Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[OH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1>CN(C=O)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Oc2ncc(Br)cn2)CC1
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-chloro pyrimidine (1.00 g, 5.17 mmol) and ethyl 4-hydroxycyclohexanoate (0.834 mL, 5.17 mmol) in DMF (20 mL) was added sodium hydride NaH (60% weight in mineral oil, 0.227 g, 5.69 mmol). The reaction mixture was stirred for 16 hours before being diluted with saturated aqueous sodium bicarbonate (50 mL), ethyl acetate (50 mL), and diethyl ether (50 mL). The layers were separated and the organic layer was washed with water (3×50 mL) and then brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to yield ethyl 4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate as a mixture of cis and trans isomers. MS ESI calc'd. for C13H18BrN2O3 [M+H]+ 329 and 331. found 329 and 331.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.CN1C2C=CC(C3NN=C(N)C=3)=CC=2N=C1.[O:33]1[CH2:35][CH:34]1[CH2:36][N:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1.CCN(C(C)C)C(C)C>CCO>[CH2:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:45][CH2:46][N:37]1[CH2:36][CH:34]([OH:33])[CH2:35][NH:16][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)[NH:15][N:14]=1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: Cn1cnc2ccc(-c3cc(N)n[nH]3)cc21
Agent: Cn1cnc2cc(-c3cc(N)n[nH]3)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1cnc2ccc(-c3cc(NCC(O)CN4CCc5ccccc5C4)n[nH]3)cc21
Yield: 4.1 %

Procedure:
A solution of 5-(1-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-3-amine and 5-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-3-amine (60 mg, 0.27 mmol), 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (54 mg, 0.27 mmol) and DIPEA (72 mg, 0.54 mmol) in EtOH (5 mL) was stirred overnight at 120° C. The mixture was concentrated and then purified by prep-HPLC and prep-TLC to give the desired 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((5-(1-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-3-yl)amino)propan-2-ol (4.5 mg, Yield 4.1%) 1H NMR (400 MHz, MeOD) 8.21-8.16 (m, 1H), 7.86 (s, 1H), 7.71-7.64 (m, 2H), 7.20-7.06 (m, 4H), 5.96 (s, 1H), 4.50-4.39 (m, 1H), 4.29-4.00 (m, 4H), 3.97-3.89 (m, 3H), 3.30-3.11 (m, 2H), 3.08-2.92 (m, 4H). LCMS: RT=0.788 min, M+H+=403.2.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1ccccn1
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccccn1

Procedure:
2-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine was alkylated with 2-chloromethylpyridine by method F and the crude product was deprotected by method H without purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>C(#N)C>[O:30]=[C:29]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3([CH3:28])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:11][CH2:10]2)[C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[NH:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@H]3N)CC2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
A solution of tert-butyl 4-[4-[[(1R,2R)-2-aminocyclohexyl]amino]-1-piperidyl]-4-methyl-piperidine-1-carboxylate in acetonitrile (20 mL) was added with 1,1′-carbonyldiimidazole (1.30 g, 8.0 mmol) and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue was taken up in water (20 mL) and dichloromethane (80 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified with preparative LC/MS (high pH) to give the title compound as white solid (849 mg, 30% over two steps). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.95 (s, 3H), 1.31-1.40 (m, 4H), 1.42 (s, 9H), 1.44-1.48 (m, 2H), 1.52-1.63 (m, 1H), 1.64-1.89 (m, 8H), 1.93-1.99 (m, 1H), 2.08-2.21 (m, 2H), 2.25-2.32 (m, 1H), 2.89-3.10 (m, 4H), 3.28-3.36 (m, 1H), 3.42-3.53 (m, 2H), 3.54-3.65 (m, 1H). MS (M+1): 421.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.CCN(C(C)C)C(C)C.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=1>CN(C=O)C.O>[CH3:17][N:11]1[C:6]2([CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:28]4[N:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=4)[CH:3]=3)[CH2:7]2)[C:14](=[O:15])[NH:13][C:12]1=[O:16]
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)NC(=O)N2C)ncn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
500 mg (2.16 mmol) 5′-amino-3-methyl-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-2,5-dione (Bioorg. Med. Chem. Lett.; 2006; 16; 24; 6165-6169) and 400 μL (2.33 mmol) DIPEA were added to 400 mg (2.14 mmol) ethyl 6-chloropyrimidine-4-carboxylate in 10 mL DMF and the reaction mixture was stirred for 8 h at 100° C. The reaction mixture was diluted with 60 mL water and stirred for 30 min. The precipitate was suction filtered and the filtrate was extracted with dichloromethane (3×40 mL). The organic phases were combined, dried on magnesium sulphate, filtered and evaporated down i.vac. The residue was dissolved in DMF and purified by preparative HPLC. The product fractions were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:37](F)(F)[C:38]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:37]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:38]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(C(F)(F)F)c1)CC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC3)cc1F

Procedure:
2-Fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}benzoic acid, m/z (ES+): 509.2 (M+H+.), was prepared in analogy to example 9, steps 1 to 5. Step 4 was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:2][C@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@@H]1CO
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(R)-hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and pyrrolidine. MS (M+H) 403.2
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
2-Amino-3-nitrophenol (0.5 g, 3.2 mmol) was dissolved in 10 mL 2-butanone, and potassium carbonate (0.54 g, 3.9 mmol) and methyl iodide (0.4 mL) were added. The suspension was stirred overnight at room temperature. The reaction mixture was filtered through a plug of Celite, and the solid residue was washed with ethyl acetate. The resulting filtrate was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.52 g of 2-methoxy-6-nitroaniline, which was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.74 (d, 1H), 6.87 (d, 1H), 6.61 (dd, 1H), 6.42 (b, 2H), 3.92 (s, 3H). MS (EI): 169 (MH+).
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=S)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[N:28]([CH2:31][C:32](=[O:34])[CH3:33])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]4[O:34][C:32]([CH3:33])=[CH:31][N:28]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(=O)CN=[N+]=[N-]
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C)o3)nc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 25 %

Procedure:
To a solution of N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 121B, 45.7 mg, 0.120 mmol) in dioxane (343 μL) was added 1-azidopropan-2-one (14.28 mg, 0.144 mmol) and triphenylphosphine (37.8 mg, 0.144 mmol). The contents of the flask were immersed into a preheated oil bath for 35 min and cooled to room temperature. The residue was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on an Isco 12 g column eluting with 1-10% MeOH/CH2Cl2. The pale yellow solid was taken up in MeOH and further purified by preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(5-methyloxazol-2-ylamino)-1,6-dihydro imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide was isolated (10 mg, 25% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[F:20][CH2:21][CH2:22][NH:23][C:24](=O)[O:25]C1C=CC=CC=1.O>CN(C)C=O>[F:20][CH2:21][CH2:22][NH:23][C:24]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:25]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: O=C(NCCF)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
Sodium hydride (60% in oil) (360 mg) was added to a solution of 2.0 g of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in 30 ml of dimethylformamide at room temperature. After stirring for 5 minutes, the mixture was placed in an ice bath and 1.8 g of phenyl N-(2-fluoroethyl)carbamate was added while cooling. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and extraction was performed with ethyl acetate. The extract was passed through a glass filter coated with silica gel. The ethyl acetate layer was washed once with sodium bicarnobate water and dried over magnesium sulfate. The drying agent was filtered off to obtain 1.93 g of a faint brown powder.
Reaction SMILES: C([Cl:4])(=O)C.Cl.C(OC([N:13]1[CH:18]([CH3:19])[CH:17]=[C:16]([CH3:20])[CH:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[O:14]1)=O)(C)(C)C>CO>[ClH:4].[CH3:19][CH:18]1[CH:17]=[C:16]([CH3:20])[CH:15]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=2)[O:14][NH:13]1
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(C2ON(C(=O)OC(C)(C)C)C(C)C=C2C)cc1
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C2ONC(C)C=C2C)cc1

Procedure:
Acetyl chloride (30 ml) was added dropwise over 10 mins to a cooled solution of methanol (300 ml) The resulting solution of hydrogen chloride in methanol was added to a stirred solution of 2-t-butoxycarbonyl-3, 6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1, 2-oxazine (11.6 g, 34.8 mmol) in methanol (50 ml). After 4 h at room temperature the mixture was evaporated to a solid (8.35 g), triturated with diethyl ether and the solid filtered to give 3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine hydrochloride.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Cl:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
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: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
HATU (458 mg, 1.21 mmol) was added to a solution of 6-chloro-3-pyridinecarboxylic acid (supplied by Aldrich) (174 mg, 1.10 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.437 ml, 2.50 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (308 mg, 1.0 mmol) was added and stirring was continued for 1.25 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 solution (20 ml each). The layers were separated and the aqueous layer was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in pentane, gave the title compound (439 mg) as a pale yellow gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:23][I:24]>>[I-:24].[CH3:23][P+:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: CI
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Product: Cc1ccc([P+](C)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Product: [I-]
Yield: 91.5 %

Procedure:
Starting from 10.37 g (34.1 mmol) of tris (4-methylphenyl)phosphine and 6.7 g (48 mmol, 1.4 eq) of methyl iodide, 13.92 g (31.2 mmol, 91.5%) of methyltris(4-methylphenyl)phosphonium iodide was obtained: mp 213°-216° C.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH2:9](Br)[C:10]#[CH:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[N+:1]([C:4]1[N:5]([CH2:11][C:10]#[CH:9])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a round bottom flask was added 2-nitroimidazole (500 mg, 4.42 mmol), propargyl bromide (631 mg, 5.31 mmol), potassium carbonate (733 mg, 5.31 mmol) and DMF (5 mL). The reaction was stirred overnight at RT. TLC (EtOAc) indicated complete reaction. The reaction was poured onto water (20 mL) and extracted into EtOAc (3×20 mL). The combined organics were washed with water (5×20 mL). The organic layer was then concentrated in vacuo and purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford 571 mg (85% yield) of 10 as a pale yellow solid. 1H NMR (CDCl3, 400 MHz), δ: 2.63 (1H, d, J=5.6 Hz), 5.23 (2H, d, J=2.4 Hz), 7.20 (1H, d, J=1.2 Hz), 7.46 (1H, s). Mass Spec (lo-res): Calc'd for C6H5N3O2: 151.04; found: 152.10 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:14]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=2)[CH:21]=1)(=[O:18])[C:15]([CH3:17])=[CH2:16].C(O)(=O)C(C)=C.C1(C=CC(O)=CC=1)O>C(N(CC)CC)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:30][C:24]2[CH:25]=[CH:26][C:27]3[C:22](=[CH:21][C:20]([O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:29][CH:28]=3)[CH:23]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)Oc1ccc2ccc(O)cc2c1
Reactant: C=CCOc1ccc(C(=O)Cl)cc1
Agent: C=C(C)C(=O)O
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(C(=O)Oc2ccc3ccc(OC(=O)C(=C)C)cc3c2)cc1
Yield: 95 %

Procedure:
In the same way as described in Example 2, 29.5 g (0.15 mol) of 4-allyloxybenzoyl chloride and 34.5 g (0.15 mol) of 2,7-naphthalenediol monomethacrylate (obtainable in a manner similar to that of the hydroquinone monomethacrylate referred to in Example 2 of U.S. Pat. No. 4,604,342) were reacted with triethylamine as acid scavenger. 7-Methacryloyloxy-2-naphthyl 4-allyloxybenzoate, C22H20O5, with an m.p. of 85° C. was obtained in 95% yield. The 1,4-, 1,5- and 2,6-disubstituted naphthalene derivatives can be prepared in the same way.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@H:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][C:26](O)=[O:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH2:58]([NH:65][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C@H:14]1[CH2:13][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:15]1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2[nH]cc([C@H]3C[C@H](NC(=O)OCc4ccccc4)C3)c2c1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[trans-N-(benzyloxycarbonyl)-3-aminocyclobutyl]indol-5-yl acetic acid (1g, 2.76 mmol) in DMF (5 ml) was added TBTU (0.97 g 3.04 mmol), Et3N (0.42 ml 3.04 mmol) and benzylamine (0.33 ml 3.04 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum and the residue chromatographed on Silica 5% MeOH/94% CHCl3 /1% 88O NH3 to give a pale yellow oil. yield: 0.81 g (80%) MS 468 (M+1), 392, 333.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23]CC2C=CC=CC=2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH2:5][CH3:6].C1COCC1>[Pd].CO>[OH:23][C:21]1[CH:20]=[C:10]([CH:9]=[C:8]([O:7][C@H:4]([CH2:3][O:2][CH3:1])[CH2:5][CH3:6])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12]
Reactant: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](COC)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 6 h
Yield: 102.5 %

Procedure:
To a solution of 3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (4.6 g, 11 mmol) in 1:1 THF:methanol (100 mL) was added 10% w/w palladium on carbon (450 mg) and the resulting mixture was stirred under an atmosphere of hydrogen for 6 hours. The atmosphere was replaced with argon and the mixture was filtered and evaporated to afford the title compound as a white solid (3.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[S:12]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CNCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 0.75 g (1.803 mmol) of the product of Example 51 in 5 mL of dichloromethane was added was added 2.0 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue was diluted with ether. The organics were washed with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.515 g (90%) of the amine as a colorless oil pure enough for use in the next step. Electrospray Mass Spec: 316.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.O[C:21]1C=CC(O)=C[C:22]=1C(=O)C.C(C1C=CC(C=O)=CC=1)C>>[CH2:21]([C:7]1[CH:6]=[CH:5][C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)=[CH:3][CH:2]=1)[CH3:22]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CCc1ccc(C=O)cc1
Product: CCc1ccc(C2CC(=O)c3cc(O)ccc3O2)cc1

Procedure:
2-(4-Ethylphenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 1.0 g of 2′,5′-dihydroxyacetophenone and 0.8 ml of 4-ethylbenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 7.43 (d, 2H, J 8.1 Hz), 7.25 (d, 2H, J 8.1 Hz), 7.11 (d, 1H, J 3.1 Hz), 7.03 (dd, 1H, J 8.9, 3.1 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.51 (dd, 1H, J 13.0, 2.9 Hz), 3.15 (dd, 1H, J −16.9, 13.0 Hz), 2.75 (dd, 1H, J −16.9, 2.9 Hz), 2.62 (q, 2H, J 7.5 Hz), 1.18 (t, 3H, J 7.5 Hz).