Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13][N:12]([C:32]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[O:33])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[OH:40][C:41]1([C:44](O)=[O:45])[CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17](=[O:30])[C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)[CH2:14][CH2:13][N:12]([C:32]([CH:34]3[CH2:39][CH2:38][N:37]([C:44]([C:41]4([OH:40])[CH2:43][CH2:42]4)=[O:45])[CH2:36][CH2:35]3)=[O:33])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)C1(O)CC1
Reactant: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3(O)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.1 %

Procedure:
To a solution of N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(piperidin-4-ylcarbonyl)piperidin-4-yl]-N-methyl-4-morpholin-4-ylbenzamide monohydrochloride (200 mg) obtained in Example 621, 1-hydroxycyclopropanecarboxylic acid (44.5 mg) and triethylamine (143 μL) in acetonitrile (5 mL) were added WSC.HCl (96 mg) and HOBt (76.8 mg), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (119 mg, 55%) as a white crystal powder.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C@H:21]([C@@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[CH2:20][C:19]1=[O:29].[CH:36](=[O:38])[CH3:37]>CCCCCC.O1CCCC1>[CH3:13][O:14][C:15]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C@H:21]([C@@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[C@@H:20]([C@H:36]([OH:38])[CH3:37])[C:19]1=[O:29]
Reactant: CC=O
Reactant: COc1ccc(CN2C(=O)C[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(CN2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Reaction time: 0.75 h

Procedure:
0.65 ml of a 1.7M solution of butyl lithium in hexane is added to a solution, cooled to -65°, of 111 mg (1.1 mmol) of diisopropylamine in 4 ml of tetrahydrofuran. The mixture is cooled to -78° and treated after 15 minutes with a solution of 321 mg (1 mmol) of (S)-1-(2,4-dimethoxy-benzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone in 1 ml of tetrahydrofuran. The mixture is stirred at -78° for 45 minutes and then a solution of 100 mg (2,27 mmol) of acetaldehyde in 0.5 ml of tetrahydrofuran is added dropwise within 3 minutes thereto, whereby the temperature rises to -70°. The mixture is stirred for 10 minutes, the cooling bath is removed, the reaction solution is treated with 2 ml of 14 percent aqueous ammonium chloride solution and extracted with 30 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on 10 g of silica gel with ethyl acetate/hexane (2:1) as the eluent. There is obtained (3S,4S)-1-(2,4-dimethoxybenzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-[(R)-1-hydroxyethyl]-2-azetidinone which is obtained as fine needles of melting point 145°-146° after crystallization from ethyl acetate/hexane.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([N:14]3[CH2:23][C@H:22]4[N:18]([CH2:19][CH2:20][CH2:21]4)[C:17]4[N:24]=[C:25]([S:28][CH3:29])[N:26]=[CH:27][C:16]=4[C:15]3=[O:30])[CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=1)#[N:2].[OH-:31].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:29][S:28][C:25]1[N:26]=[CH:27][C:16]2[C:15](=[O:30])[N:14]([C:10]3[CH:9]=[C:8]([C:6]4[O:7][C:3]([C:1]([NH2:2])=[O:31])=[CH:4][N:5]=4)[CH:13]=[CH:12][CH:11]=3)[CH2:23][C@H:22]3[N:18]([CH2:19][CH2:20][CH2:21]3)[C:17]=2[N:24]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncc(C#N)o3)c1)C2=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncc(C(N)=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
(S)-5-[3-(5-Cyano-1,3-oxazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (140 mg, 0.334 mmol) obtained in Step 3 of Example 125 was dissolved in ethanol (5 mL), and the mixture was stirred at room temperature for 2 hours after adding a 2 mol/L aqueous sodium hydroxide solution (1.67 mL, 3.34 mmol). The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-5-carboxamide (50.3 mg, 34%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH3:10].[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([F:9])[C:3]=1[CH3:10]
Reactant: Cc1c(F)ccc(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)cc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
To 2,3,6-trifluorotoluene (55 g) is added conc. sulfuric acid (366 ml) and the mixture is cooled to 0° C. Thereto a solution of potassium nitrate (44 g) in conc. sulfuric acid (120 ml) is added dropwise at below 10° C. and then the mixture is stirred for 15 minutes. The mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off to give 2,3,6-trifluoro-5-nitrotoluene (68.25 g), as yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][CH2:13][C:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: C1CCNCC1
Reactant: O=C(O)CCC1CCc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2CCC1CCC(=O)N1CCCCC1
Yield: 86.2 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-oxo-2-naphthalenepropanoic acid (6.3 g), piperidine (3.7 g) and BOP Reagent (15.4 g) in dichloromethane (150 ml) was added dropwise triethylamine (3.5 g) at 25° C., and the mixture was refluxed for three hours. The reaction mixture was washed successively with water and 10% hydrochloric acid, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (7.1 g) as an oily product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([C:10]([C:13]2[NH:17][CH:16]=[N:15][N:14]=2)([CH3:12])[CH3:11])[N:3]=1.Br[CH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[CH:19]([C:13]1([C:10]([N:4]2[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]2)([CH3:12])[CH3:11])[N:17]=[CH:16][NH:15][NH:14]1)([CH3:21])[CH3:20]
Reactant: Cc1nn(C(C)(C)c2nnc[nH]2)cc1[N+](=O)[O-]
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1nn(C(C)(C)C2(C(C)C)N=CNN2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-4H-1,2,4-triazole (1.3 g, 5.5 mmol) in CH3CN (30 mL) was added 2-bromopropane (813 mg, 6.60 mmol) and Cs2CO3 (1.79 g, 5.50 mmol). The mixture was stirred at 50° C. overnight. After cooling down, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to afford the title compound (1.06 g, 70%). LC-MS (ESI): m/z=279 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][OH:25])[CH:5]=[CH:6][CH:7]=1.[CH3:26]C(C)([O-])C.[Na+].CI.Cl>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(CCCO)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CC(C)(C)O
Product: CCn1c(=O)c(CCCOC)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 60 °C
Yield: 34.6 %

Procedure:
To a 10 ml tert-butanol solution containing 500 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one were added 300 mg of sodium tert-butoxide and 0.2 ml of methyl iodide successively, followed by stirring under heating at an oil bath temperature of 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, water and 1M hydrochloric acid were added thereto, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from diisopropyl ether to obtain 180 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-methoxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: C[C:2]1([O:23][C@@H:22]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:4]1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3].[BH4-].[Na+].CC(C)=O.C(O)(=O)C>C(O)C>[CH2:6]([O:5][C@@H:4]([C@@H:13]([C@H:22]([CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:23])[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:2][OH:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1(O)O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Methyl 2,3,5-tri-O-benzyl-L-xylofuranose (11.7 g, 27.92 mmol) is dissolved in ethanol (150 mL) and sodium borohydride (0.844 g, 30.5 mmol) was added. The mixture is stirred 2 hours at 0° C. The reaction is treated successively by acetone and acetic acid. The mixture is concentrated under reduced pressure. The residue is taken with water, extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 1:1 mixture of hexane and ethyl acetate yield 2,3,5-tri-O-benzyl-L-xylitol (10.2 g, 86.5%) as an oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:21]=[C:20]2[C:33]1[N:34]=[N:35][N:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)[CH:37]=1.[N:52]1[NH:53][C:54](=[O:58])[CH:55]=[CH:56][CH:57]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl>[N:46]1([C:44]([C:41]2[CH:42]=[CH:43][C:38]([N:36]3[CH:37]=[C:33]([C:20]4[C:19]5[C:23](=[CH:24][CH:25]=[C:17]([CH2:16][N:53]6[C:54](=[O:58])[CH:55]=[CH:56][CH:57]=[N:52]6)[CH:18]=5)[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:21]=4)[N:34]=[N:35]3)=[CH:39][CH:40]=2)=[O:45])[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(CO)ccc21
Reactant: O=c1cccn[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(Cn3ncccc3=O)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIAD (0.30 mL; 1.54 mmol; 2.3 eq.) was added dropwise over 1 min to a solution of tert-butyl 5-(hydroxymethyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-1-carboxylate (340 mg; 0.67 mmol; 1.0 eq.), 3(2H)-pyridazinone (100 mg; 1.04 mmol; 1.5 eq.) and triphenylphosphine (354 mg; 1.35 mmol; 2.0 eq.) in DCM (15 mL). The reaction mixture was stirred for 4 h at RT then poured into HCl (0.1N solution) and extracted with DCM. Combine organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (gradient 20:80 to 90:10, MeOH pure) to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.52 (s, 1H), 8.19 (d, J=8.6 Hz, 2H), 8.13 (d, J=8.7 Hz, 1H), 7.98 (dd, J=1.6, 3.9 Hz, 1H), 7.77-7.61 (m, 3H), 7.45 (dd, J=3.9 Hz, 1H), 7.01 (dd, J=9.5 Hz, 1.6, 1H), 5.46 (s, 2H), 3.76-3.35 (m, 8H), 1.69 (s, 9H). HPLC (Condition A): Rt 3.74 min (purity 91.1%). MS (ESI−): 483.4.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:70]([O:74][C:75](=[O:85])[NH:76][CH2:77][CH2:78][CH:79]1[CH2:80][CH2:81][N:82]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:83][CH2:84]1)([CH3:73])([CH3:71])[CH3:72]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 2,6-Bis-(4-cyano phenoxy)-nicotinic acid, 0.335 g (0.94 mmol), in 5 ml of DMF was added dropwise to the stirred suspension of 0.489 g (0.94 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) in 5 ml of DMF and followed by N,N-diisopropylethylamine 0.242 g (1.88 mmol) while the temperature was maintained below 5° C. during the addition. The mixture was stirred for 10 min and a solution of (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.214 g, 0.94 mmol) in 2 ml of DMF was added. The mixture was stirred overnight at RT. The solvent was concentrated under reduced pressure and the residue was dissolved in a mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2-3 with 6 N HCl and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with 10% solution of potassium hydrogen sulphate followed by saturated sodium bicarbonate solutiona and saturated brine solution, and dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.4 g of the required product. Percentage purity: 36.3%, (M+1)=567.2. 1H NMR (DMSO-d6): δ 1.35 (3H, m), 1.38 (9H, s), 1.65 (2H, m), 2.71 (2H, m), 2.95 (4H, m), 3.75 (2H, m), 6.80 (1H, t), 6.95 (1H, d), 7.32 (4H, d), 7.68 (1H, m), 7.85 (4H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]([CH2:19][OH:20])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:24]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]([CH2:19][O:20][CH3:24])=[C:10]([CH:21]([CH3:23])[CH3:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(C=O)c(C(C)C)c1CO
Product: COCc1c(C(C)C)nc(-c2ccc(F)cc2)c(C=O)c1C(C)C

Procedure:
3.15 g (96% of theory) of colorless crystals of m.p. 77° C. (from MeOH) are obtained from 3.15 g (10 mmol) of the compound from Example 122 in analogy to the instructions from Example 59
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH2:36])(=[O:35])=[O:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:26]([CH2:25][CH2:24][NH:23][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:21])([CH3:22])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:31]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: NCCc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(NCCc3cc(Cl)ccc3S(N)(=O)=O)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (100 mg, 0.31 mmol), 2-(2-amino-ethyl)-4-chloro-benzenesulfonamide (150 mg, 0.64 mmol) and DIEA (80 mg, 0.62 mmol) in THF (4 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title compound (53.3 mg, 0.060 mmol, 26% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.18-8.00 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.50-7.34 (m, 2H), 4.41-4.23 (m, 1H), 3.89-3.51 (m, 2H), 3.41-3.33 (m, 2H), 3.29-3.22 (m, 1H), 2.04-1.80 (m, 1H), 1.80-1.68 (m, 2H), 1.67-1.38 (m, 3H), 1.05-0.93 (m, 6H). MS (ESI) m/z 479.1, 481.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11](=[O:25])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5]1.[C:26]([OH:37])(=O)[C:27]1[CH:35]=[CH:34][CH:33]=[C:29]([C:30]([OH:32])=O)[CH:28]=1>>[NH2:1][CH2:2][CH2:3][NH:4][C:30]([C:29]1[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=1)[C:26]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11](=[O:25])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5]1)=[O:37])=[O:32]
Reactant: NCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Product: NCCNC(=O)c1cccc(C(=O)NCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1

Procedure:
The title compound was prepared following a similar procedure as described in Example 13, by substituting the appropriate biphenyl-2-ylcarbamic acid 1-(aminoethyl)piperidin-4-yl ester in place of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester and substituting isophthalic acid in place of terephthalic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)=[CH:3][CH:2]=1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NCC1CCCCC1
Reactant: CC1(C)CN(Cc2ccncc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccncc2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(4-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (5.8 mg, 19%) having the following characteristics.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.O.C[N+]1([O-])CC[O:16]CC1.[NH4+].[Cl-].CCOC(C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:16]
Reactant: Fc1ccc(CBr)c(Br)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)cc1Br
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of the benzyl bromide of Step 1 (59 g, 220 mmol) in dioxane (500 mL) at r.t. was added N-methylmorpholine N-oxide monohydrate (89 g, 660 mmol). The reaction mixture was stirred for 1 hour at 70° C. and poured into a mixture of saturated aqueous NH4Cl and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4 and concentrated to give 44 g of the title compound as a white solid and used as such.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.P(Cl)(Cl)(Cl)=O.O>ClCCCl>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([C:11]([F:13])([F:14])[F:12])=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1F
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 35 °C
Yield: 92.6 %

Procedure:
To a solution of 266 g of 3-chloro-2-fluoro-6-trifluoromethylbenzamide in 2.5 liters of 1,2-dichloroethane was added 339 g of phosphorus oxychloride and then the mixture was heated at reflux for 18.5 hours. After cooling, the solution was gradually added into 2 liters of water maintained at 30-40° C. to hydrolyze the excess amount of phosphorus oxychloride and was then separated. The aqueous layer was extracted with chloroform, and the extract was combined with the organic layer previously obtained, washed with IN aqueous solution of sodium hydroxide, water and saturated saline solution in series, and then dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude product obtained was washed with chilled n-hexane and then filtered to obtain 228 g of the title compound(mp. 43-44° C.).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[CH3:17])[O:8][CH:7]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[CH3:28][C:29](CC(O)=O)=[O:30]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([O:18][C:29](=[O:30])[CH3:28])=[CH:12][C:13]=3[CH3:17])[O:8][CH:7]=2)=[CH:19][CH:20]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)cc2occ(-c3ccc(O)cc3)c(=O)c12
Reactant: CC(=O)CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2coc3cc(OC(C)=O)cc(C)c3c2=O)cc1
Temperature: 107.5 °C
Yield: 91 %

Procedure:
A mixture of 4′,7-dihydroxy-5-methylisoflavone (1.51 g, 5.6 mmol), acetic anhydride (9 ml) and pyridine (1.7 ml) was heated in an oil bath at 105-110° C. for 1 h. After cooling the mixture to room temperature, it was stirred for a further 30 min during which time the diacetate crystallised from the solution. The product was filtered, washed thoroughly with water and recrystallised from methanol to yield 4′,7-diacetoxy-5-methylisoflavone as colourless prisms (1.8 g, 91%). m.p. 195-97° C., 1H NMR (CDCl3): δ 2.32 (s, 3H, OCOCH3), 2.35 (s, 3H, OCOCH3), 2.87 (s, 3H, Me), 6.92 (bs, 1H, H8), 7.12 (bs, 1H, H5), 7.16 (d, 2H, J 8.7 Hz, ArH), 7.55 (d, 2H, J 8.7 Hz, ArH), 7.89 (s, 1H, H2).