Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[O:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[Br:19]Br>ClCCl>[Br:19][C:10]1[O:11][C:12]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCc1cccc2c(-c3ccccc3)coc12
Reactant: BrBr
Solvent: ClCCl
Product: OCCc1cccc2c(-c3ccccc3)c(Br)oc12
Reaction time: 0.08 h

Procedure:
To a solution of 3.0 g. (0.0126 mole) of 7-(2-hydroxyethyl)-3-phenylbenzofuran in 50 ml. of dichloromethane is added dropwise 2.1 g. of bromine. After stirring for five minutes the mixture is evaporated, benzene is added to the residue and it is evaporated again. The residue is mixed with petroleum ether and crystallizes. Recrystallization from hexane gives 2-bromo-7-(2-hydroxyethyl)-3-phenylbenzofuran, m.p. 108°-112° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[ClH:30].O1CCOCC1>ClCCl>[ClH:30].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccco3)c2)COC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(c2cccc(NC(=O)c3ccco3)c2)COCC(N)=N1
Temperature: 40 °C

Procedure:
A solution of (5-{3-[(furan-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (39.9 mg, 0.1 mmol) in dichloromethane was treated with 4M HCl in dioxane (40 eq). The mixture was warmed to 40° C. for 10 h and then evaporated under reduced pressure to yield the title compound (hydrochloride salt) in the form of a colourless solid. 1H-NMR (500 MHz, DMSO-d6): 10.65 (1H, NH), 10.31 (s, 1H), 9.14 (br, 1H), 8.52 (br, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.77 (d, 1H), 7.40 (m, 2H), 7.18 (d, 1H), 6.72 (m, 1H), 4.59 (s, 2H), 3.87 (dd, 2H), 1.64 (s, 3H); MS: 300 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 50.5 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol) 4-(acetyl)benzoic acid, 16.5 mg (50.5%) of the title compound were recovered.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:19]=[CH:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([CH3:20])=[N:10]3)[N:7]=1)(=O)C.[BrH:21]>>[Br:21][CH2:5][C:6]1[CH:19]=[CH:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([CH3:20])=[N:10]3)[N:7]=1
Reactant: Br
Reactant: CC(=O)OCc1ccc2ccc3ccc(C)nc3c2n1
Product: Cc1ccc2ccc3ccc(CBr)nc3c2n1
Yield: 42 %

Procedure:
The acetate (21) was dissolved in 60 mL of 31% HBr in HoAc and refluxed for 4 hours. After cooling, all the solvent was removed in vacuo. The resulting black residue was suspended in a mixture of CH2Cl2 and dilute aqueous NaHCO3. Four 200 mL CH2Cl2 extracts removed the desired bromide from the insoluble material floating at the solvent interface. After drying over Na2SO4 and removal of the solvent, the dark residual solid was relatively pure phenanthroline (22) containing a trace amount of 2,9-dimethyl-1,10-phenanthroline. The dark impurities were removed by chromatography on silica gel using CH2Cl2 as the eluent which gave 3.5 g (42%) of 22. 1H NMR (CDCl3) 2.9 (s, 3H); 4.94 (s, 2H); 7.43 (ABq, 1H, J=9 Hz), 7.6 (s, 2H); 7.8 (ABq, 1H, J=9 Hz); 7.97 (ABq, J=9 Hz); 8.1 (ABq, 1H, J=9 Hz).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>Cl>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC(=O)OC(CCc2ccc(C(=O)O)c(F)c2)(C2CCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Methyl 4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorobenzoate (example B(5)) (300 mg) was treated with 4N NaOH (10 ml) and stirred for 4 hrs at room temperature. The mixture was then acidified with 1N HCl (20 ml) and the product was extracted with ethyl acetate (2×20 ml). The combined organic layers were dried over magnesium sulfate and concentrated to a solid. The solid was recrystallised from diethyl ether to afford the title compound as a white solid (120 mg). 1H NMR (300 MHz, MeOD): δ 1.38-2.30 (m, 11 H), 2.80-3.12 (m, 6 H), 6.91 (d, J=7.19 Hz, 1 H), 7.17 (m, 1 H), 7.86 (d, J=719 Hz, 1 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[OH:22][CH:23]1[CH2:26][N:25]([C:27](=[O:29])[CH3:28])[CH2:24]1.CC(C)([O-])C.[K+]>CN(C)C=O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:22][CH:23]2[CH2:26][N:25]([C:27](=[O:29])[CH3:28])[CH2:24]2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(=O)N1CC(O)C1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), 1-(3-hydroxyazetidin-1-yl)ethan-1-one (1 g, 8.69 mmol) and potassium t-butoxide (500 mg, 5.21 mmol) in N,N-dimethylformamide (5 mL) kept under nitrogen in a 30-mL sealed tube was stirred overnight at room temperature. The reaction mixture was filtered through a frit filter and the filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 160 mg (29%) of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one as a yellow solid. LC-MS: m/z=+403 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([O:18][C:19]([N:21]1[C@@H:25]([C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23][C@H:22]1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([OH:43])=O)=[N:39][CH:40]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:25]1[CH2:24][CH2:23][C@@H:22]([CH2:34][C:35]2[CH:40]=[N:39][C:38]([C:41]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:43])=[CH:37][CH:36]=2)[N:21]1[C:19]([O:18][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:20]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCN(Cc4ccccn4)CC3)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 0.018 g (0.102 mmol) of (1-(pyridine-2-ylmethyl)piperazine and 0.035 g (0.085 mmol) of 5-{((2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl)methyl}pyridine-2-carboxylic acid in 2 mL of N,N-dimethylformamide was added 0.074 mL (0.425 mmol) of N,N-diisopropylethylamine and 0.065 g (0.170 mmol) of HATU. The resulting mixture was stirred under an atmosphere of nitrogen for 3 h and then purified directly by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[CH3:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]([CH3:33])=[O:32])[CH:27]=[CH:26][C:25]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:31](=[O:32])[CH3:33])=[CH:29][C:24]=2[CH3:23])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Br)c(C)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c(C)c1
Temperature: 90 °C
Yield: 20.3 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 4-bromo-3-methylacetanilide (0.228 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.020 g) in ethanol (3 ml) with heating at 90° C. for 2 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane, then by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution to give the title compound as an oil (0.041 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.NC(N)=[S:14].[OH-].[K+].[OH-].[Na+]>O.C(O)C>[SH:14][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: NC(N)=S
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccnc(S)c1
Yield: 51 %

Procedure:
To 1.0 g of 2-chloro-4-trifluoromethylpyridine (Lancaster Chemical Co) is added 10 ml of absolute ethanol and 417 mg of thiourea. The reaction mixture is heated at reflux for 4 hours and 1.25 ml of a solution of 7.44 g KOH in 20 ml of water is added. The solution is heated at reflux for an additional 1 hour. The reaction solution is cooled and poured into 100 ml of a 0.1N NaOH solution. The resulting solution is extracted three times with 100 ml of methylene chloride and the resulting aqueous solution is acidified to pH 4 by addition of glacial acetic acid. The aqueous solution is extracted three times with 100 ml of methylene chloride and the organic solution is dried over anhydrous sodium sulfate. Filtration followed by evaporation to dryness gives 501 mg of a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[C:6]=1[C:7](=[O:9])[NH2:8].[H][H]>[Pd].CO>[NH2:1][C:2]1[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[C:6]=1[C:7](=[O:9])[NH2:8]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc([N+](=O)[O-])cc2)c(C(N)=O)c1N
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(-c2ccc(N)cc2)c(C(N)=O)c1N
Yield: 105.4 %

Procedure:
0.075 g (0.216 mmol) of tert-butyl 2-amino-3-carbamoyl-4-(4-nitrophenyl)-pyrrole-1-carboxylate is added at a temperature in the region of 25° C. to a suspension of 0.008 g (0.0076 mmol) of 10% palladium on carbon in 12 cm3 of methanol. After hydrogenating for 17 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.072 g of tert-butyl 2-amino-4-(4-aminophenyl)-3-carbamoylpyrrole-1-carboxylate, in the form of a yellow solid; 1H NMR (400 MHz, (CD3)2SO, —δ in ppm); 1.55 (s: 9H); from 4.80 to 5.35 (very broad m: 1H); 5.22 (broad s 2H); 6.32 (s: 1H); from 6.40 to 6.85 (very broad m: 1H); 6.60 (broad d, J=8.5 Hz: 2H); 6.99 (broad d, J=8.5 Hz: 2H); 7.01 (broad s: 2H).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([O:28][CH3:29])[CH:25]=[CH:26][C:27]=1/[N:15]=[N:14]/[C:11]1[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: COc1cccc(OC)c1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: COc1ccc(/N=N/c2ccc(S(F)(F)(F)(F)F)cc2)c(OC)c1
Yield: 97.7 %

Procedure:
Diazonium salt 1 (9.8 mg, 0.030 mmol) in 1 mL of 95% aqueous ethanol was added to a solution of 1,3-dimethoxybenzene (8.7 mg, 0.063 mmol) in 0.5 mL of 95% aqueous ethanol. After 2 weeks, the solvent was evaporated to give a red oil, whose purification by SiO2 column chromatography (1:1 hexane/CH2Cl2) afforded 27a as orange crystals (10.8 mg, 98%); m.p. 88.0-88.5° C. IR (ATR): {tilde over (v)}=2943, 1600, 1496, 1471, 1294, 1253, 1211, 767 cm−1. MS (GC, EI): m/z=368 [M+], 241 [M+-SF5], 165 [M+-C6H4SF5]. 1H NMR (500 MHz, CDCl3): δ=7.89 (d, J=9.0 Hz, 2H), 7.86 (d, J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.56 (dd, J=9.0, 2.4 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=164.8 (C), 159.5 (C), 154.4 (C), 154.1 (C), 136.7 (C), 126.9 (2CH), 122.5 (2CH), 118.2 (CH), 105.9 (CH), 98.9 (CH), 56.3 (CH3), 55.7 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=84.3 (quint, J=150 Hz, 1 F), 63.2 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: C[Si](C)(C)[CH2:3][CH2:4][O:5]CCl.[N+:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[N:15]=CC(=O)[NH:18]2)([O-:12])=[O:11]>O1CCCC1>[N+:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[NH:15][C:4](=[O:5])[CH:3]=[N:18]2)([O-:12])=[O:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1cnc2c([N+](=O)[O-])cccc2[nH]1
Solvent: C1CCOC1
Product: O=c1cnc2cccc([N+](=O)[O-])c2[nH]1

Procedure:
Chloromethyl 2-(trimethylsilyl)ethyl ether (10.0 mL, 56.3 mmol) was added to tetrahydrofuran solution (500 mL) containing a mixture (21.6 g) of the 5-nitroquinoxalin-2-one derivative and the 8-nitroquinoxalin-2-one derivative obtained in the above (1), and then sodium hydride (2.30 g, 60% dispersion in oil, 57.3 mmol) was added thereto under ice-cooling. After the resulting reaction solution was stirred at room temperature for 1.5 hours, aqueous ammonium chloride solution was added thereto, and the mixture was extracted with chloroform. After the organic layer was washed with saturated brine, it was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. To the resulting residue was added 4N hydrogen chloride/1,4-dioxane solution (100 mL), and the solution was stirred at room temperature for 1 hour. After removal of the insolubles by filtration, the filtrate was concentrated in vacuo. The resulting residue was purified by a column chromatography on silica gel to obtain the above 5-nitroquinoxaline-2-one derivative (11.6 g) protected with SEM, as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 60 °C
Yield: 32.6 %

Procedure:
To a solution of methyl 4-[6-(3-fluoropyridin-4-yl)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-2-yl]benzoate (Example 10, 0.041 g, 0.097 mmol) in a mixture of THF/ethanol 1:1 (1.2 mL), 2N sodium hydroxide aqueous solution (0.1 mL) was added. The mixture was heated at 60° C. for 3 h and then neutralised with 2N hydrogen chloride aqueous solution. The solvent was evaporated and the crude mixture was purified by silica gel flash chromatography (78:10:10:2 dichloromethane/ethanol/ethyl acetate/acetic acid) to give the title compound (0.013 g, 31% of yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:17][C:16]=2[F:29])=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=2)[S:10][N:9]=1>>[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][C:16]=2[F:29])=[C:11]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2snc(Cl)c2COc2c(F)cc(CCCO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 156 following Step 2 by LAH reduction of ethyl 3-(4-((3-chloro-5-(4-ethylphenyl)isothiazol-4-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.51 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.80 (d, J=9.2 Hz, 2H), 5.08 (s, 2H), 3.58 (t, J=6.4 Hz, 2H), 2.63-2.75 (m, 4H), 1.80-1.84 (m, 2H), 1.30 (t, J=7.6 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H20ClF2NO2S, 424.1 (M+H). found 424.1.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[CH:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: [H][H]
Product: c1ccc(C2CCCCC2)cc1

Procedure:
In the embodiment illustrated in FIG. 7, phenol process 700 comprises: Step 710: treating hydrogen stream 702 and recycle stream 704 to at least partially remove at least one impurity and form stream 708; optional Step 720: treating benzene stream 706 to at least partially remove at least one impurity to form stream 711; Step 730: hydroalkylating streams 708 and 711 to form at least some cyclohexylbenzene in stream 733; Step 740: oxidizing at least a portion of the cyclohexylbenzene in stream 733 to form cyclohexylbenzene peroxide in stream 744; Step 750: cleaving the cyclohexylbenzene peroxide in stream 744 to form at least some phenol and cyclohexanone in stream 755; and Step 760: dehydrogenating at least a portion of the cyclohexanone in stream 755 to form at least some additional phenol in stream 766 and at least some hydrogen in recycle stream 704.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[CH3:5][OH:6]>>[CH:1]([O:4][C:5]([CH2:3][C:1]1[O:4][C:1]([CH3:3])([CH3:2])[O:4][C:5](=[O:6])[CH:2]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: CO
Product: CC(C)OC(=O)CC1=CC(=O)OC(C)(C)O1

Procedure:
The reaction was carried out in the same manner as in Example 2 except that 10 mL of isopropyl alcohol was used as the alcohol in lieu of methanol. The reaction mixture was treated in the same manner as mentioned above and the organic layer obtained by phase separation was dried and concentrated to give 0.999 g of nearly pure 6-isopropoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. The yield of 6-isopropoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one was 74 mol% based on the starting material 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. The NMR spectrum data on this compound are shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([C:19]2[S:23][C:22]([C:24]([CH:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)([OH:26])[CH3:25])=[N:21][CH:20]=2)[CH:3]=1.[O-:32][C:33]#[N:34].[K+].O.Cl>O1CCCC1>[OH:26][C:24]([CH:27]1[CH2:31][CH2:30][N:29]([C:33]([NH2:34])=[O:32])[CH2:28]1)([C:22]1[S:23][C:19]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=3)[N:5]=2)=[CH:20][N:21]=1)[CH3:25]
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCNC3)s2)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCN(C(N)=O)C3)s2)c1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To the solution of 1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol (20 mg, 0.044 mmol, 1:1 mix of diastereomers) in tetrahydrofuran (0.4 mL) was added potassium cyanate (25 mg, 0.308 mmol), water (1.2 mL) and HCl (2 M in water, 0.14 mL, 0.280 mmol). The mixture was stirred at 55° C. for 3 hours then cooled to room temperature. The mixture was purified on reversed phase HPLC (Sunfire prep C18 OBD 5 uM, acetonitrile/water+0.1% TFA) to afford 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxamide as a 1:1 mixture of diastereomers. MS ESI calc'd. for C22H23F3N6O2S [M+H]+ 493. found 493. 1H NMR (500 MHz, CD3OD) δ 8.65-8.60 (m, 1H, two sets of doublets overlap from two diastereomers), 8.39 (d, 1H, two singlets from two diastereomers), 7.86 (s, 1H), 7.51 (d, 1H, two singlets from two diastereomers), 7.46-7.42 (m, 1H, two sets of doublets overlap from two diastereomers), 7.05 (s, 1H), 3.65-2.82 (m, 5H, two sets of peaks from two diastereomers), 2.50 (s, 3H), 2.20-2.00 (m, 2H), 1.69 (s, 3H). rhSyk activity=+++.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]1([CH2:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:3][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:24]=1)[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: Oc1cccc(CN2CCCCC2)c1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC(O)COc1cccc(CN2CCCCC2)c1

Procedure:
18.7 g (0.092 mole) of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione are mixed with 17.5 g (0.092 mole) of 3-(1-piperidinylmethyl)-phenol and the resulting mixture heated for 10 minutes to 130° C. After cooling, the reaction mixture is dissolved in 200 ml of chloroform and the organic phase is washed three times in succession with 30 ml of 1N NaOH-solution, then with 30 ml of water and finally with 30 ml of saturated aqueous NaCl-solution. After the organic phase has been dried over Na2SO4, it is concentrated in vacuo. The residue contains the title compound in the form of a viscous oil.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]3[NH:19][C:20](=[O:22])[NH:21][C:13]3=[CH:12][C:11]=2[CH:10]=1>CO.CN(C)C=O>[OH:3][CH:4]([CH3:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]3[NH:19][C:20](=[O:22])[NH:21][C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: CC(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Sodium borohydride (1.00 g, 26 mmol) was added portionwise to a stirred suspension of 1,3-dihydro-7-(4-oxopentoxy)-2H-imidazo[4,5-b]quinolin-2-one (3.70 g, 13 mmol) in methanol (85 mL) and dimethylformamide (85 mL). The mixture was stirred at room temperature for 3 hours and then the solvent removed in vacuo. The residual oil was triturated with water (50 mL) and the solid material filtered off, washed with water and dried in air. Crystallization from aqueous dimethylformamide followed by trituration with methanol afforded 1,3-dihydro-7-(4-hydroxypentoxy)-2H-imidazo[4,5-b]-quinolin-2-one (3.20 g, 86%), m.p. 301°-303° C.