Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccccc1CCCC(Cc1ccccc1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCCC(N)Cc1ccccc1

Procedure:
A solution of 30f (crude 7.7 mmol) in MeOH (40 mL) was hydrogenated using 10% Pd/C (817 mg, 0.77 mmol) as catalyst at atmospheric pressure overnight. The catalyst was removed by filtration, and the solution was evaporated at reduced pressure to afford the crude desired product as yellow oil, which was used without further purification in the next step.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19]>CO>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3=[CH:1][CH:2]=[C:3]([OH:4])[C:5]4[O:9][C@H:8]5[C:10]([CH2:12][CH2:13][C@@H:14]2[C@:7]5([C:6]=43)[CH2:21][CH2:20]1)=[O:11]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 7 °C

Procedure:
A 1 L round bottom flask equipped with return condenser and nitrogen inlet was charged with methanol (650 mL) and morphine free base (50.0 g, 175.2 mmol). The mixture was stirred magnetically and heated to reflux under nitrogen until all morphine dissolves (45 min) then treated with the solution of the catalyst added via a cannula. The resulting brown solution was stirred and heated to reflux under nitrogen for 1 hour, then volume of the mixture was reduced to ca 400 mL by distillation. The resulting slurry was cooled to 7° C. in an ice bath, stirred at this temperature for 1 hour and filtered. The filtered solid was washed with isopropanol (3×60 mL) and dried in an oven at 95° C. to give hydromorphone free base as a white solid. The yield was 41.71 g, 83.4%.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[C:11](=[O:17])[NH:12][N:13]=[CH:14][C:15]=1[Cl:16].[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:15]1[CH:14]=[N:13][NH:12][C:11](=[O:17])[C:10]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]ncc(Cl)c1-c1ccccc1
Yield: 73.4 %

Procedure:
Phenyl magnesium bromide (prepared from bromobenzene (171 g), magnesium (38.8 g) and diethyl ether (1.6 l)) was slowly added to a stirred solution of 4,5-dichloro-3[2H]-pyridazinone (60 g) in tetrahydrofuran (1 l) cooled at water bath temperature. This mixture was stirred at room temperature for 30 minutes and hydrolysed with 20% ammonium chloride solution (800 ml) in the cold. The aqueous layer was extracted with diethyl ether and the combined organic extracts were washed with dilute hydrochloric acid, water, brine, dried (MgSO4) and evaporated under reduced pressure to give 5-chloro-4-phenyl-3[2H]-pyridazinone (55.13 g), m.p. 193°-5° C. on recrystallisation from ethyl acetate.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:14](=[O:17])[NH:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1COCC1>[CH:18]([NH:21][C:2]1[C:3]2[N:4]([C:14](=[O:17])[NH:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: O=c1[nH]nc2c(Br)nc(-c3ccccc3)cn12
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2ccccc2)cn2c(=O)[nH]nc12

Procedure:
A solution of 29 mg of the product of Step A and 118 mg of isopropylamine in THF (5.0 mL) was heated at reflux for 16 h. The reaction was concentrated to one-quarter volume, diluted with water, and the pH was adjusted to pH 2 with 2N HCl. The solid was collected and triturated for one h in isopropyl ether at 60° C. before being collected and dried to give the title compound as a tan solid. MS (M+H+)=270.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(F)cc1
Temperature: 82.5 °C

Procedure:
To a 5 mL round bottom flask fitted with a stir bar and septum was added 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2 4-dichlorophenyl]pyrimidine (85 mg, 0.16 mmol) as described in Reference Example 17, anhydrous potassium carbonate (66 mg, 0.48 mmol) and 4-fluorobenzeneboronic acid (44 mg, 0.32 mmol) in 1 mL 80/20 toluene/ethanol. The mixture was degassed under nitrogen with three freeze-thaw cycles and tetrakis(triphenylphosphine) palladium (27 mg, 0.024 mmol) was added to the reaction mixture and the mixture was heated between 75-90° C. for 4 h. The solvent was removed under reduced pressure and the residue flash chromatographed with 95/5 hexane/ethyl acetate to recover the desired product. HPLC/MS: m/e=477 (M+−1); Rt=4.54 min. 1H-NMR 500 MHz (CDCl3): δ 3.97 (s, 3H), 6.96 (m, 2H), 7.02-7.20 (m, 7H), 7.33 (d, J=2 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:34]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(F)cc1F
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(F)cc2F)c2ccccc2)c1
Yield: 37.2 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.2 g of 2-(2-amino-N-phenyl-acetamido)-N-(2,4-difluorophenyl)-N-methylacetamide and 0.46 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: dichloromethane/methanol (99-1 by volume)], collecting 15 cm3 fractions. Fractions 24 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diisopropyl ether, 0.6 g of N-(2,4-difluorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 100° C. is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8].I[CH:19]([CH3:21])[CH3:20].O>CC(C)=O.C(Cl)Cl>[C:7]([C:10](=[N:16][O:17][CH:19]([CH3:21])[CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=NOC(C)C)C(C)=O
Reaction time: 0.42 h

Procedure:
52 g of potassium carbonate were added to a mixture of 397.8 g of ethyl 2-acetyl-2-hydroxyiminoacetate in 200 ml of pure acetone cooled on an ice bath and then 25 ml of 2-iodopropane were added thereto over 25 minutes. The mixture was stirred for 2 hours and 800 ml of water and 500 of methylene chloride were added thereto. The mixture was stirred and decanted and the aqueous phase was extracted with methylene chloride. The mixture was dried and vacuum filtered and the filtrate was evaporated to obtain 41.5 g of ethyl 2-acetyl-2-(1-methylethoxyimino)-acetate.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=2[C:8]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]2[CH:22]=[C:21](C(F)(F)F)[CH:20]=[CH:19][N:18]=2)=[O:9])[N:3]=[CH:4][CH:5]=1.[F:31][C:32]([F:47])([F:46])C1C=CC(CC2CCCC2N)=NC=1.N1N(C2C=CC=CC=2C(O)=O)N=CC=1>>[N:3]1[N:2]([C:6]2[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=2[C:8]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:32]([F:47])([F:46])[F:31])=[CH:19][N:18]=2)=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: NC1CCCC1Cc1ccc(C(F)(F)F)cn1
Reactant: O=C(NC1CCCC1Cc1cc(C(F)(F)F)ccn1)c1ccccc1-n1nccn1
Agent: O=C(O)c1ccccc1-n1nccn1
Product: O=C(NC1CCCC1Cc1ccc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-N-(2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentyl)benzamide (Example 22) from 2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-amine (Intermediate 13; 33 mg, 0.14 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 31 mg, 0.16 mmol) and then was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:17][C:14]1[N:13]=[CH:12][C:11]([C:7]2[O:8][C:9]([CH3:10])=[C:5]([CH2:4][CH2:3][OH:2])[N:6]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)nc2)nc1CCO
Reaction time: 1 h

Procedure:
To a solution of [2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (4.0 g, 15 mmol) from step B in THF (50 mL) is added a solution of lithium aluminum hydride in THF (1.0 M, 12.5 mL, 12.5 mmol) at 0° C. After 1 hr, the reaction is quenched by water and sodium hydroxide, filtered, concentrated. The crude material is used for the next step.
Reaction SMILES: CCO.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[O:9][CH2:10][C:11](=O)[C:12]#[C:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O.Cl.[NH2:33][OH:34].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[O:9][CH2:10][C:11]1[CH:12]=[C:13]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[O:34][N:33]=1
Reactant: NO
Reactant: COc1ccc(OCC(=O)C#C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(OCc2cc([C@@H]3CCCN3)on2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 107 %

Procedure:
To an EtOH (10 mL) solution of the compound (390 mg) obtained in Example 14-(2), hydroxylamine hydrochloride (139 mg) was added and the mixture was heated under reflux for 20 hours. The reaction mixture was concentrated to give a brown oil, to which CHCl3 (1.0 mL) and TFA (5.0 mL) were added, followed by stirring at room temperature for 21 hours. After concentrating the reaction mixture, saturated aqueous sodium bicarbonate (50 mL) was added and the organic layer extracted with CHCl3 (50 mL×2) was dried (Na2SO4), filtered and concentrated to give the titled compound (326 mg, brown oil) as a mixture with impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CCO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), ethanol (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml ethanol. The cis to trans ratio is 82 to 85/18 to 15. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: [CH2:1]=[C:2]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4]>O1CCOCC1.[Pd]>[CH3:1][CH:2]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: C=C(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Yield: 99.2 %

Procedure:
A solution of α-methylenefluorene-2-acetic acid (2.6g.) in dioxane (50ml.) is hydrogenated in the presence of 5% palladium on charcoal (800mg.). The mixture is filtered and the filtrate evaporated to dryness. The residue is sublimed to afford the title compound (2.6g.). The analytical sample is prepared by recrystallization from aqueous methanol, mp 181°-182°.
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:25][C:26]1[CH:32]=[C:31]([O:33][C:34]2[C:43]3[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:27]=1[NH2:28].C1(C)C=CC=CC=1>C(O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:25][C:26]1[CH:32]=[C:31]([O:33][C:34]2[C:43]3[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:27]=1[NH:28][C:23]([NH:22][C:20](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[S:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Methoxy-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (36 mg, yield 45%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:20]([NH2:22])=[O:21])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C(Cl)(Cl)(Cl)Cl>[O:9]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH2:26][Br:1])[C:20]([NH2:22])=[O:21])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: Cc1ccc(C(N)=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(N)=O)ccc1CBr
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
N-Bromosuccinimide (NBS) (0.507 g, 2.85 mmol) was added to a solution of 3-t-butyldimethylsiloxy-4-methyl benzamide (Compound 7.1) in 30 mL CCl4. The mixture was irradiated with a 275 W sunlamp (Sears, #34-7105) at 60° C. Each irradiation took 10 minutes followed by 10 minutes to let the lamp cool down. It took 2 hours of irradiation over a period of 4 hours to complete the reaction. After the solvent was removed at reduced pressure, the residue was subjected to flash silica gel chromatography to yield the product as a white solid (0146 g, y=81.7%). 1H NMR (CDCl3) δ 0.318 (s,6H), 1.05 (s,9H), 4.51 (s,2H), 6.10 (b, 2H), 7.25 (d,J=7.8 Hz, 1H), 7.32 (s,1H), 7.39 (d,J=7.9 Hz, 1H); --C NMR (CDCl3 ) δ 4.08, 18.28, 25.76, 27.87, 117.99, 118.07, 119.49, 131.23, 132.54, 134.97, 168.46.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C@H:19]([O:21][CH2:22][C:23]3([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]>FC(F)(F)C(O)=O>[C:36]1([C:23]2([CH2:22][O:21][C@@H:19]([C:11]3[CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=3)[CH3:20])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OCC1(c2ccccc2)CCNCC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 4-((1-(4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (10 mg, 0.018 mmol) was dissolved in trifluoroacetic acid (33% in dichloromethane, 1.5 mL). The resulting solution was stirred at room temperature for 1 h and concentrated. The crude salt was loaded onto an SCX cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 7.2 mg (88%) as a colorless film. 1H NMR (500 MHz, CDCl3) δ ppm 7.73 (d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.38 (s, 2H), 7.20-7.35 (m, 4H), 7.16 (m, 1H), 4.29 (q, J=6.4 Hz, 1H), 3.46 (s, 1H), 3.33 (d, J=9.2 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.90 (m, 2H), 2.73 (m, 2H), 2.00-2.25 (m, 2H), 1.80-1.99 (m, 2H), 1.35 (d, J=6.4 Hz, 3H). Mass spec.: 465.20 (MH)+. Accurate mass spec.: m/z 465.2136 [MH]+, Δ=3.8 ppm.
Reaction SMILES: [C:1]([C@@H:4]1[N:8](C(OC)=O)[C@H:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]1)#[C:2][CH3:3].I[Si](C)(C)C>C(Cl)(Cl)Cl>[CH:1]([C@@H:4]1[NH:8][C@H:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]1)=[CH:2][CH3:3]
Reactant: CC#C[C@H]1CC[C@@H](C(=O)OC)N1C(=O)OC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC=C[C@H]1CC[C@@H](C(=O)OC)N1
Temperature: 25 °C

Procedure:
A solution of dimethyl (2S,5R)-5-propynyl-pyrrolidine-1,2-dicarboxylate (4.25 g, 18.90 mmol) and iodotrimethylsilane (3.23 mL, 22.7 mmol, Example 85A) in chloroform (60 mL) was heated to 65° C. for 3 hours, was cooled to room temperature, concentrated under reduced pressure and flash chromatographed with 35% ethyl acetate/65% hexane to provide the titled compound. MS (DCI/NH3) m/e 168 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N[C@@H]1CCCC[C@H]1N.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([NH2:39])=[O:38]>O1CCOCC1.[Cu]I>[CH3:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([NH:39][C:37]([C:33]3[O:32][CH:36]=[CH:35][CH:34]=3)=[O:38])=[CH:3][CH:4]=2)[N:9]=1
Reactant: NC(=O)c1ccco1
Reactant: Cc1nc(N2CCCC2)c2ccc(Br)cc2n1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc(N2CCCC2)c2ccc(NC(=O)c3ccco3)cc2n1
Yield: 21.9 %

Procedure:
A suspension of 0.12 g (0.41 mmol) of 7-bromo-2-methyl-4-pyrrolidin-1-yl-quinazoline, 3.9 mg (0.021 mmol) of copper (I) iodide and 0.267 g (0.82 mmol) of caesium carbonate in dioxane (5 ml) was treated at RT under argon with 4.7 mg (0.041 mmol) of trans-1,2-diaminocyclohexane and 0.18 g (1.6 mmol) of 2-furamide and then heated at reflux under argon for 20 h. The reaction mixture was partitioned between EtOAc and water, the layers were separated, the organic layer washed twice with water dried over sodium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (9:1:0.5) as eluent. Combination of the purified fractions and concentration in vacuo gave 29 mg (22%) of the furan-2-carboxylic acid (2-methyl-4-pyrrolidin-1-yl-quinazolin-7-yl)-amide as an off white solid. ISP mass spectrum, m/e: 323.4 (M+1 calculated for C18H18N4O2: 323).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][CH:3]1[OH:15].[OH-].[Na+].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.O>[OH:15][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[CH:2]1[NH:1][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][CH:20]=1)=[O:25]
Reactant: NC1c2cc([N+](=O)[O-])ccc2CCC1O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC1c2cc([N+](=O)[O-])ccc2CCC1O)c1ccc(-c2ccccc2)cc1

Procedure:
Stir a mixture of 1-amino-7-nitro-1,2,3,4-tetrahydronaphthalen-2-ol (500 mg, 2.40 mmol) and 1N NaOH (4.8 mL, 4.8 mmol) in a mixture of 50 mL of toluene and 50 mL of water for 30 minutes. Added biphenyl-4-carbonyl chloride (570 mg, 2.64 mmol) slowly and stir for four hours at room temperature. Remove the solid by filtration, and wash with toluene. Evaporate solvent under reduced pressure. Biphenyl-4-carboxylic acid (2-hydroxy-7-nitro-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide is obtained in 54% as a white solid: 1H NMR (DMSO-d6) δ 8.87 (1H, d, J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz), 7.99 (2H, d, J=7.6 Hz), 7.79 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz), 7.50 (2H, t, J=7.2 Hz), 7.43(2H, t, J=6.8 Hz), 5.22 (1H, d, J=4.4 Hz), 5.11 (1H, t, J=7.6 Hz), 3.95-4.01 (1H, m), 2.87-3,07(2H, m), 2.08-2.15 (1H, m), 1.81-1.94 (1H, m); MS 389(MH+). The above compound (0.25 g, 0.64 mmol) is reduced in 10 mL of DMF with 48 mg of 10% Pd-C at room temperature under 60 psi (414 kPa) for overnight to form biphenyl-4-carboxylic acid (7-amino-2-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, obtained in 96% as a yellow oil. MS 359 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]2([CH3:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].[Li+].[OH-]>CN(C=O)C.O>[O:19]1[C:15]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=4[CH:23]=3)=[CH:7][CH:6]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:16][N:17]=[CH:18]1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Reactant: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cnco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(COc3ccc([C@H](CC(=O)O)c4cnco4)cc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A mixture of 75.5 (0.1 mmol), 6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.12 mmol) and cesium carbonate (0.15 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added LiOH in water (1 mL, 1N solution), and the reaction was stirred at 50° C. for 3 hours. The mixture was filtered and purified by reverse phase HPLC to give 75 (12 mg, 0.03 mmol) after lyophilization. MS ESI (pos.) m/e 434.2 (M+H). 1H NMR (500 MHz) (CDCl3) δ 7.94 (s, 1H); 7.31-7.41 (m, 3H); 7.22 (d, J=8.5 Hz, 2H); 6.99 (d, J=8.5 Hz, 2H); 6.87 (s, 1H); 4.99 (s, 2H); 4.58 (t, J=7.9 Hz, 1H); 3.14 (dd, J=16.5, 7.6 Hz, 1H); 2.99 (dd, J=16.5, 7.6 Hz, 1H); 1.72 (s, 4H); 1.31 (s, 12H).