Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][CH:19]=[O:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1.O.[O-:30]Cl=O.[Na+].Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][C:19]([OH:30])=[O:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1
Reactant: CCCC1(CC=O)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
To a solution of [8-fluoro-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetaldehyde (8) (99 mg, 0.255 mmol) in DMSO (3.5 mL) was added a solution of NaH2PO4 in H2O (0.36 mL of 0.7 M in H2O, 0.255 mmol) at room temperature. To the mixture was added a solution of NaClO2 in H2O (1.52 mL of 0.5 M in H2O, 0.765 mmol). After stirring for 20 hours at room temperature, the mixture was acidified with HCl. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give 77 mg (75%) of title compound as a white solid. Mp=98–100° C.; HRMS (ESI) [M+H]+ calculated for C21H26FN2O5 405.1820, found 405.1821; 1H NMR (DMSO-d6): 300 MHz δ 12.30 (bs, 1H), 11.45 (s, 1H), 6.95–6.85 (m, 2H), 3.92 (m, 2H), 3.66 (m, 2H), 3.45 (m, 1H), 3.15 (m, 1H), 2.94 (d, J=10.2 Hz, 2H), 2.70 (d, J=10.2 Hz, 2H), 2.59 (m, 1H), 2.57 (s, 1H), 2.51 (m, 2H), 1.99 (t, J=5.10 Hz, 2H), 1.31 (m, 1H), 0.86 (m, 1H), 0.08 (t, J=5.10 Hz, 3H). LCMS retention time: 2.073 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[N:11][OH:12])[NH2:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[C:25]([C:31](OC2C=CC(F)=CC=2)=O)[NH:26]3)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[N:10]=[C:31]([C:25]3[NH:26][C:27]4[C:23]([CH:24]=3)=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)[CH:30]=[CH:29][CH:28]=4)[O:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(Cl)cc1)=NO
Reactant: CN1CCN(c2cccc3[nH]c(C(=O)Oc4ccc(F)cc4)cc23)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3[nH]c(-c4nc(Cc5ccc(Cl)cc5)no4)cc23)CC1
Yield: 4.4 %

Procedure:
To a stirred solution of (4-chlorophenyl)acetamidoxime (2.21 g from above, assumed 10 mmol, 15 equivalents) and sodium hydride (60% in oil, 0.460 g, 11.5 mmol, 17 equivalents) in anhydrous tetrahydrofuran (25 mL) was added crude 4-methyl-1-(2-(4-fluorophenoxycarbonyl)-1H-indol4-yl)piperazine (0.225 g from above, assumed 0.68 mmol), and the resulting reaction mixture was heated at reflux under nitrogen for 6 hours. A saturated solution of sodium hydrogen carbonate (25 mL) was added, and the resulting aqueous mixture was extracted with ethyl acetate (2×25 mL). The organic extracts were combined, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 25 g) and elution with methylene chloride/methanol/ammonium hydroxide [10:1:0.1] to afford the title compound (0.013 g, 0.03 mmol, 4%) as an off-white foam: 13C NMR (acetone-d6) δ170.3, 169.5, 147.2, 139.7, 135.0, 132.3, 130.7, 128.5, 126.2, 121.5, 119.9, 107.0, 106.4, 106.2, 55.3, 51.2, 45.5, 31.0; LRMS (m/z, relative intensity) 409 ([M+ with 37Cl], 30), 408 (27), 407 ([M+ with 35Cl], 100), 392 (7), 337 (23), 322 (16), 170 (16), 70 (41); HRMS calculated for C22H22ClN5O [with 35Cl] 407.1516, found 407.1516.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:6]([CH3:21])[N:5]=[C:4](N)[CH:3]=1.[I:23]CI.C(ON=O)(C)(C)C>CC#N>[I:23][C:4]1[N:5]=[C:6]([CH3:21])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(N)nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Reactant: ICI
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1cc(I)nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.2 %

Procedure:
4,6-Dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.41 g, 1.4 mmol), KI (2.30 g, 13.9 mmol), and diiodomethane (4 mL, 49.6 mmol) were combined and stirred at RT. The suspension was treated with tert-butylnitrite (1.0 mL, 8.3 mmol) and the reaction mixture was stirred at RT for 12 h. The mixture was diluted with MeCN (10 mL), additional tert-butylnitrite (1.0 mL, 8.3 mmol) was added and stirring was continued at RT for 24 h. The reaction mixture was partitioned between EtOAc (120 mL) and sat. NaHCO3 (aq) (20 mL). The aqueous phase was collected and the organic phase was washed with sat. NaHCO3 (aq) (2×20 mL), 10% Na2S2O3(aq) (2×20 mL), and brine (2×20 mL). The combined aqueous washes were back-extracted with EtOAc (2×20 mL) and the combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/DCM) to afford 6-iodo-2,4-dimethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.24 g, 43%) as an off white solid that was used in the next step without further purification. MS (ESI) m/z: 407.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[C:9]([CH3:10])=[CH:14][N:15]([CH3:16])[CH3:17])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)c1ccc(Cl)cc1
Product: CC(=CN(C)C)C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 50.0 g of p-chloropropiophenone and 200 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 28 hours. The reaction mixture was evaporated in vacuo to give a yellow oil. The oil was then subjected to Kugelrohr distillation. The residual oil from the distillation was collected and triturated with hexane to provide crystals. The solid was collected by filtration and gave 21.5 g of 4'-chloro-3-dimethylamino-2-methylacrylophenone as yellow crystals, mp 45°-47° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([OH:25])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:24])[CH2:22]O)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:28](Cl)(OC1C=CC=CC=1)([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:26])([CH3:27])[C@@H:14]([OH:25])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:24])[CH2:22][PH:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)CO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C[PH](=O)Oc1ccccc1

Procedure:
Following the general procedure for phosphorylation of Description 23, (2-hydroxyacetyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (45) (40 mg, 0.10 mmol) dissolved in 2 mL of anhydrous dichloromethane (DCM) was reacted with 60 L (78 mg, 0.29 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of pyridine (15.6 μL, 15.3 mg, 0.19 mmol) and triethylamine (TEA) (13.5 μL, 9.8 mg, 0.10 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude title compound (53a) was obtained and used in the next step without purification. MS (ESI) m/z 646.05 (M+H)+, 668.02 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[N:13]1([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(N)CN>C(#N)C.CO.C(Cl)Cl>[C:22]([CH2:21][CH:20]([N:24]1[CH:28]=[C:27]([C:29]2[C:30]3[CH:37]=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:26]=[N:25]1)[CH2:19][N:13]1[CH2:14][CH2:15][N:16]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:8])[CH2:17][CH2:18]1)#[N:23]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cc2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Cyanobenzoyl chloride (7.91 mg, 0.0478 mmol), 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (from example 1, step 4; 0.02 g, 0.0398 mol) and triethylamine (16.6 μL, 0.119 mmol) were dissolved in acetonitrile (0.2 mL). The mixture was stirred at RT for 1 h. Solvents were evaporated and the crude product was treated with DCM (0.2 mL) and trifluoroacetic acid (0.2 mL, 0.002 mol) for 30 min. The reaction mixture was concentrated under reduced pressure. To the residue was added methanol (1 mL) and ethylenediamine (0.1 mL, 0.001 mol) and the resultant mixture was stirred at RT for 30 min and evaporated under reduced pressure. The residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 30 mL/min) to give the desired product. LCMS calculated for C25H24N9O(M+H)+: m/z=466.2; Found 466.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:19]1([CH2:25][CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([CH2:25][CH:26]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=CCc1ccccc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=CCc1ccccc1
Yield: 69.3 %

Procedure:
To a solution of 12.15 mL (45.78 mmol) of t-butyldiethylphosphonoacetate in 100 mL of THF under argon at 25° C. is added 1.83 g (45.78 mmol) of 60% NaH in oil dispersion. The reaction mixture is stirred at 25° C. for 45 minutes at which time 5.41 mL (41.62 mmol) of phenylacetaldehyde is added. After 30 minutes at 25° C. the reaction is partitioned between 1 N HCl and ethyl ether. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash silica gel chromatography affords 6.3 g (69%) of t-butyl 4-phenylbut-2-enoate as a yellow oil.
Reaction SMILES: [Li].Br[CH:3]1[CH:7]2[CH2:8][CH2:9][CH:4]1[CH2:5][CH2:6]2.[C:10](=[O:12])=[O:11]>O1CCCC1>[CH:7]12[CH:3]([C:10]([OH:12])=[O:11])[CH:4]([CH2:9][CH2:8]1)[CH2:5][CH2:6]2
Reactant: O=C=O
Reactant: BrC1C2CCC1CC2
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(O)C1C2CCC1CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-4′-di-t-butylbiphenyl (8.25 g, 31 mmol) in anhydrous tetrahydrofuran (70 mL) under a nitrogen atmosphere was added freshly cleaned lithium wire (0.21 g, 30 mmol). The resulting mixture was stirred at room temperature for 15 minutes to initiate reaction, then cooled in an ice bath and stirred for an additional 4 hours. The resulting blue solution was cooled with a dry ice/acetone bath and a solution of 7-bromo-bicyclo[2.2.1]heptane (2.0 g, 11.4 mmol) in anhydrous tetrahydrofuran (5 mL) was added in one portion. The reaction mixture was stirred for 20 minutes, during which time the blue color changed to orange. Solid dry ice was then added to the reaction, which became colorless. The dry ice bath/acetone bath was removed and the reaction was stirred for 2 hours, during which time it came up to room temperature. 2.5 N aqueous sodium hydroxide (200 mL) was added and the mixture was stirred for 5 minutes. The layers were separated and the aqueous layer was extracted twice with diethyl ether (50 mL). The aqueous layer was then made acidic by addition of concentrated HCl and extracted with three portions of diethyl ether (75 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to yield the desired compound of formula (VIII) as a white solid (1.54 g, 96%), mp=74–75 ° C. (lit. mp=77.5–785° C., J. Am. Chem. Soc. 1954, 76, 4072).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][C:5]=1[CH3:15].Cl[CH2:17][CH2:18][OH:19].Cl>O>[OH:19][CH2:18][CH2:17][O:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][C:5]=1[CH3:15]
Reactant: Cc1cc(C(O)C(=O)O)ccc1O
Reactant: OCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(O)C(=O)O)ccc1OCCO
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.0 g (200 mmol) of sodium hydroxide in 15 ml of water is added dropwise over a period of one hour to a solution of 18.2 g (100 mmol) of 4-hydroxy-3-methylmandelic acid (Example 13), 4.0 g (100 mmol) of sodium hydroxide and 13.4 ml (200 mmol) of 2-chloroethanol in 60 ml water heated to 70° C. Another 6.7 ml (100 mmol) of 2-chloroethanol and 4.0 g (100 mmol) of sodium hydroxide in 10 ml of water are then added. After another 15 minutes, the reaction mixture is acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organic phases are washed with water, combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. This gives 23.0 g (about 100%) of 4-(2-hydroxyethoxy)-3-methylmandelic acid as a yellowish resin (compound (203), Table 2).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([C@@H:18]([CH2:27][O:28]C(=O)C2C=CC=CC=2)[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:37]1[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]1=[O:39])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@H:8]([C@@H:18]([CH2:27][OH:28])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@@H:6]([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H]([C@@H](COC(=O)c2ccccc2)OCc2ccccc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H]([C@@H](CO)OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of nucleoside 15 (3.00 g, 4.88 mmol) in methanol (50 cm3) was added sodium methoxide (0.79 g, 14.7 mmol). The reaction mixture was stirred for 14 h at room temperature and subsequently neutralised with dilute hydrochloric acid (5 cm3) whereupon ice-cold H2O (50 cm3) was added. The resulting mixture was extracted using ethyl acetate (3×100 cm3) and the combined organic phase was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v) as eluent to give nucleoside 16 as white solid material (2.00 g, 88%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:19][NH2:20])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl[C:22](OCC)=[O:23]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[C:22]([OH:23])[NH:20][N:19]=1
Reactant: NN=C(Cc1ccnc2ccccc12)c1ccccn1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: Oc1[nH]nc(-c2ccccn2)c1-c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-pyridin-2-yl-2-quinolin-4-yl-ethylidene)-hydrazine (2.0 g, 7.6 mmol) in pyridine (20 mL) at 0° C. is added ethyl chloroformate (2 mL) dropwise. The mixture is warmed to room temperature and stirred for 2 h. The solution is refluxed for 12 h and concentrated in vacuo. The residue is treated with dichloromethane/methanol and the precipitate collected by vacuum filtration. The precipitate is triturated with ethanol to yield the title compound, 300 mg (13%), as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16](Br)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.Cl[Pd]Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[Cl:25])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(Br)c3O2)cc1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Temperature: 100 °C
Yield: 53 %

Procedure:
A solution of (8-bromo-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate, prepared in Example 37, step 5 (1.0 g, 2.42 mmol) and 2-chlorophenylboronic acid (1.14 g, 7.26 mmol) in dioxane (18 mL) was added a solution of potassium carbonate (1.0 g, 7.26 mmol) in water (6 mL) and the mixture purged with nitrogen for 20 minutes. Trans-dichlorobis(tri-o-tolylphosphine)palladium (II) (95 mg, 0.12 mmol) was added and the reaction mixture heated at 100° C. for 2 hours. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and 2.0 M aqueous sodium hydroxide (100 mL). The organic layer was separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane gave 0.57 g (53%) of [8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a white solid. HRMS: calcd for C23H18ClFO4S+NH4+, 462.09366. found (ESI, [M+NH4]+), 462.0916.
Reaction SMILES: [CH:1]([C:9]1[C:17]2[CH2:16][CH2:15][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:12]=2[NH:11][N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[N:29][CH:28]=1.CC1SC(C(N2C3C(=CC=C(OC4C=C([NH-])C=CC=4)C=3)C(C=CC3C=CC=CC=3)=N2)=O)=NC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:20]=[C:21]([NH:25][C:32]([C:30]4[S:31][C:27]([CH3:26])=[CH:28][N:29]=4)=[O:33])[CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(OC2=Cc3[nH]nc(C=Cc4ccccc4)c3CC2)c1
Reactant: Cc1cnc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cnc(C(=O)n2nc(C=Cc3ccccc3)c3ccc(Oc4cccc([NH-])c4)cc32)s1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)Nc2cccc(Oc3ccc4c(C=Cc5ccccc5)n[nH]c4c3)c2)s1

Procedure:
3-(3-Styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine was converted to 5-methyl-thiazole-2-carboxylic acid (3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxy]-phenyl amide by treatment with 5-methyl-thiazole-2-carboxylic acid and HATU (o-(2-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) in DMF and analogous work-up, DDQ treatment and isolation to Example 4(a), step (iv) (50% yield): 1H NMR(DMSO-d6) δ 10.85 (s, 1H), 8.45 (d, 1H, J=9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7547.34 (m, 5H), 6.96 (d, 1H, J=8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)CCC>[F:13][C:12]([F:15])([F:14])[C:4]1[N:3]=[C:2]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Reactant: NCc1ccc(-c2ccccc2C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(O)c1ccccc1-c1ccc(CNc2nc(C(F)(F)F)nc3c2CCCC3)cc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
To 10 mL of n-butanol were added 0.526 g of 4-chloro-5,6,7,8-tetrahydro-2-trifluoromethylquinazoline, 0.408 g of 4' aminomethyl-(1,1'-biphenyl)-2-carboxylic acid and 1.1 g of sodium acetate. The resulting mixture was refluxed for 3 days, cooled to room temperature and all solvents were removed by evaporation. The residue was taken up in ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to yield an off-white solid which was purified by silica chromatography to yield the desired product (0.39 g, 59%). The compound was characterized as its sodium salt: 1H NMR (DMSO-d6, 400 MHz) δ 7.88 (t, J=6.0 Hz, 1H), 7.39 (m, 2H), 7.28 (m, 3H), 7.17 (m, 3H), 4.60 (d, J=5.9 Hz, 2H), 2.61 (m, 2H), 2.38 (m, 2H), 1.74 (m, 4H); negative FAB-MS m/e 448(M-H), 426(M-Na). Anal. calcd for C23H19F3N3NaO2.1.0H2O: C, 59.10; H, 4.53; N, 8.99. Found: C, 59.03; H, 4.48; N, 9.09.
Reaction SMILES: [Na].O=[C:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH:6]([CH2:11][CH2:12]O)[C:5]([CH3:14])=[CH:4]1.CC12[O:24][CH2:23][CH2:22]C1C(C)(C)CC=C2.CC12OCCC1C(C)(C)CC(=O)C2>>[CH3:14][C:5]1[CH:6](/[CH:11]=[CH:12]/[C:23]([CH3:22])=[O:24])[C:7]([CH3:10])([CH3:9])[CH2:8][CH2:3][CH:4]=1
Reactant: CC1=CC(=O)CC(C)(C)C1CCO
Reactant: CC1(C)CC=CC2(C)OCCC12
Agent: CC1(C)CC(=O)CC2(C)OCCC12
Agent: [Na]
Product: CC(=O)/C=C/C1C(C)=CCCC1(C)C

Procedure:
Identification has been carried out by mass spectrum as stated above. The composition can be characterized by the presence of compounds 1 [2-(4-hydroxy-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and 2 [2-(4-keto-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and especially 3 [1,5,5-trimethyl-9-oxa-bicyclo[4.3.0]non-2-ene] and 4 [1,5,5-trimethyl-9-oxa-bicyclo[4.3.0]nonan-3-one]. (See Table A).
Reaction SMILES: [B:1]12[B:4]3[B:5]4[B:2]1[C:3]234.[O-2:6].[O-2].[Ti+4:8].[CH4:9].[C-]#[Si+]>CO>[B:1]12[B:4]3[B:5]4[B:2]1[C:3]234.[O-2:6].[O-2:6].[Ti+4:8].[C:9]
Reactant: C
Agent: [Ti+4]
Agent: B12B3B4B1C234
Agent: [C-]#[Si+]
Solvent: CO
Product: [C]

Procedure:
To the boron carbide powder, 14.5 mol % of the submicron-size or nano-size titanium dioxide powder and 21.5 mol % of carbon black were incorporated, and using a methanol solvent, mixing was carried out by a planetary ball mill made of silicon carbide (SiC) at a rotational speed of 270 rpm for 1 hour, followed by drying by a evaporator and further by drying at 150° C. for 24 hours. Then, the mixture was sieved through a sieve with an opening of 250 μm to obtain a boron carbide-titanium dioxide-carbon mixed powder.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=3)=[CH:17][C:16]=2F)=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NC1C=CC(OC2C=CN=C(C(=[S:45])N)C=2)=CC=1>>[C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28](=[S:45])[NH2:29])[CH:23]=3)=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C#N)c3)cc2F)ncn1
Reactant: NC(=S)c1cc(Oc2ccc(N)cc2)ccn1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C(N)=S)c3)cc2)ncn1

Procedure:
The title compound was prepared in the same manner as described for 1-(6-tert-butylpyrimidin-4-yl)-3-[4-(2-cyanopyridin-4-yloxy)-2-fluorophenyl]urea, replacing 4-(4-amino-3-fluorophenoxy)pyridine-2-car-bonitrile for 4-(4-aminophenoxy)pyridine-2-thioamide. 1H-NMR (DMSO-d6) δ 10.32 (broad s, 1H), 10.20 (broad s, 1H), 10.13 (s, 1H), 9.93 (broad s, 1H), 9.72 (s, 1H), 8.74 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.7 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.64 to 7.60 (m, 2H), 7.21 to 7.17 (m, 2H), 7.12 (dd, J=5.7, 3.0 Hz, 1H), 1.26 (s, 9H); LC-MS m/z 423 [M+H]+, RT=3.39 min.