Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: CNCCOC
Agent: Cl
Product: COCCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 20.9 mg (0.23 mmol) of N-(2-methoxyethyl)-N-methylamine are reacted together by general method E. 22.1 mg (35.1% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[S:17][CH:18]=[C:19]([Cl:21])[N:20]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[S:17][CH:18]=[C:19]([Cl:21])[N:20]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1csc(Cl)n1
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1nc(Cl)cs1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 475, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2,4-dichlorothiazole (prepared according to Reynaud, Pierre; Robba, Max; Moreau, Robert C; New synthesis of the thiazole ring; Bulletin de la Societe Chimique de France (1962), 1735-8). MS m/z: 321 (23%, M+1), 265.0 (100%, M−55.1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C:16](=[O:24])[CH2:17][CH2:18]1)=[CH:13][C@H:12]3[CH3:25])(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>O1CCCC1.C(O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)=[CH:13][C@H:12]3[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](C)C=C4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](C)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -3 °C

Procedure:
Add slowly a solution of 7α-methylandrost-5-en-3-on-17β-ol 17 acetate (L74a, 6.3 g, 18.9 mmol) in tetrahydrofuran (50 mL) to a solution of sodium borohydride (0.72 g, 18.9 mmol) in 95% ethanol (200 mL) cooled to −3° C. in a salt/ice bath with stirring. Stir at this temperature for 3 hours and decompose the excess reagent by cautious addition of acetic acid (10 mL). Remove the solvents and purify the resulting crude product by flash chromatography to give 7α-methylandrost-5-ene-3β,17β-diol 17 acetate (L75a) as a white solid. Similarly prepare the following analogs:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2C(=O)C(C)(C)C3C(=CC([N+]([O-])=O)=CC=3)C2=O)[C:6]([N+:26]([O-:28])=[O:27])=[CH:5][C:4]=1[C:29]1[NH:30][C:31]2[C:32]([N:39]=1)=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2.O.NN>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:26]([O-:28])=[O:27])=[CH:5][C:4]=1[C:29]1[NH:30][C:31]2[C:32]([N:39]=1)=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2
Reactant: COc1ccc2[nH]c(-c3cc([N+](=O)[O-])c(N4C(=O)c5cc([N+](=O)[O-])ccc5C(C)(C)C4=O)cc3OC)nc2n1
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2[nH]c(-c3cc([N+](=O)[O-])c(N)cc3OC)nc2n1

Procedure:
One half gram of 2-[2-methoxy-5-nitro-4-(4,4-dimethyl-7-nitro-2H,4H-isoquinolin-1,3-dione-2-yl)-phenyl]-5-methoxy-imidazo[4,5-b]pyridine is suspended in 10 ml of isopropanol, mixed with 0.5 ml of 80% hydrazine hydrate, and refluxed for 1.75 hours with stirring. The reaction mixture is concentrated by evaporation, the residue is triturated with 50 ml of ice water, and the product precipitated is purified by chromatography on silica gel [eluant: methylene chloride/ethanol (100:0 to 100:2)].
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: CCCOc1ccc(C(N)CC(=O)O)cc1OC
Product: CCCOc1ccc(C(N)CC(=O)OC)cc1OC

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-methoxy-4-propoxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.77-6.86 (m, 3H), 4.32 (q, 1H, J=5 Hz), 3.87-3.95 (m, 2H), 3.80 (s, 3H), 3.61 (s, 3H), 2.62 (d, 2H, J=5 Hz), 1.76 (s, 2H), 0.97 (t, 3H, J=6 Hz).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1NC.IC1C=CC=CC=1.CCCCCCCCCCCC>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:15]1([NH:4][C:1](=[O:3])[CH3:2])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)=O
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (10 mg, 0.0525 mmol, 5.0 mol %), acetamide (170 mg, 2.88 mmol), K3PO4 (450 mg, 2.12 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (17 μL, 0.108 mmol, 10 mol %), iodobenzene (115 μL, 1.03 mmol) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 60° C. for 4 h. After the resulting suspension was allowed to reach room temperature, ethyl acetate (1 mL) and dodecane (235 μL, internal GC standard) were added. GC analysis indicated 100% yield of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[C:18]3=[N:19][S:20](=[O:23])(=[O:24])[CH2:21][CH2:22][N:17]3[CH2:16][CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: COc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Platinum(IV) oxide (37 mg) was added to a solution of 9-[4-(3-methoxyphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (129 mg) in THF (dry) (20 mL) and MeOH (20 mL) and the mixture was stirred at room temperature under hydrogen overnight. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (70.2 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:16]([N:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Br:1])[C:3]1=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Cl)cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=c1c(Br)cc(Cl)cn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A mixture of 3-bromo-5-chloro-1H-2-pyridone (950 mg, 4.56 mmol), freshly ground potassium carbonate (1.26 g, 9.1 mmol) and tetrabutyl ammonium chloride (100 mg) in was stirred mechanically without solvent for 30 min and benzyl bromide (0.56 mL, 4.7 mmol) was added. The mixture was stirred at room temperature for 72 hr. The mixture was diluted with ethyl acetate and filtered, washing the solids with ethyl acetate. The filtrate was evaporated to dryness and the residue was triturated with several portions of hexane. The residue was chromatographed over 90 g of silica gel eluting with 3:1 hexane:ethyl acetate followed by 100% ethyl acetate to give 1-benzyl-3-bromo-5-chloro-2-pyridone (423 mg, 31%), mp 108-110° C. LR(+)LSIMS: m/z 595 (2M+H, 2 Cl, 2 Br), 298 (M+H, 1 Cl, 1 Br).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC(C=O)=CC=1)([O-])=O.S1CC(=O)NC1=O.N1CCCCC1>C1(C)C=CC=CC=1.C(O)(=O)C.O>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)S1
Agent: O=C1CSC(=O)N1
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Nc1ccc(C=C2SC(=O)NC2=O)cc1

Procedure:
Prepared by catalytic hydrogenation of 5-(4-nitro-benzylidene)-thiazolidin-2,4-dione [melting point: 265-270° C.; obtained by heating 4-nitro-benzaldehyde and 2 equivalents of thiazolidin-2,4-dione in the presence of piperidine in toluene using a water separator] in glacial acetic acid on palladium/charcoal (10%) (50° C., 3.5 bar, 0.5 hours).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH2:15][CH2:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: c1ccc(COc2cccc3c2NCC3)cc1
Reaction time: 4 h
Yield: 87.3 %

Procedure:
A magnetically stirred solution of 7-benzyloxyindole (16.0 g, 71.66 mmol) in glacial acetic acid (200 ml) at 10° C. under nitrogen was treated with sodium cyanoborohydride (10.0 g, 0.159 mol) in portions via a powder funnel maintaining an addition temperature of below 17° C. Resulting white suspension was stirred below 20° C. for 4 h and quenched with water (300 ml). Evaporation in vacuo gave a colourless oil which was diluted with ethyl acetate (300 ml) treated with 2M sodium hydroxide (400 ml) and stirred vigorously for 16 h. The organic layer was separated, the aqueous was extracted with ethyl acetate (3×100 ml), the combined organic phases were washed with aqueous 2M NaOH(aq) (200 ml) brine (2×200 ml), dried (Na2SO4) and evaporation of the solvent gave the crude product as an oily white solid. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:9) provided the title compound (14.1 g, 89%) as white crystals. Crystallised from ethyl acetate and light petroleum (b.p. 40-60° C.) as colourless plates (m.p. 58-60° C.). (Found: C, 80.04; H, 6.58; N; 6.19. C15H15NO requires C, 79.97; H, 6.71; N, 6.22%); νmax (nujol)/cm−1 3332, 30338, 1885, 1618, 1591; δH (270 MHz) 3.02 (2H, 2×2-H, 3J2,3=8.4 Hz); 3.51 (2H, 2×3-H, 3J3.2=8.6 Hz); 3.80 (1H, bs, N-H); 5.02 (2H, s, CH2Ph); 6.65 (2H, m, 4-H, 5-H); 6.80 (1H, m, 6-H); 7.33 (5H, m, Ph). δc (67.8 MHz) 30.3 (2-C); 47.62 (3-C); 70.1 (OCH2Ph); 110.8 (6-C); 117.5 (5-C); 118.9 (4-C); 130.4 (3a-C); 137.2 (7a-C); 140.9 (benzyl ipso-C); 144.4 (7-C). Remaining signals lie between 127.3-128.4 ppm; m/z 225.2 (17.24, M+), 134.1 (100), 116.1 (14.06), 91.1 (29.15).
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([CH:20]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]2[CH2:19][C:18](=[C:20]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(C(Br)c2ccccc2)cc1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(=C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
A solution of 0.280 g (1 mmol) of 1-[bromo(phenyl)methyl]4-chlorobenzene, 0.120 g (0.5 mmol) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate (Example 22, Step 1) and 0.12 mL (0.7 mmol) of diisopropylethylamine in 10 mL of acetonitrile was heated at 40° C. for 18 h. The solution was concentrated and the residue was dissolved in 20 mL of ethyl acetate. This solution was washed with 10 mL water and the aqueous layer was washed with a second aliquot of 20 mL ethyl acetate. The organic extracts were washed with brine, combined, and concentrated. The residue was dissolved in acetonitrile and purified by reverse phase chromatography (Waters Xterra C18, 19 mm×50 mm) using a gradient of acetonitrile-water-triethylamine (30:70:1 to 60:40:1) to afford the title compound; 1NMR (CDCl3) δ 3.74 (s, 3H), 3.88 (m, 2H), 4.24 (m, 2H), 4.55 (s, 1H), 6.70-6.86 (m, 3H), 7.21-7.43 (m, 911); Mass Spectrum: m/e=440 (M+1 35Cl) and 442 (M+1 37Cl).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@@H:14]1[CH3:23].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C@@H:14]1[CH3:23])=[O:11]
Reactant: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO2006087543. 2.8 g, 14.53 mmol) and methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.5 g, 14.53 mmol) in dichloromethane (200 mL) was added HOBT (2.22 g, 14.53 mmol) and N-methyl morpholine (4.82 mL, 43.60 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (5.12 g, 26.16 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica, 35% ethylacetate in pet ether) afforded methyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate 3.4 g (67%) as brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:25])[CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1
Reactant: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(C)c2)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassium carbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2cccc(F)c2)c2cccc(Br)c21
Reaction time: 0.33 h

Procedure:
4-Bromo-1H-indole-2,3-dione (6.38 g) was dissolved in 100 mL of DMF and at 0° C., and 60% NaH (1.32 g) was added in portions. The mixture was stirred for 20 minutes before adding 3-fluorobenzyl bromide. The solution was stirred for approximately 30 minutes, quenched with water, and partitioned between water and diethyl ether. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 9.18 g 4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione that was sufficiently pure for use in step 2 below. MS: 385 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]2([CH2:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)SCCCS2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].IC.C[OH:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:36])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC2(Cc3cc(OC)c(OC)c(OC)c3)SCCCS2)cc(OC)c1OC
Reactant: CO
Solvent: CI
Product: COc1cc(CC(=O)Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 72 g of the compound prepared in (b) above in 96% aqueous methanol was heated to 40° C., after which time 50 ml of iodomethane was added. The reaction mixture was then stirred for 24 hours, while the temperature was maintained at 40° C. The solvent was then evaporated to give an oily residue which was crystallized from a mixture of ethyl acetate and petroleum ether to yield a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>CN(C)C=O>[C:13]([CH:3]1[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][O:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)([OH:14])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)c1cccc(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1cccc(OCC2CCCCC2C(=O)O)c1
Temperature: 170 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To 2-(3-hydroxyphenyl)propionic acid (19.2 g) were added cis-2-(hydroxymethyl)cyclohexanecarboxylic acid lactone (19.5 g), potassium carbonate (19.2 g) and dimethylformamide (200 ml). The mixture was heated with stirring for 3 hours in an oil bath maintained at 170° C. The reaction mixture was treated in substantially the same manner as in Reference Example 2. There was obtained the title compound (14 g) as an oil. IR νmaxfilm cm-1 : 1700 (C=O). MS m/e: 306 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[K+]>CS(C)=O.O>[F:16][C:14]1[CH:15]=[C:10]([C:5]2([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:11]=[C:12]([F:17])[CH:13]=1
Reactant: COC(=O)C1(c2cc(F)cc(F)c2)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)C1(c2cc(F)cc(F)c2)CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)cyclopentanecarboxylic acid methyl ester (Step A, 2.0 g, 8.3 mmol) in dimethylsulfoxide (5 mL) was added potassium hydroxide (1.9 g, 33 mol) in 2 mL of water. After stirring at room temperature for 2.5 h, the reaction mixture was partitioned between ether (50 mL) and saturated aqueous hydrochloric acid (2 N, 50 mL). The organic layer was separated and the aqueous layer extracted with ether (2×50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (400 MHz, CD3OD): δ 6.97 (m, 2H), 6.80 (m. 1H), 2.60 (m, 2H), 1.84 (m, 2H), 1.74 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CBr
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83.4 %

Procedure:
To a 0° C. solution of a solution of COMPOUND 249 (150 mg, 0.483 mmol) in CH2Cl2 (10 mL) and DIPEA (0.170 mL, 0.966 mmol) was added methyl bromoacetate (0.055 mL, 0.579 mmol), and the reaction mixture was stirred for 17 hr at room temperature. Saturated NaHCO3 (10 mL) was added to the reaction mixture, which was then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by radial chromatography on silica gel (20:1:0.5 CH2Cl2:MeOH:NH4OH) to give {4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-acetic acid methyl ester (154 mg, 83%). 1H NMR (CDCl3) δ 1.86-1.92 (m, 4H), 1.98-2.07 (m, 2H), 2.08 (s, 6H), 2.45-2.50 (m, 1H), 2.96-2.99 (m, 2H), 3.17 (s, 2H), 3.71 (s, 3H), 3.83 (s, 4H), 7.07 (dd, 2H, J=4.8, 7.5 Hz), 7.34 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8])[C:2]#[CH:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])[C:2]#[CH:3]
Reactant: C#CCSc1ccccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To CH2Cl2 was added the benzyl alcohol (22 g) from Step B, above and then pyridinium chlorochromate (30.75 g; 0.15 mmol). The reaction mixture was stirred at room temperature for 2 hours then filtered and concentrated to afford 12.0 g of the subtitle compound. Several lots of the subtitle compound were prepared according to the procedures of Step A, B, and C, and were combined to afford 35.2 g of the subtitle compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].CO>C(OCC)(=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(diphenylmethyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 81% overall yield. mp 160°-161°. FDMS m/e=441 (M+ of free base). α[D]589 =-8.71 (c=0.89, methanol).