Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:15]([CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)[CH2:16][CH3:17].Cl>[Zn].C(OCC)(=O)C>[F:8][C:2]([F:9])([CH:30]([OH:31])[CH:27]1[CH2:26][CH2:25][CH:24]([CH:21]2[CH2:22][CH2:23][CH:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]2)[CH2:29][CH2:28]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCCC1CCC(C2CCC(C=O)CC2)CC1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC1CCC(C2CCC(C(O)C(F)(F)C(=O)OCC)CC2)CC1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 10.7 g of well-dried zinc, 25.0 g of ethyl bromodifluoroacetate (e-14) and 25 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 19.4 g of 4′-propyl-[1,1′-bi(cyclohexane)]-4-carboaldehyde (e-1) and 100 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 300 ml of 1 N HCl aqueous solution and 300 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 16.2 g of ethyl 2,2-difluoro-3-hydroxy-3-(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)propanoate (e-15) was obtained. A yield based on compound (e-1) was 54.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1I.[C:22]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])(=[O:25])[CH:23]=[CH2:24].C([O-])(=O)C.[Na+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:24]=[CH:23][C:22]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25]
Reactant: C=CC(=O)OCC(F)(F)F
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(I)c2)c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=CC(=O)OCC(F)(F)F)c2)c1=O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A suspension of 5.0 g of 3-[4-chloro-3-iodophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 2.0 g of 2,2,2-trifluoroethyl acrylate, 0.5 mg of palladium acetate and 1.1 g of sodium acetate in 50 ml of dimethylformamide was stirred for 4 hours at 120° C., after which further palladium acetate and 2,2,2-trifluoromethyl acrylate were added and stirring was continued for a further 2 hours at 120° C. The cooled reaction mixture was added to 200 ml of water and the precipitate was isolated, washed with petroleum ether and dried under greatly reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([O:12]CC)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH3:15]>>[NH2:1][C:2]1[C:3]([C:10]([NH2:15])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCOC(=O)c1nccc(C#N)c1N
Reactant: N
Product: N#Cc1ccnc(C(N)=O)c1N
Temperature: 100 °C
Yield: 94 %

Procedure:
A mixture of liquid ammonia (30 ml) and ethyl 3-amino-4-cyanopyridine-2-carboxylate (Preparation 11; 2.8 g, 0.0147 mol) was heated at 100° C. in an autoclave for 18 hours. The ammonia was allowed to evaporate and the resulting product crystallized from ethyl acetate to give the title compound as an off-white solid (2.2 g, 94%), m.p. >310° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[N:25]1([C:11](=[O:13])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH2Cl2 (40 ml, with a catalytic amount of DMF) at 0° C. under N2 was added oxalyl chloride (1.1 ml) drop wise. The reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4-yl-2-(3-nitro-pheny)-ethanone as a solid (2 g). A mixture of 1-morpholin-4-yl-2-(3-nitro-pheny)-ethanone (2 g) and 10% Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl-ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCl (15 ml), cooled to 0° C., and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCl (30 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1-morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCl (1 ml) were refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide 2-[3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10][C:9]=1Cl)=[O:6])=O.[ClH:19]>[OH-].[K+].CO>[Cl:19][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:5](=[O:6])[NH:4][N:3]=[CH:1]2)=[CH:13][C:12]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)NNC=O)c1
Reactant: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-n2cn[nH]c2=O)ccc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 1-formyl-4-(2-chloro-5-carbomethoxyphenyl)semicarbazide (0.03 g, 0.11 mmol) in 1.0 M KOH in methanol (MeOH) (0.44 mL) was heated at 80° C. for 72 hours and cooled to room temperature. 1.0 N HCl (0.8 mL) was added and the mixture evaporated to dryness in vacuo. The residue was taken up in MeOH (1.5 mL) and filtered. The filtrate was concentrated in vacuo to yield 0.028 g (100%) of the title intermediate as an amorphous solid. Mass Spectrum (M−H): 3:1 ratio of 238 and 240.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]1[CH2:26][C:27](OCC)=[O:28])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]1[CH2:26][C:27]([NH:10][C:9]([NH2:11])=[NH:8])=[O:28])[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC(C)CN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 40 h
Yield: 57.3 %

Procedure:
(−)-N-[(2-Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-y)acetyl]guanidine is prepared as described in Example 1, starting with 2.6 g of potassium tert-butoxide, 2.6 g of guanidinium chloride and 1.25 g of ethyl (−)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol1-y)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 40 hours and is then filtered. The filtrate is taken up in 80 cm3 of water and 120 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is separated out and the aqueous phase is extracted with twice 120 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 40° C. The evaporation residue is taken up in 30 cm3 of diethyl ether and the precipitate formed is filtered off and then washed three times with 5 cm3 of diethyl ether. The solid is dried under reduced pressure (10 Pa) at a temperature in the region of 45° C. 0.75 g of (−)-N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of an off-white solid melting at 264° C. (αD20=−10.2°±0.6 in methanol at 0.5%). Mass spectrum EI: m/e 288 (M+), m/e 245, m/e 201, m/e 132.
Reaction SMILES: O.[CH3:2][C:3]1([CH3:25])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[N:17])[CH:12]=3)[C:7]=2[C:6](=[O:18])[C:5]2[CH:19]=[CH:20][C:21]([CH:23]=C)=[CH:22][C:4]1=2.I([O-])(=O)(=O)=[O:27].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH:23]([C:21]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:8]4[C:13](=[CH:12][C:11]([C:16]#[N:17])=[CH:10][CH:9]=4)[NH:14][C:15]=3[C:3]([CH3:2])([CH3:25])[C:4]=2[CH:22]=1)=[O:27]
Reactant: C=Cc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1(C)c2cc(C=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To the THF (24 ml) and distilled water (6 ml) suspension of 6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-24, 600 mg, 1.920 mmol), t-butanol solution of osmium tetraoxide (192 μl, 0.1 eq.) and sodium meta periodate (821 mg, 2.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. Aqueous solution of sodium thiosulfate (0.3 M) was added to the solution, which was then extracted with an ethyl acetate. The organic layer was washed with 10% aqueous solution of disodium ethylenediamine tetraacetic acid. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (470 mg, 77%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2ccc(CCC(=O)O)cc2)cc(C(C)(C)C)c1O
Yield: 77.1 %

Procedure:
A mixture of 4.0 g of 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, 200 ml of ethanol of 0.1 g of 10% palladium on charcoal catalyst was placed on a Paar apparatus. Hydrogen uptake was complete after 30 minutes. Under a nitrogen atmosphere, the reaction mixture was filtered to remove catalyst The filtrate was evaporated to give an oil which was coevaporated with hexane to remove all traces of ethanol and then triturated with hexane to give a light orange crystalline solid. This solid was recrystallized from a mixture of ethanol and water to give 3.1 g 3-[N-(3,5-di-tertiary-butyl-4-hydroxyphenyl)-4-aminophenyl]propionic acid, m.p. 140°-142° C. Analysis: Calculated for C23H31NO3 : %C, 74.8; %H. 8.5; %N. 3.8; Found: %C, 74.7; %H, 8.3; %N, 3.9.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>>[C:11]12([C:21]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=4)[NH:8][CH:9]=3)=[O:22])[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(c1c[nH]c2ncc(Br)nc12)C12CC3CC(CC(C3)C1)C2

Procedure:
Adamantan-1-yl-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone was prepared starting from 2-bromo-5H-pyrrolo[2,3-b]pyrazine and adamantane-1-carbonyl chloride following general procedures as described in these Examples. MP 279-280° C., M+H=360.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:25])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.53) (0.21 g, 0.52 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.21 g, 0.62 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.15 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:35]=[CH:34][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:28]([O:30]C)=[O:29])[CH2:21][C:22]([CH3:27])([CH3:26])[O:23]4)=[CH:18][C:17]=3[C:32]#[N:33])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O.CO>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]([CH3:26])([CH3:27])[O:23]4)=[CH:18][C:17]=3[C:32]#[N:33])=[CH:34][CH:35]=2)=[O:10])=[CH:36][CH:37]=1
Reactant: COC(=O)C1CC(C)(C)Oc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(C(=O)O)c2cc(C#N)c(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)cc2O1
Reaction time: 3 h
Yield: 30.9 %

Procedure:
Methyl 7-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylate (2.0 mg, 0.00385 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (0.00771 mL, 0.0385 mmol) and 200 μL of water and methanol. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a 0.5 mm preparative TLC plate, eluting with 5% methanol/0.5% acetic acid/CH2Cl2 to yield the title compound (0.6 mg, 30.8% yield) as a white solid. MS (ESI)=504.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CS[C:18]1[NH:27][C:26](=[O:28])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>N1C=CC=CC=1>[O:28]=[C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[N:27]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CSc1nc2ccccc2c(=O)[nH]1
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(Nc2nc(=O)c3ccccc3[nH]2)cc1
Yield: 19.3 %

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (2 g) and 2-methylthio-4-quinazolinone (2.98 g) in dry pyridine (15 ml) was heated under reflux for 90 hours. The mixture was filtered and the solid digested with boiling acetonitrite to leave a solid (0.66 g), m.p. 313°-319° C. The combined filtrates were evaporated and the residue was heated with pyridine (3 ml) in the absence of a condenser, in an oil bath at 160° C. for 3 hours. The residue was digested with acetonitrile as before to give the title compound, (0.55 g), m.p. 312°-315° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](=[O:42])[C:32]2[C:27](=[CH:28][C:29]([Cl:43])=[CH:30][CH:31]=2)[N:26]=1)[CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([C@@H:21]([C:25]1[N:34]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:33](=[O:42])[C:32]2[C:27](=[CH:28][C:29]([Cl:43])=[CH:30][CH:31]=2)[N:26]=1)[CH:22]([CH3:23])[CH3:24])[C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N(CCCN)[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet and cold bath was charged with 400.0 g of {3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (the compound of Formula 304 prepared, e.g., as described in Example 1.8 or 3.3) and 1500 g of TFA (20 eq) premixed in DCM (6000 g). The mixture was stirred at room temperature for about 6 hours at which time the reaction was determined to be complete by TLC. The reaction vessel was cooled and slowly charged with 4N sodium hydroxide until basic. The resulting solution was washed with brine, dried over sodium sulfate and concentrated under reduced pressure at 35° C. to give the title compound of Formula I, (R)-N-(3-amino-propyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinalolin-2-yl)-2-methyl-propyl]-4-methyl-benzamide, 325 g (97% yield) as a white foam solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]I)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOCC.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.[Fe]>[C:20]1([CH2:16][C:15]([CH3:18])([CH3:19])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(CI)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Ni]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: CCOCC
Product: CC(C)(Cc1ccccc1)CC1CCNCC1
Yield: 56 %

Procedure:
A mixture of 26 mg (0.07 mmol) of 1-(t-butoxycarbonyl)-4-(3-iodo-2,2-dimethylpropyl)piperidine (from EXAMPLE 98, Step H) and 2 mg (0.007 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]nickel (II) chloride in ether (5 mL) at reflux was treated with phenylmagnesium bromide (0.13 mL of 3.0 M solution in ether). The resulting mixture was heated at reflux for 12 h, cooled and quenched with H2O and sat'd NaCl. The mixture was extracted 3× with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated. The residue was purified by column chomatography on 10 g of silica using a gradient of 0-5% MeOH/CH2Cl2 (v/v), then 10% MeOH/CH2Cl2+2% NH401H (v/v), to give 9 mg (56%) of the title compound: 1H NMR (500 MHz) δ 0.89 (s, 6H), 1.18-1.27 (4H), 1.52-1.59 (m, 1H), 1.71 (d, J=12.3,21).2.46 (bs, 1H) 2.52 (s, 2H), 2.65 (t, J=11.9, 2H). 3.06 (d,J=12.2, 2H), 7.13 (d, J=7.3, 2H), 7.22 (t, J=7.1, 11H), 7.28 (t, J=6.7, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH:23]=O)=[C:20]([CH3:22])[CH:21]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH:23]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:20]([CH3:22])[CH:21]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: CCOC(=O)c1cc(C)c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]1
Yield: 93.9 %

Procedure:
5-Chloro-1,3-dihydroindol-2-one (2.22 g, 13.2 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.43 g) using method E to give 4.1 g (94%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:27])=[CH:22]/[C:23](OC)=[O:24])=[CH:17][CH:16]=1.[H-].[Al+3].[H-].[H-]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[C:21](/[CH3:27])=[CH:22]/[CH2:23][OH:24])=[CH:19][CH:20]=1
Reactant: COC(=O)/C=C(\C)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Product: C/C(=C\CO)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 63 %

Procedure:
According to the same manner as that described in reference Example 10, methyl (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-butenoate was reduced with sobutyl aluminum hydride to give (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-butenol (yield: 63%). This product was recrystallized from ethyl acetate-ether. colorless crystals, mp: 126-127° C.