant: COc1cc(Br)cc(Br)c1
Reactant: CCC[S-]
Agent: [Na+]
Product: CCCSc1cc(Br)cc(OC)c1
Yield: 38.6 %

Procedure:
A similar procedure as described in Example 47, step 2 was used, starting from 3,5-dibromoanisole (5.3 g, 19.93 mmol) and sodium 1-propanethiolate (2.47 g, 23.92 mmol) to afford 1-bromo-3-methoxy-5-propylsulfanyl-benzene (2.01 g, 39%) as a light yellow oil: EI(+)-HRMS m/e calcd for C10H13BrOS (M)+ 259.9870, found 259.9870.
Reaction SMILES: C(OC(=O)[N:7]([C:39]1[CH:40]=[N:41][C:42](Cl)=[CH:43][CH:44]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:16]2[C:24]3[C:23]([CH:25]4[CH2:27][CH2:26]4)=[N:22][CH:21]=[N:20][C:19]=3[N:18]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:17]=2)[OH:15])=[C:10]([F:38])[N:9]=1)(C)(C)C.[CH:47]1([Mg]Br)[CH2:49][CH2:48]1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:47]1([C:42]2[N:41]=[CH:40][C:39]([NH:7][C:8]3[N:9]=[C:10]([F:38])[C:11]([CH:14]([C:16]4[C:24]5[C:23]([CH:25]6[CH2:26][CH2:27]6)=[N:22][CH:21]=[N:20][C:19]=5[N:18]([Si:28]([CH:32]([CH3:33])[CH3:34])([CH:35]([CH3:36])[CH3:37])[CH:29]([CH3:31])[CH3:30])[CH:17]=4)[OH:15])=[CH:12][CH:13]=3)=[CH:44][CH:43]=2)[CH2:49][CH2:48]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc2F)c2c(C3CC3)ncnc21
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(Nc3ccc(C4CC4)nc3)nc2F)c2c(C3CC3)ncnc21
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To (6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-carbamic acid tert-butyl ester (81, 0.51 g, 0.77 mmol) in 12 mL of toluene, [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.13 g, 0.17 mmol) is added under nitrogen and the reaction stirred for 5 minutes. Cyclopropylmagnesium bromide (17, 15.29 mL, 0.50 M in tetrahydrofuran, 7.65 mmol) is added slowly and the reaction is heated at 65° C. for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (82, 400 mg).