Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][CH:40]=1)[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:31]S(C(C)(C)C)=O)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=1)[C:16]1[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:31][C:15]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=1)([C:16]1[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=1)[CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][C:8]1[CH:38]=[CH:39][CH:40]=[C:6]([OH:5])[CH:7]=1
Reactant: Cn1cncc1C(CCCCOCc1cccc(OC(C)(C)C)c1)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cncc1C(N)(CCCCOCc1cccc(O)c1)c1ccc(C#N)c(F)c1
Reaction time: 1 h

Procedure:
2-Methyl-propane-2-sulfinic acid [5-(3-tert-butoxy-benzyloxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-pentyl]-amide (A) (0.396 g, 0.58 mmol) was dissolved in methanol (15 mL) and treated with 4M HCl in dioxane (9 mL). After 1 h, the reaction mixture was concentrated in vacuo, azeotroped with CH2Cl2 (3×), rinsed with CH2Cl2, and the solid collected to give enantiomer A of the title compound. MS (M+1) 409. Using the same procedure, diastereomer B (Step D) (0.110 g, 0.161 mmol) gave enantiomer B of the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[C:12]([OH:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.CCN(CC)CC>[C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[C:12]([O:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of methyl α-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate from Preparation 6 (1.5 g, 5.7 mmol) in CHCl3 (20 ml) and Et3N (1 ml) is treated with benzoyl chloride (1.0 g, 7.1 mmol). The resulting solution is stirred at room temperature for 4.5 hours. The reaction mixture is concentrated and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The organic phases are combined, dried (MgSO4) and concentrated. The residue is purified by silica gel chromatography (50% EtOAc/Heptane). An oil of methyl α-(acetylamino)-3-[(phenylcarbonyl)oxy]-4-(2-propenyl)benzeneacetate is obtained (2.1 g, quantitative).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(O)(C)(C)C>[CH3:15][O:16][C:17](=[O:24])[CH2:18]/[C:19](/[C:20]([O:22][CH3:23])=[O:21])=[CH:7]\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(=O)OC
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C/C(=C\c1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of potassium t-butoxide (16.8 g) in t-butyl alcohol (150 ml) is added dropwise with stirring a solution of benzaldehyde (15.9 g) and succinic acid dimethyl ester (26.3 g) in t-butyl alcohol (20 ml) at room temperature, and the mixture is stirred for 30 minutes. The reaction mixture is poured into ice-water (200 ml), and the mixture is extracted with isopropyl ether. The pH value of the aqueous layer is adjusted to pH 2-3, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is dissolved in methanol (75 ml), and thereto is added dropwise thionyl chloride (10.9 ml) under ice-cooling. The mixture is allowed to stand at room temperature overnight, and then evaporated to remove the solvent. To the residue is added isopropyl ether, and the mixture is washed, dried, and evaporated to remove the solvent. The resulting residue is distilled under reduced pressure to give (E)-3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester (23.2 g) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[NH2:9][C:10]1[N:18]=[C:17]([CH2:19][O:20][CH3:21])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:9][C:10]1[N:18]=[C:17]([CH2:19][O:20][CH3:21])[CH:16]=[CH:15][C:11]=1[C:12]([NH:8][CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: COCc1ccc(C(=O)O)c(N)n1
Reactant: NCc1ccc(Br)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)NCc2ccc(Br)s2)c(N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
To a solution of C-(5-bromo-thiophen-2-yl)-methylamine (250 mg, 1.3 mmol) in N,N-dimethylformamide (5 mL) were added tiethylamine (0.54 mL, 3.9 mmol), 2-amino-6-methoxymethyl-nicotinic acid (240 mg, 1.3 mmol) described in Preparation Example A-11, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (690 mg, 1.6 mmol) sequentially on an ice bath, then, the solution was stirred for 2 days at room temperature. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1), and the title compound (370 mg, 1.0 mmol, 79%) was obtained as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](B2OCC(C)(C)CO2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].Cl[C:48]1[N:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([C:48]2[N:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: COc1ccc(Cl)nn1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(B2OCC(C)(C)CO2)cc1C)C(=O)OC(C)(C)C
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(-c2ccc(OC)nn2)cc1C)C(=O)OC(C)(C)C
Yield: 49.3 %

Procedure:
Using the compound (510 mg, 0.802 mmol) of Example 295, step A and 3-chloro-6-methoxypyridazine (139 mg, 0.962 mmol), and according to the method of Example 295, step B, N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[4-(6-methoxypyridazin-3-yl)-2-methylphenyl]-N1-{2-[(tert-butoxycarbonyl)(ethyl)amino]ethyl}glycinamide (250 mg) was obtained as a brown oil. Using this oil (210 mg, 0.332 mmol), and according to the method of Example 46, step B, the title compound (92 mg, yield 53%) was obtained as a pale-yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH2:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15]1)(=O)=O>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2([CH2:13][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:17][CH2:16][CH2:15]2)=[CH:19][CH:20]=1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3cncn3)CCC2)cc1
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
4.1 g of 1,2,4-triazole in 15 ml of N,N-dimethylformamide were added to 0.66 g of sodium hydride (80% strength dispersion in mineral oil) in 15 ml of N,N-dimethylformamide at room temperature, under nitrogen. The mixture was stirred for 30 minutes, after which 5.1 g of [1-(4-chlorophenyl)-cyclobut-1-yl]-methyl methanesulfonate in 15 ml of N,N-dimethylformamide were added dropwise, and the mixture was stirred for 24 hours at room temperature and for 12 hours at 100° C., then hydrolyzed with water and extracted with ethyl acetate. 2.6 g of 1-(4-chlorophenyl)-1-(1,2,4-triazol-1-ylmethyl)-cyclobutane of melting point 124°-125° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24](O)=[O:25].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)=[O:25]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CCOC(=O)c1ccc(Oc2ccc(N)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccc(NC(=O)c3ccc(C)c(C)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (14.15 g, 54.8 mmol) in DMF (100 mL) were added 3,4-dimethylbenzoic acid (8.23 g, 54.8 mmol), 1-hydroxybenzotriazole monohydrate (8.4 g, 54.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.6 g, 65.7 mmol) under ice cooling, and then stirred for 30 minutes under ice cooling and for 17 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added water (200 mL), and extracted with ethyl acetate (250 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 16.15 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][O:18][C:19]1[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])[CH:7]=1
Reactant: COc1ccccc1N
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2OC)c1
Yield: 79 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.40 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of o-anisidine (0.19 go 1.54 mmol) in dioxane (1 ml) and NaHCO3 (0.26 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether—ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.42 g, 79%) as a white solid 1H NMR (DMSO-d6, HMDSO), δ: 3.43 (3H, s); 3.72 (3H, s); 6.60 (1H, d, J=16.0 Hz); 6.72-7.27 (4H, m); 7.45-8.12 (5H, m); 9.47 (1H, s).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=1.[N:20]1([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)CCl>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:35][CH:34]=2)=[N:16][CH:17]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NNc1ccc(F)cn1)c1ccc(CN2CCOCC2)cc1
Yield: 75 %

Procedure:
HOBt (53 mg, 0.39 mmol) was added to (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 500 mg, 3.94 mmol), 4-morpholin-4-ylmethyl-benzoic acid (1.04 g, 4.72 mmol) and EDC (907 mg, 4.72 mmol) in DCM (5.0 mL) and the reaction stirred for 4 h. The reaction was partitioned between DCM (75 mL) and saturated aqueous NaHCO3 (75 mL) and the aqueous layer extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo then purified by FCC using [0.5-7.5% 2M NH3 in MeOH] in DCM to give the title compound (980 mg, 2.97 mmol, 75%). LCMS (Method 4): Rt 0.27, m/z 331 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C(C)=CC=CC=1>[OH:16][C:15]1[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=1[C:2]1[N:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:15]([OH:16])=[CH:17][C:18]=2[OH:19])[N:5]=[C:4]([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Cn1cccc1-c1nc(Cl)nc(Cl)n1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Cn1cccc1-c1nc(-c2ccc(O)cc2O)nc(-c2ccc(O)cc2O)n1
Yield: 81 %

Procedure:
Friedel-Crafts acylation: In a 500 ml sulfonation flask having a stirrer, dropping funnel, condenser and internal thermometer, 22.9 g (0.1 mol) of 2,4-dichloro-6-(1-methylpyrrol-2-yl)-1,3,5-triazine and 24.2 g (0.22 mol) of resorcinol are initially introduced into 200 ml of xylene (isomer mixture). At 45-50° C., 29.3 g (0.22 mol) of aluminium chloride are slowly introduced and the mixture is stirred at 80-83° C. until the evolution of HCl has ended (about 2 hours). The warm reaction solution is allowed to run into dil. hydrochloric acid with stirring, and the solid is filtered off with suction and washed with acetone/water until neutral. Drying is carried out at 100° C. in vacuo. 30.5 g (81.0% of theory) of 2,4-bis(2,4-dihydroxyphenyl)-6-(1-methylpyrrol-2-yl)-1,3,5-triazine are obtained as a yellow powder (m.p.>300° C.). The structure is in agreement with the 1H-NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(C(F)(F)F)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethyl)phenol: ESMS m/e: 603.1 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9](=[O:22])[C@H:10]([CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[NH2:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][CH2:12][C@@H:10]([C:9]([NH2:8])=[O:22])[NH2:11])=[CH:20][CH:19]=1
Reactant: Cc1ccc(CSC[C@H](N)C(=O)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(CSC[C@H](N)C(N)=O)cc1

Procedure:
Treat the product of Step 1 (2.79 g) in CH2Cl2 (40 ml) with trifluoroacetic acid (10 ml) at room temperature for 18 hr. Concentrate the reaction mixture in vacuo. Dissolve the residue in CH2Cl2 and concentrate in vacuo (twice). Dissolve the white solid in EtOAc and extract with 10% sodium bicarbonate solution. Dry (MgSO4) the EtOAc and concentrate in vacuo to give the title compound, a white solid (1.53 g) m.p. 94°-95°, [α]D26 =-1.3° (MeOH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:17][CH2:18][C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11][N:10]1[CH:14]=[N:15][CH:16]=[C:9]31.[Cu][C:20]#[N:21].N.C(OCC)(=O)C>CN1CCCC1=O>[CH:16]1[N:15]=[CH:14][N:10]2[CH2:11][CH2:12][CH2:13][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:20]#[N:21])=[CH:3][C:4]=4[CH2:18][O:17]3)[C:9]=12
Reactant: N#C[Cu]
Reactant: Brc1ccc2c(c1)COC21CCCn2cncc21
Agent: N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)COC21CCCn2cncc21
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.93 mmol of 5-bromo-6′,7′-dihydro-3H,5′H-spiro[2-benzofuran-1,8′-imidazo[1,5-a]pyridine] and 9.63 mmol of copper(I) cyanide in 10 ml of N-methyl-pyrrolidone is heated to 150° C. for 72 h. The reaction mixture is cooled to room temperature and poured into a mixture of 25% aqueous ammonia and ethyl acetate. The mixture is stirred vigorously for 15 minutes and the layers are separated. The aqueous layer is extracted with ethyl acetate and the combined organics are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) followed by crystallization from diethyl ether to afford the title compound as a beige solid. Rf=0.15 (dichloromethane-2M ammonia in ethanol 97:3); Rt=4.66 (gradient II).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21]O)[CH2:11]1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.[N+:24]([C:27]1[CH:46]=[CH:45][C:30]([CH2:31][O:32][C:33]([N:35]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:42]2[CH2:43][CH2:44][CH:39]([N:35]([C:33]([O:32][CH2:31][C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:46][CH:45]=3)=[O:34])[CH2:36][CH:37]=[CH2:38])[CH2:40][CH2:41]2)[CH2:11]1)[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1C[C@H](CO)[C@@H](c2ccccc2)C1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Agent: Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedures as in Example 11, Steps C and D but starting with 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopentane (Higher Rf isomer) from Step G (257 mg, 0.84 mmol) and using 4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidine hydrochloride, the title compound was obtained and was the same as the racemic product from Example 15, [α]D=+15.9 (MeOH, c=0.21).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]([C:14]#[C:15][C:16](OC)=[O:17])=[O:13]>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]2[C:3]=1[C:16](=[O:17])[CH:15]=[C:14]([C:12]([O:11][CH3:10])=[O:13])[NH:5]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1cc(C)cc(N)c1
Product: COC(=O)c1cc(=O)c2c(C)cc(C)cc2[nH]1
Yield: 3.3 %

Procedure:
Using the method described in Example 18a with 3,5-dimethylaniline (20 g) and dimethylacetylene dicarboxylate (23.4 g) as reagents gave methyl 5,7-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.25 g), m.p. 227°-229° C. δ (360 MHz, DMSO-d6) 2.34 (3H, s, 7-Me), 2.74 (3H, s, 5-Me), 3.94 (3H, s, CH3O), 6.49 (1H, s, 3-H), 6.89 (1H, s, 6-H) and 7.54 (1H, s, 8-H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[N:7]2[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1
Reactant: CN1Cc2c(Br)cccc2NC1=O
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: CN1Cc2c(Br)cccc2N(Cc2cccc(F)c2)C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
To a solution of 5-bromo-3-methyl-3,4-dihydro-1H-quinazolin-2-one (132 mg, 0.55 mmol) in 5 ml anhydrous dimethylformanide was added sodium hydride (33 mg of a 60% suspension in mineral oil, 0.83 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial offgassing ended. 3-Fluorobenzyl bromide (0.08 ml, 0.65 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting residue was purified by flash chromatography to give 156 mg of 5-bromo-1-(3-fluoro-benzyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one as a yellow solid (81%). MS: 349.1 (M+H)+.
Reaction SMILES: [K].N#N.C(=[C:7]([CH:9]([CH2:11][OH:12])[OH:10])[OH:8])(C)C.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>C1C=CC=CC=1>[CH2:33]([O:12][CH2:11][CH:9]([CH2:7][OH:8])[OH:10])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: CC(C)=C(O)C(O)CO
Agent: N#N
Agent: [K]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Potassium metal (1.5 g, 38.36 mmol) and anhydrous benzene (180 ml) were placed in a 500 ml three-neck round-bottomed flask equipped with a reflux condenser, dropping funnel, stir bar, and N2 atmosphere. The reaction mixture was refluxed. When the potassium metal had melted, isopropylidene glycerol (6 ml, 48.25 mmol) was added dropwise and the reaction continued to reflux an additional 2.5 hours. A solution of hexadecyl methane sulfonate (10.0 g 32.25 mmol) in anhydrous benzene (80 ml) was added dropwise and the reaction refluxed overnight. The heat was removed and the reaction mixture was cooled to 0° C. Water was added and the benzene layer was removed, washed with H2O, dried (MgSO4) and filtered. This residue was treated as in METHOD A for the hydrolysis of the acetal group to provide compound 35, rac-1-O-hexadecylglycerol (7.65 g 75%, based on mesylate 34).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:30])[NH:15][CH2:16][C@H:17]([OH:29])[CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:14]([NH:15][CH2:16][C@H:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-tert-butyl-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxyl propyl)carbamoyl)phenyl)carbamate (500 mg, 1.18 mmol) in DCM (8 mL) was added TFA (8 mL). The mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated to give the crude title product that was used without further purification (400 mg). LCMS (m/z): 326.2 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:16]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:8]([C:16]2[NH:15][C:23]3[C:18]([C:17]=2[CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:1][CH:2]([CH3:7])[CH3:3])=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Product: CC(=O)NCCc1c(C(CC(C)C)C2=C(O)C(Cc3ccccc3)OC2=O)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with 3-methyl-butyraldehydeand and N-[2-(1H-indol-3-yl)-ethyl]-acetamide) to give the title compound as a yellow solid. MS: 459.1 ([M−H ]−).