Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[C:10]3=[CH:9][C:8]=2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:20][CH:21]=1
Reactant: CC(=O)Cl
Reactant: CSc1nccc(-c2cc3c(N)n[nH]c3nc2-c2ccc(F)cc2)n1
Product: CSc1nccc(-c2cc3c(NC(C)=O)n[nH]c3nc2-c2ccc(F)cc2)n1

Procedure:
Following a similar procedure to that described in example 245, but starting from 3-amino-6-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)pyrazolo[3,4-b]pyridine (obtained in example 180) and acetyl chloride, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[O:15][CH3:16]>CO.[OH-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(=O)C(C)(C)c1ccc(F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)(C)C(=O)O)ccc1F
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of methyl 2-(4-fluoro-3-methoxyphenyl)-2-methylpropanoate (146 g) in MeOH (2 L) and 25% NaOH in H2O (590 mL) was heated at reflux for 5 h. The reaction mixture was then allowed to cool to room temperature and concentrated at reduced pressure. The residue was dissolved in H2O (2 L) and washed with ether (500 mL). The aqueous layer was acidified cautiously with conc HCl to pH 2. The resulting mixture was extracted with DCM (3 L), and combined extracts were dried over MgSO4, and concentrated at reduced pressure to give 2-(4-fluoro-3-methoxyphenyl)-2-methylpropanoic acid (95 g, 84% over 2 steps). 1H NMR (400 MHz, CDCl3): δ 7.06-7.00 (m, 2H), 6.93 (m, 1H), 3.90 (s, 3H), 3.86 (s, 2H), 1.60 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[O:9]1[CH2:13][CH2:12][N:11]=[C:10]1[C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[N:4][C:5]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([C:10]4[O:9][CH2:13][CH2:12][N:11]=4)=[CH:29][CH:28]=3)[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Reactant: Brc1ccc(Br)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A mixture of 4.1 parts of 3,6-dibromopyridazine, 4.34 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine, 6.4 parts of sodium carbonate and 1878 parts of N,N-dimethylformamide was stirred overnight at 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol 98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1.1 parts (16.4%) of 3-bromo-6-[4-[3-[4(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine; mp. 169.1° C. (comp. 75).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: Cn1c(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)nc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution containing the product from Example 59E (0.025 g, 0.070 mmol) in a mixture of THF (0.3 mL) and water (0.3 mL) was treated with lithium hydroxide monohydrate (0.004 g, 0.094 mmol), and the mixture was stirred at 25° C. for 18 hours. The solvent was concentrated to give the crude product, which was used without purification.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[CH3:25][N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:23][CH:24]=1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: O=C1CCc2ccccc21
Product: CN(C)CCCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Yield: 98.5 %

Procedure:
Interaction of 56 g of 1-indanone and 88 g of 4-(3-dimethylaminopropoxy)benzaldehyde according to the procedure described in Example 1A, gives 134.2 g of an oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCc1cccs1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) and 385 mg (2.00 mmol) methanesulfonic acid thiophen-2-ylmethyl ester in 20 mL DMF is added 451 mg (3.26 mmol) potassium carbonate at RT. The reaction mixture is stirred overnight at RT and is diluted with 60 mL of EtOAc. The organic phase is washed three times with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[C@H:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=3[OH:29])[CH2:5]2)[O:3]C1.Cl.O1CCCC1.[Cl-].[Na+]>CCOCC>[CH3:28][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C@H:6]2[C@H:7]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5]2)=[C:15]([OH:29])[CH:16]=1)([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(C)(C)c1ccc([C@@H]2CC3(CC[C@H]2CCCO)OCCO3)c(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)CC[C@H]2CCCO)c(O)c1
Yield: 82 %

Procedure:
A mixture of 4.0 g. (9.56 mmoles) of trans-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(3-hydroxypropyl)-cyclohexanone ethylene ketal, 50 ml. of 2N hydrochloric acid and 100 ml. of tetrahydrofuran was heated at reflux for 2 hours. The reaction was cooled and added to 500 ml. saturated sodium chloride and 250 ml. ether. The ether extract was separated and washed once with 500 ml. saturated sodium chloride, once with 500 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated (aspirator) to an oil. The crude oil was purified via column chromatography on 200 g. of silica gel eluted with 80% ether-hexane to yield 2.93 g. (82%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:12][CH:11]=[CH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC[Mg]Br
Reactant: O=Cc1cccc(Br)c1
Solvent: CCOCC
Product: C=CCC(O)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromobenzaldehyde (15.8 g, 85.6 mmol) in dry diethyl ether (200 mL) at 0° C. under nitrogen atmosphere with stirring is added allylmagnesium bromide solution in ether (85.6 mL, 85.6 mmol) dropwise. The resulting mixture is warmed to room temperature over 1 hr and is quenched by the addition of 1 N HCl aqueous solution. The reaction is extracted with dichloromethane, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with 0% to 100% dichloromethane in hexanes over 50 minutes to give the title compound as a racemic mixture (17.01 g, 88%). ES/MS m/e (79Br/81Br) 227, 229 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[C@@H:34]([CH:35]=[CH2:36])[CH2:33][O:32][C:31]1([CH3:38])[CH3:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C1CCCCC1)C1CCCCC1.CN(C)C=O>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:37][C:31]1([CH3:38])[N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C@@H:34](/[CH:35]=[CH:36]/[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([N:12]3[CH2:18][CH2:17][CH2:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[CH2:13]3)[CH:3]=2)[CH2:33][O:32]1
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reactant: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2cc(N3CCCc4ccccc4C3)nc3ccccc23)COC1(C)C
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 76.1 %

Procedure:
The mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (310 mg, 1.0 mmol), (S)-2,2-dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester (273 mg, 1.2 mmol), bis(tri-tert-butylphosphine)palladium(0) (51 mg, 0.1 mmol), methyl dicyclohexylamine (293 mg, 1.5 mmol) and N,N-dimethylformamide (6 mL) was heated with stirring in a 20 mL microwave process vial for 2.5 hours at 120° C. under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by flash column to give 380 mg of product as a white solid (yield was 76%). MS obsd. (ESI+) [(M+H)+] 500.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]3[CH2:13][CH:12]([CH2:14][OH:15])[O:11][CH:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[OH2:40]>C(Cl)Cl>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]3[CH2:13][CH:12]([CH2:14][OH:15])[O:11][CH:10]3[C:4]=2[CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O-:38])(=[O:37])=[O:40])=[CH:32][CH:31]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCC1CC2c3ccccc3Cc3ccc(F)cc3C2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[2R-(2α, 3aα, 12bβ)]-11-fluoro-2-hydroxymethyl-3,3a,8,12b-tetrahydro-2H-dibenzo [3,4:6,7]cyclohepta[1,2-b]furan (4.1 g, 0.0144 mol) was dissolved in DCM (20 ml). Triethylamine (0.0173 mol) was added and the mixture was cooled on an ice-bath. A solution of 4-methyl-benzenesulfonyl chloride (0.0159 mol) in DCM (10 ml) was added over ±5 min. The mixture was stirred for 2 hours at 0° C. then allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. Water (20 ml) was added. The layers were separated. The organic phase was stirred in a 10% aqueous potassium carbonate solution for one hour. The layers were separated. The organic layer was dried (MgSO4), filtered and the solvent evaporated. The residue was stirred in toluene (30 ml). A 10% aqueous potassium carbonate solution (30 ml) was added. The layers were separated. The organic layer was dried (MgSO4), filtered and the solvent evaporated, yielding 5.8 g (92%) of [2R-(2α, 3aα, 12bβ)]11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-methanol-4-methylbenzenesulfonate, intermediate 1. An alternative method of preparing this intermediate is described in W003/048146 [CAS number=543741-40-8].
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](COCC[Si](C)(C)C)[N:11]=[C:10]2[C:24]1[N:28](COCC[Si](C)(C)C)[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=1.C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH:28]1[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[N:25]=[C:24]1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:41])[CH:8]=2)[NH:12][N:11]=1
Reactant: CN(C)CCCNc1ccc2c(c1)c(-c1nc3ccccc3n1COCC[Si](C)(C)C)nn2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: CN(C)CCCNc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 70 °C

Procedure:
A solution of N,N-dimethyl-N′-{1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-propane-1,3-diamine in THF was treated with ethylene diamine (20 equivalents) and tetrabutylammonium fluoride (20 equivalents) and heated at 70° C. overnight. The resulting crude residue was purified by reverse phase HPLC to N′-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-N,N-dimethyl-propane-1,3-diamine. LC/MS (m/z) 335.1 (MH+), Rt 1.30 minutes.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.1 %

Procedure:
A mixture of ethyl 2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetate (0.463 g, 0.991 mmol), potassium hydroxide (0.224 g, 3.99 mmol) in THF (5 mL) and water (5 mL) was stirred for 40 minutes at room temperature then poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was dried for 15 hours at 80° C. to yield the title compound as a light yellow solid (0.314 g, 78%), mp 169–171° C. A sample was crystallized from acetonitrile for analysis. Mass spectrum (+APCI, [M+H]+) m/z 440; 1HNMR (400 MHz, DMSO-d6): δ13.8–14.2 (br, 1H), 8.75 (s, 1H), 8.45 (d, 1H, J=1.5 Hz), 7.75–7.8 (m, 2H), 7.7 (d, 1H, J=8.5 Hz), 7.6 (dd, 1H, J=8.7 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.25–7.35 (m, 5H), and 5.65 ppm (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:13]([F:12])([F:24])[F:25])=[O:23]
Reactant: O=C=Nc1ccccc1OC(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1OC(F)(F)F
Yield: 59.6 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.69 g, 60%). EI-MS m/z 358(M+H)+
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>CN(C=O)C.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)ccc1Cl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1-n1cncn1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To a solution of 2,5-dichlorobenzonitrile (10 g, 58.1 mmol) in DMF (100 ml) is added cesium carbonate (22.7 g, 69.8 mmol) and 1,2,4-triazole (4.8 g, 69.8 mmol) and the reaction mixture is stirred at 65° C. for 5.5 h, at 75° C. for 16 h, at 85° C. for 7 h. More 1,2,4-triazole (5 g) is added and the reaction mixture is stirred at 85° C. for 18 h and at 100° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The combined organic layer is washed with aqueous LiCl, dried on sodium sulfate, concentrated in vacuo to give 5-Chloro-2-[1,2,4]triazol-1-yl-benzonitrile as a white solid which is used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[CH2:15][O:16][CH3:17].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH3:17][O:16][CH2:15][CH:3]1[CH:2]([NH:1][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCC1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1CN(C(=O)OC(C)(C)C)CCC1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,1-dimethylethyl 4-amino-3-[(methyloxy)methyl]-1-piperidinecarboxylate D33 (0.7 g), and benzoyl chloride (490 mg, 3.5 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Fisher) were dissolved in dichloromethane (30 ml) and then triethylamine (1.3 ml, 8.7 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, then washed with water (2×), brine, dried with MgSO4, filtered and solvent removed to obtain a yellow oil of crude product which was purified by column chromatography on silica gel eluting with pet eth/EA (2/1) to give clean desired product D34 as a yellow oil in 0.8 g. LCMS [M-56+H] 293.1@1.62 min (5 min run)
Reaction SMILES: [F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3](Cl)=[O:4].[OH:38][C:39]1[CH:81]=[CH:80][C:42]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:56]4[CH:55]=[CH:54][C:53]([C:74]5[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=5)([C:63]5[CH:68]=[CH:67][C:66]([N:69]6[CH2:73][CH2:72][CH2:71][CH2:70]6)=[CH:65][CH:64]=5)[O:52][C:51]=4[CH:50]=3)=[CH:45][CH:44]=2)=[CH:41][CH:40]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:56]4[CH:55]=[CH:54][C:53]([C:74]5[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=5)([C:63]5[CH:68]=[CH:67][C:66]([N:69]6[CH2:73][CH2:72][CH2:71][CH2:70]6)=[CH:65][CH:64]=5)[O:52][C:51]=4[CH:50]=3)=[CH:47][CH:48]=2)=[CH:80][CH:81]=1)=[O:4]
Reactant: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 45.8 %

Procedure:
Solid 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-tricosafluorododecanoyl chloride (0.37 g, 0.58 mmol) was added to a solution of 6-[4′-(hydroxy)biphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[2,1-b]pyran (0.33 g, 0.58 mmol) in DCM (100 mL) containing 4-dimethylaminopyridine (0.05 g) and pyridine (2 mL) under N2 with stirring. The mixture was stirred at room temperature for 3 h, poured into HCl (2 M, 100 mL), extracted with EtOAc (3×30 mL), washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (60% in hexanes as eluent), the solvent removed under reduced pressure. Hexane was added and the resulting solid filtered to give the title compound (0.31 g, 46%) as a colourless powder, mp 129-130° C.
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.O.[CH3:13][N:14]1C(=O)CCC1>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.[C-]#N.[C-]#N.[Zn+2]>[Cl:11][C:10]1[C:2]([C:13]#[N:14])=[CH:3][C:4]2[N:8]=[CH:7][NH:6][C:5]=2[CH:9]=1
Reactant: Clc1cc2[nH]cnc2cc1Br
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc2nc[nH]c2cc1Cl
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 248 (550 mg, 2.38 mmol), Pd(PPh3)4 (275 mg, 0.238 mmol), and Zn(CN)2 (279 mg, 2.38 mmol) in NMP (10 mL) was stirred under nitrogen atmosphere at 120° C. for 18 h. The reaction mixture was poured into water (50 mL), extracted with EtOAc (3×20 mL), and concentrated to dryness in vacuo. The crude was purified by SiO2 chromatography eluting with DCM:MeOH (12:1) to afford 217 mg (51.5%) of 6-chloro-1H-benzo[d]imidazole-5-carbonitrile (250) as yellow solid (217 mg, 51.5%): MS (ESI) m/z=178.2 (M+1).