Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]([OH:16])=[O:15])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.N.[CH2:23](O)[CH3:24]>>[CH2:23]([O:15][C:14]([C:10]12[CH2:11][CH:12]1[CH2:13][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9]2)=[O:16])[CH3:24]
Reactant: O=C(O)C12CC1CN(Cc1ccccc1)C2
Reactant: CCO
Agent: N
Agent: O=S(=O)(O)O
Product: CCOC(=O)C12CC1CN(Cc1ccccc1)C2

Procedure:
To a suspension of 3-benzyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (8.5 gm, 0.0390 mole), (prepared as described in EP 0413455A2) in ethyl alcohol (250 ml) was added conc. H2SO4 (10 ml). The resulting pale yellow solution was heated at reflux for 2 hours, cooled to 0° C. and neutralized with aqueous ammonia. The neutralized solution was concentrated and was dissolved in dichloromethane. The organic layer was washed with saturated NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and was concentrated to give the crude product which was further purified by column chromatography (100-200 mesh, silicagel), eluting the compound with 5% ethyl acetate in hexane to give the pure product as yellow oil.
Reaction SMILES: BrBr.COC1C=CC2C(=CC=CC=2)C=1.Br.Br[C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:28][CH3:29]>CC(O)=O.O.[Fe]>[CH3:29][O:28][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[CH:17]=1
Reactant: COc1ccc2cc(Br)ccc2c1Br
Agent: [Fe]
Agent: Br
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2cc(Br)ccc2c1
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
A solution of 81 g of bromine in 25 cm3 of CH3COOH was added over 35 minutes to a very well stirred suspension of 39.25 g of 2-methoxy-naphthalene in 125 cm3 of glacial CH3COOH, heated to 30° C., keeping the temperature at 40°-45° C., avoiding that the formed hydrobromic acid leaves the reaction medium; when the addition was over, the bulk was stirred for 1.5 h at 45° C. in order to complete the reaction. 14 g of iron in the form of powder were then added, in small doses, over 1.5 hours, slowing down at intervals the reaction exothermicity by means of a cold bath; one stirred at 45° C. till 1,6-dibromo-2-methoxy-naphthalene disappeared (on thin layer chromatography) and then the bulk was diluted with 0.5 liters of H2O. Then the compound was filtered, washed with H2O and dissolved in CH2Cl2 ; lastly the chloromethylenic solution was washed with NaOH at 5%, dehydrated and evaporated. 55.2 g of raw 2-methoxy-6-bromo-naphthalene were obtained; after a crystallization from 250 cm3 of isobutanol, 45 g of pure product were obtained (gas-chromatographic analysis) having a melting point ranging between 105° and 106° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1/[C:11](/[CH3:20])=[CH:12]/[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[Cl-].[NH4+].O1CCCC1.CO>[Fe].O>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1/[C:11](/[CH3:20])=[CH:12]/[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: CCCCOC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)/C=C(\C)c1ccc(N)cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Compound 5a (1.05 g), iron powder (1.11 g), and ammonium chloride (0.32 g) were added to a mixed solution of tetrahydrofuran (4 ml), methanol (4 ml), and water (4 ml). The mixture was stirred at 60° C. for 2 hours. The same amount of iron powder and ammonium chlorides were further added thereto, and the obtained mixture was stirred at 70° C. for 1 hour. After the reaction mixture was allowed to cool, and filtered, insoluble substances were filtered through Celite. The filtrate was condensed under reduced pressure to give Compound 5b (939 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15](=[N:17]O)[CH3:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.N.[Ni]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:16])[NH2:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C)=NO)cc1OC1CCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(C(C)N)cc1OC1CCCC1
Yield: 100.1 %

Procedure:
A solution of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone oxime (15.3 g) in methanol/ammonia (350 ml) was hydrogenated for 3 hours with Raney nickel (3 g) as a catalyst. After uptake of H2, the catalyst was filtered off, washed with methanol and the filtrate was evaporated. Toluene was added and azeotroped on the rotary evaporator, yielding 14.45 g (100%) of (±)-3-(cyclopentyloxy)-4-methoxy-α-methylbenzene-methanamine (interm. 5).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:20](Cl)[N:21]=[CH:22][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:29])[CH2:25][CH:26]([CH3:27])[CH3:28])=[C:20]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:32])[CH:38]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:30])[C:13]1=[O:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)CC(O)c1c(Cl)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CC(O)c1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 25 °C
Yield: 25.9 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (See Compound 48, step 1, 100 mg, 0.212 mmol), 3-chlorophenyl boronic acid (66 mg, 0.424 mmol), aq. 2M K3PO4 (0.53 ml, 1.06 mmol) in dioxane (1 mL) and water (0.2 mL) was added Pd(dppf)Cl2 (5 mg, 0.0068 mmol). The reaction was degassed with nitrogen (3×), heated at 120° C. (MW) for 1.5 h, cooled to RT, diluted with EA (2 mL) and water (2 mL) then filtered through Celite. The filtrate was concentrated to a residue which was purified by Prep TLC PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenyl)-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 26% yield) as colorless oil. LCMS: MH+ 546 and TR=2.569 min.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[C:5]=1[C:6]([OH:8])=[O:7].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>O1CCCC1>[Cl:16][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Sc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
An ice-cooled suspension of 3.0 g (0.125 mol) of oil-free sodium hydride in 100 ml of tetrahydrofuran was treated portionwise during ten minutes with 12.2 g (0.052 mol) of 2,6-dichloro-3-nitrobenzoic acid [Lehmstedt and Schrader, Ber. 70B, 1526 (1937)]. After stirring for ten minutes, the suspension was treated dropwise with 7.0 g (0.05 mol) of 4-methoxybenzenethiol [C. M. Suter and H. L. Hansen, J. Am. Chem. Soc., 54, 4100 (1934)] in 50 ml of tetrahydrofuran. After stirring for 30 minutes at 0° C., the cooling bath was removed and the mixture was maintained at 25° C. for 12 hours. The mixture was acidified with 150 ml of 10% aqueous HCl, then treated with 200 ml of ethyl acetate. The organic layer was separated and the aqueous phase was extracted with 100 ml of ethyl acetate. The combined organic phases were dried (MgSO4), and concentrated to a yellow solid which was purified by flash chromatography on silica gel, utilizing dichloromethane:methanol (8:1) as eluting solvent, to give 11.9 g of 6-chloro-2-[(4-methoxyphenyl)thio]-3-nitrobenzoic acid, mp 154°-157° C., following crystallization from toluene.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[O:18][C:19]=2[CH3:20])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:17]1[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][OH:2])=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[N:16]=1
Reactant: COC(=O)c1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of methyl 5-formyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate (8.18 g) in tetrahydrofuran (50 mL)-ethanol (50 mL) was gradually added sodium borohydride (0.91 g) at room temperature. After stirring for 2 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-5-hydroxymethylbenzoate as pale-yellow crystals (6.53 g, yield 79%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 131-132° C.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]([O:12]C)=[O:11])=[C:6]([CH2:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl.CO.[NH4+].[OH-].Cl>CO>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]([OH:12])=[O:11])=[C:6]([CH2:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1cc(C(C)=O)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1cc(C(C)=O)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a solution of 0.556 g (1.50 mmol) of the product of Step B dissolved in 4.0 mL of methanol was added 0.45 mL (2.25 mmol) of a 5.0N aqueous solution of sodium hydroxide. The reaction mixture was stirred at room temperature and monitored by TLC (CHCl3 --MeOH--NH4OH 80:15:1). After 4 hours the reaction was judged to be complete and the reaction mixture was adjusted to pH=7 with 6.0N HCl. The mixture was then evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.416 g (78%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.S(O)(O)(=O)=O.[NH2:25][OH:26]>CO>[CH3:1][NH:2][C:3](=[O:19])/[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:25]/[OH:26]
Reactant: NO
Reactant: CNC(=O)C(=O)c1ccccc1Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 95.5 %

Procedure:
N-Methyl-2-(2-phenoxyphenyl)-2-oxoacetamide (2.55 g, 10 mmol) was dissolved in methyl alcohol (10 ml). Hydroxylamine sulfate (0.99 g, 12 mmol) was added, followed by heating under reflux for 3 hours. After completion of the reaction, methyl alcohol was evaporated under reduced pressure. Toluene (10 ml) and conc. hydrochloric acid (1.04 g) were added to the resulting residue (E/Z=41/59), and the mixture was stirred at room temperature for 20.5 hours. After completion of the reaction, water (300 ml) was added. The mixture was extracted with ethyl acetate (300 ml), washed with brine twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E)-N-methyl-2-(2-phenoxyphenyl)-2-hydroxyiminoacetamide (2.58 g, Yield: 95.6%, E/Z=96/4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36]C)[N:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.Br.CC(O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25][C:26]4[CH:27]=[CH:28][N:29]=[C:30]5[C:35]=4[NH:34][C:33](=[O:36])[C:32]([O:38][CH3:39])=[CH:31]5)=[CH:23][CH:24]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2nc1OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2[nH]c1=O
Temperature: 85 °C

Procedure:
4-(4-Chlorophenyl)-N-(4-(6,7-dimethoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (40 mg, 72 μmol) was added to a pyrex reaction tube along with 2 mL of 1:1 HBr:AcOH. The tube was sealed and the mixture was heated at 85° C. for 1.5 h. Upon cooling the mixture was diluted with water and brought to basic pH by dropwise addition of 6N NaOH. The solids were filtered, washed with water, and dried. The crude material was purified by silica gel chromatography, 10-50% 90/10/1 DCM/MeOH/NH4OH in DCM to provide 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)-3-methoxy-1,5-naphthyridin-2(1H)-one as a light yellow solid. MS: [M+H]=539.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3cccc(C(=O)O)c3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-bromomethylbenzoic acid as described for compound 83. Purified by chromatography (ethyl acetate). Crystallized from diethyl ether. M.p. 133°-136° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.O[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
A solution of 116 mg (0.5 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoic acid, 58 mg (0.5 mmol) of ethyl 4-hydroxybenzoate, 117 mg (0.56 mmol) of 1,3-dicyclohexylcarbodiimide and 30 mg (0.25 mmol) of 4-dimethylaminopyridine in 15 ml of methylene chloride was stirred at room temperature for 12 hours. The reaction mixture was then filtered and the filtrate concentrated in-vacuo. The resultant residue was purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as white crystals.
Reaction SMILES: B.C1COCC1.[CH3:7][NH:8][C:9]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1)=O>CO>[CH3:7][NH:8][CH2:9][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1
Reactant: CNC(=O)c1cc2ccccc2o1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc2ccccc2o1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
To a solution of 1.0 M BH3/THF (30 mL, 30 mmole) at 0° C. was added N-methylbenzofuran-2-carboxamide (1.75 g, 10 mmole). The reaction mixture was allowed to warm to RT, then was heated at reflux overnight. The reaction was cooled to 0° C. and excess methanol was added. The resulting solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (3% MeOH/CH2Cl2). The tile compound (0.2 g, 12%) was obtained as a white solid: MS (ES) m/e 162 (M+H)+.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].O[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:12]=1)([CH3:10])[CH3:9].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:20][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:19])[CH3:18])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(C)(O)c1cccc(C(C)(C)O)c1
Agent: O=S(=O)(O)O
Product: CC(C)(C)OOC(C)(C)c1cccc(C(C)(C)OOC(C)(C)C)c1

Procedure:
1,3-Bis(2-t-butylperoxy-2-propyl)benzene (meta I) was prepared by reacting 29.7 grams (0.231 mole) of aqueous 70% t-butyl hydroperoxide with 20.4 grams (0.105 mole) of 1,3-bis(2-hydroxy-2-propyl)benzene in the presence of 26.8 grams (0.21 mole) of 77% sulfuric acid according to the procedure of Example I. The stripped product weighed 32.6 grams. It crystallized upon cooling and had a melting point of 45°-52° C. This example is for comparative purposes and does not fall under the specifications of this invention. The peroxide assay was 97% of theoretical.
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.C1([Mg]Br)CCCC1>>[CH3:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][C:17]1[O:18][C:14]2[CH:13]=[CH:12][C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[CH:4]=[O:28])=[CH:27][C:15]=2[CH:16]=1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Agent: Br[Mg]C1CCCC1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C=O)c3)ccc2o1
Reaction time: 8 h
Yield: 16 %

Procedure:
The product from Example 145 and cyclopentylmagnesium bromide were processed as described in Example 146, except that additional cyclopentylmagnesium bromide was added after the reaction had stirred overnight (400 mol %) and after another four hours (600 mol %). The reaction mixture was allowed to stir for three additional days (16% yield). MS (ESI APCI) m/z 334 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.17 (d, 3H), 1.38-1.53 (m, 1H), 1.77-1.86 (m, 2H), 1.94-2.08 (m, 1H), 2.23-2.34 (m, 1H), 2.40-2.59 (m, 2H), 2.94-3.15 (m, 2H), 3.19-3.34 (m, 2H), 6.63 (d, 1H), 7.51-7.54 (m, 2H), 7.65 (dd, 1H), 7.80 (dd, 1H), 7.87 (ddd, 1H), 7.96 (ddd, 1H), 8.16 (dd, 1H), 10.07 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=[O:15])[C:5]2=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:21])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:14][OH:15])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[C:5]2=[CH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1-c1nn(C)c2nc(N)ncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CO)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzaldehyde (Example 75) (0.040 g, 0.141 mmol) is suspended in dry MeOH (2.5 ml) and THF (1 ml). The reaction mixture is cooled to 0-5° C. (ice-bath) and sodium borohydride (0.006 g, 0.1551 mmol) is cautiously added. The reaction mixture is stirred at room temperature for 24 hours, filtered, washing with MeOH and concentrated in vacuo. The resulting solid is triturated in MeOH (minimal) and collected by filtration to afford the title compound as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[O:11]1[CH2:13][CH:12]1[CH2:14][N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1>C(O)C>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][N:15]1[CH2:14][CH:12]([OH:11])[CH2:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Product: O=C1Cc2ccccc2N1CC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 33 %

Procedure:
To a solution of indolin-2-one (50.0 mg, 0.378 mmol) in ethanol (5 mL) was added 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (85.0 mg, 0.451 mmol). The mixture was heated under microwave conditions at 120° C. for 0.5 h, concentrated and purified by preparative HPLC purification. (40.0 mg, yield 33.0%) MS (ESI+) e/z: 323.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.30-7.23 (m, 2H), 7.14-7.07 (m, 4H), 7.06 (d, J=7.5 Hz, 1H), 7.01 (t, J=5.8 Hz, 1H), 4.94 (d, J=7.8 Hz, 2H), 4.31-4.18 (m, 1H), 3.97-3.86 (m, 1H), 3.82-3.72 (m, 1H), 3.71-3.64 (m, 2H), 2.90-2.73 (m, 4H), 2.73-2.59 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.[C:39](Cl)([Cl:41])=[O:40]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:39]([Cl:41])=[O:40])[C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)(=[O:28])=[O:29])[CH:24]=[CH:23][C:22]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-5-(pyrrolidine-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:21]3[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]=1>>[F:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[CH:13]([NH:12][C:7]1[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[N:25]=4)[CH:3]=3)[N:8]=1)[CH2:14][CH2:15]2
Reactant: Fc1ccc2c(c1)CCC2Nc1ccc2cc(Br)ccc2n1
Reactant: Nc1cccc(C(F)(F)F)n1
Product: Fc1ccc2c(c1)CCC2Nc1ccc2cc(Nc3cccc(C(F)(F)F)n3)ccc2n1

Procedure:
The title compound, yellow foam, MS: m/e=439.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(5-fluoro-indan-1-yl)-amine (see example 102, step A) and commercially available 2-amino-6-trifluoromethyl-pyridine.