Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.C(Cl)(=O)C(Cl)=O.Cl.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:24][NH:25][CH3:26].[Cl-].[Na+]>C1C=CC=CC=1.C(Cl)Cl.N1C=CC=CC=1.Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:24][N:25]([CH3:26])[C:8](=[O:10])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:1])([CH3:12])[O:6]1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Reactant: CNCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a suspension of (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid, Compound III-A, (4.5 g, 26.2 mmol) in benzene (30 mL) was added oxalyl chloride (15 mL) and the resulting mixture was heated at reflux for 1 h. The mixture was cooled to room temp. and concentrated. The residue was dissolved in methylene chloride (30 mL) and cooled to 0° C. To this was added a suspension of (3,4-dichloro-benzyl)-methyl-amine hydrochloride salt (5.0 g, 22.1 mmol) in methylene chloride (30 mL) and pyridine (18 mL). The resulting mixture was stirred at room temp for 18 h then diluted with 1N HCl. The aqueous phase was saturated with sodium chloride and extracted with methylene chloride (3 times). The organic layers were combined, dried (Na2SO4), and concentrated. The brown oil was purified over silica gel eluting with ethyl acetate/hexane (1:1) to give the title compound as a pale yellow oil that solidified to a white solid upon standing (6.2 g, 82% yield). 1H NMR (300 MHz, DMSO) δ: 7.44–7.10 (m, 3H), 6.16 (s, 0.66H), 6.08 (s, 0.33H), 4.59 (s, 1.33H), 4.53 (s, 0.67H), 3.02 (s, 2H), 2.97 (s, 1H), 1.74 (s, 4H), 1.69 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C[C@H]4C[O:21]C(=O)N4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.N(C1C=CC(C[C@@H:32]2[CH2:36][O:35][C:34](=[O:37])[NH:33]2)=CC=1)N.O.CN1CC=C(C2C3C(=CC=C(C[C@@H]4COC(=O)N4)C=3)NC=2)CC1.Cl>>[OH2:21].[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:32]4[CH2:36][O:35][C:34](=[O:37])[NH:33]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NNc1ccc(C[C@@H]2COC(=O)N2)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C[C@H]4COC(=O)N4)cc23)CC1
Agent: CN1CC=C(c2c[nH]c3ccc(C[C@@H]4COC(=O)N4)cc23)CC1
Agent: Cl
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc([C@@H]4COC(=O)N4)cc23)CC1

Procedure:
By steps analogous to steps (a) to (c) of Synthetic Example 14, the product from step (a) was converted to (R)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indole hydrate, mp 229°-231° C., [α]D18 +24.9° (c=0.5, 1N aqu. HCl). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: N[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N([O-])=O.[Na+].[I-:17].[K+]>Cl.O>[I:17][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cccc(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
To 2-amino-3-methoxybenzoic acid (1.00 g, 5.98 mmol) in 25% aqueous hydrochloric acid (8 ml) at 0° C. was added sodium nitrite (0.45 g, 6.50 mmol) in water (3 ml). This solution was added drop-wise to a solution of potassium iodide (15.8 g, 59.3 mmol) in water (60 ml) and allowed to warm to 25° C. then stirred for 16 h. The reaction mixture was quenched with 1 N aqueous sodium bicarbonate until the pH became basic. The solution was extracted with methylene chloride and the organic dried over sodium sulfate, filtered, and concentrated to give a purple oil. The residue was purified by column chromatography, eluting with 10% methanol in dichloromethane. Pure fractions were concentrated to afford (0.623 g, 38%) of 2-iodo-3-methoxybenzoic acid. MS (EI) for C8H7IO3: 279 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([CH:29]3[CH2:34][CH2:33][CH:32]([O:35][CH2:36]C(OCC)=O)[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.Cl>O1CCCC1>[OH:35][C:32]([CH3:33])([CH3:31])[CH2:36][O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[C:26]([CH3:28])[N:27]=[C:19]23)[CH2:30][CH2:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(=O)OCC)CC2)c2nc(C)nn12
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
Ethyl [(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.5 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 4.2 mL) was added at 0° C. After stirring at the same temperature for 1 hr, 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.32 g, 56%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.[CH2:36]([N:43]1[CH:48]2[CH2:49][CH2:50][CH:44]1[CH2:45][C:46](=O)[CH2:47]2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:36]([N:43]1[CH:48]2[CH2:49][CH2:50][CH:44]1[CH2:45][CH:46]([NH:29][C:28]1[C:20]([CH3:19])=[C:21]3[C:25](=[CH:26][CH:27]=1)[N:24]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[N:23]=[CH:22]3)[CH2:47]2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1c(N)ccc2c1cnn2C1CCCCO1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1c(NC2CC3CCC(C2)N3Cc2ccccc2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
Sodium triacetoxyborohydride (477 mg, 2.25 mmol) and then acetic acid (99 μl, 1.73 mmol) were added to a suspension of 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (400 mg, 1.73 mmol) and 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (410 mg, 1.90 mmol) in 1,2-dichloroethane (5 ml), and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and then extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/2) to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (283 mg, 38%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([F:19])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:11])[CH:9]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[F:19][C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][C:8]=1[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: COC(OC)c1ccc(F)c(C(=O)c2cccc(F)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(F)c(C(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A total of 18.7 g of [5-(dimethoxymethyl)-2-fluorophenyl](3-fluorophenyl)methanone was dissolved in 100 ml of tetrahydrofuran, and 5 ml of 5 N hydrochloric acid was added, followed by stirring at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 15.8 g of 4-fluoro-3-(3-fluorobenzoyl)benzaldehyde as a colorless oil. A total of 13.8 g of this compound was dissolved in 50 ml of dimethyl sulfoxide, and a solution of 15.2 g of sodium chlorite in 50 ml water was added dropwise over 1 hour under ice-cooling. To the reaction mixture was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was filtered using diisopropyl ether, to give 12.9 g of 4-fluoro-3-(3-fluorobenzoyl)benzoic acid as a colorless solid. A total of 11.1 g of this compound was dissolved in 50 ml of N,N-dimethylformamide, and 5.8 g of potassium carbonate and 2.9 ml of methyl iodide were added, followed by stirring at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:15), to give 11.5 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.C1C=CC=CC=1.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C2NCCS2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCSC1c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
Five (5) grams of 2-m-chlorophenyl thiazolidine was dissolved in 50 ml. of benzene and 2.6 g. of triethylamine and the mixture was stirred in a room temperature water bath, while 3.7 g. of dichloroacetyl chloride was added dropwise. After standing for about 30 minutes, the mixture was washed with water, separated and dried over magnesium sulfate and the benzene stripped under vacuum. There was obtained a yield of 7.2 g. of an oil, the title compound, ND30 =1.5805.
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:21])=[O:2])=[CH:18][CH:17]=1
Reactant: CCCCC/C(=C/C=C/C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC/C(=C/C=C/C(=O)O)c1ccc(OC)cc1
Yield: 87.6 %

Procedure:
As described in Example 99, (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester (3.6 g) was saponified in a refluxing mixture of methanol (40 mL) and 1N NaOH (40 mL). After 45 minutes the acid was isolated in the usual way and crystallized from ether-hexane to give 3.0 g of (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid, mp 86.5°-87.5° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([C@@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Reaction time: 4 h

Procedure:
(1R, 2S, 3S, 5S)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.00 g, 1.92 mmole) was refluxed in ethanol (10 mL) with isopropylamine (1.6 mL, Fluka) under nitrogen for 24 hours. A second portion of isopropylamine (0.80 mL) was added and reflux continued for an additional 4 hours. Volatiles were evaporated, the residue was redissolved in ethanol, 1N sodium hydroxide (1.90 mL) was added, and volatiles were reevaporated. The residue was chromatographed on a silica gel column. Title compound was eluted with 10% methanol-ethyl acetate as a colorless glass. Concentration of an ethanol solution gave title compound as a off-white solid foam (360 mg, 46%). Such a sample was solidified by trituration with 95% water-5% methanol to give title compound as white powder (96%), m.p. 137°-138° C.; 1H-NMR(DMSO-d6)δ: 7.60 and 7.39 (both s, 2, aromatic CH), 6.64 (d, J=7.4 Hz, 1, NH), 5.14 (t, J=4.3 Hz, 1, OH), 4.81 (d, J=7.3 Hz, 1, OH), 4.70 (d, J=3.5 Hz, 1, OH), 4.70-4.50 (m, 1, NCH), 4.50-4.30 (m, 1, OCH), 4.10-4.00 (m, 1, NCH of cyclopropylamino), 3.9-3.75 (m, 1, OCH), 3.70-3.50 (m, 2, OCH2), 2.20-1.80 (m, 3, CH2 and CH of cyclopentane), 1.24 (d, J=6.6 Hz, 6, 2 CH3); mass spectrum (CI): 374(M+1); [α]20589 -3.72°, [α]20578 -2.60°, [α]20546 -2.23°, [α]20436 -9.67°, [α]20365 -51.7° (c=0.269, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>O.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:19][OH:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Yield: 66.2 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-2-phenyl-ethan-1-one (Step 1) (12.5 g, 53.88 mmol), hydroxylamine hydrochloride (9.4 g, 135.4 mmol) and sodium acetate (268.5 mmol) in ethanol water (1:1, 250 mL) was heated at reflux for 4 hours, then was diluted with water (200 mL). The precipitate formed was filtered, dried and was recrystallized from hexane to afford 10 g (75%) of the desired product: mp 81°-82° C. 1H NMR (CDCl3) 7.50-7.06 (m, 9H), 4.18 (s, 2H). Found: Anal. Calc'd for C14H11NOCl2 :
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.[NH2:22]N>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:7]2[NH:22][N:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC
Reactant: NN
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c1-c1cc(Cl)ccc1OC

Procedure:
A solution of ethyl 2-(5-chloro-2-methoxybenzoyl)-3-(dimethylamino)acrylate (2.49 g, 8.00 mmol, 1 eq) and hydrazine (0.40 mL, 13 mmol, 1.6 eq) in 20 mL ethanol was heated at 70° C. for 2 hours. Solvent and excess hydrazine were then evaporated to provide ethyl 5-(5-chloro-2-methoxyphenyl)-1H-pyrazole-4-carboxylate, which was used without further purification. LCMS (ESI) m+H=281.3.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[P:13](Cl)([Cl:16])([Cl:15])=[O:14]>C(OCC)C>[P:13]([Cl:16])([Cl:15])([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)CO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)COP(=O)(Cl)Cl
Temperature: 0 °C
Yield: 101.1 %

Procedure:
To a solution of 1.8 ml (20 mmol) of 2-methyl-1-propanol in diethyl ether (40 ml) is added 2.02 g (20 mmol) of triethylamine, followed by 1.9 ml (20 mmol) of phosphorus oxychloride with stirring and cooling at 0° C. The mixture is stirred at 0° C. for 1 hr. It is then filtered and evaporated under reduced pressure to give 3.86 g of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH2:22]([N:24]([CH2:28]C)[CH2:25][CH2:26][NH2:27])C>>[CH3:22][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc2c1
Reactant: CCN(CC)CCN
Product: COc1ccc2c(=O)c3c(NCCN(C)C)ccc([N+](=O)[O-])c3sc2c1

Procedure:
1-[[2-(Dimethylamino)ethyl]amino]-6-methoxy-4-nitro-9H-thioxanthen-9-one was prepared similarly from 0.99 g of 1-chloro-6-methoxy-4-nitrothioxanthone and 0.67 g of N,N-diethylethylenediamine affording 0.98 g, mp 144°-145°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[CH:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: C1CCC(N2CCNCC2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)nnn2CCCCN1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-cyclohexyl)piperazine (5.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.5 g compound (I-46) with a yield of 63.7%. ESI-MS [M+H]+: m/z 341.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[CH3:23][N:24]([CH3:25])[CH2:18][CH:16]([OH:17])[CH2:15][O:14][C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CNC
Reactant: Cc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CCCCc2ccccc2OCC(O)CN(C)C)cc1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 0.63 g of 2-{2-[4-(4-methylphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran was treated with 2 ml of 50% by volume aqueous dimethylamine. The crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.65 g (yield 89%) of the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][Si:8]([C:11]#[CH:12])([CH3:10])[CH3:9].C(NCC)C>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH3:7][Si:8]([C:11]#[C:12][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1)([CH3:10])[CH3:9]
Reactant: Ic1cn[nH]c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cn[nH]c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Iodo-1H-pyrazole (20.0 g, 103 mmol) is dissolved in anhydrous THF (150 ml) and trimethylsilyl acetylene (72.8 ml, 515 mmol) is added under an inert atmosphere. Diethyl-amine (150 ml), bis-(triphenylphosphine) palladium (II) chloride (10.8 g, 15 mmol) and copper iodide (2.9 g, 15 mmol) are added and the reaction mixture is left to stir at room temperature for 3 hours. The solvent is removed under reduced pressure. The residue is dissolved in diethyl ether and the insoluble impurities are filtered off. The solvent is removed under reduced pressure. The residue is dissolved in methanol and the insoluble impurities removed. The solvent is removed under reduced pressure. The residue is purified by dry flash chromatography on silica gel eluting with a gradient system of diethyl ether: iso-hexane (20:80 to 100:0) to afford the title compound [MH+] 165.07 1H NMR (DMSO): 0.00 (s, 9H), 7.45 (s, 1H), 7.90 (s, 1H), 12.90 (br s, 1H)
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:7][C:6]([CH2:10][C@H:11]([CH3:29])[CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[Si](CC)(CC)CC)([OH:9])[CH2:5][CH2:4]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([CH2:12][C@@H:11]([CH3:29])[CH2:10][C:6]2([OH:9])[CH2:7][CH2:8][C:3]([N:2]([CH3:36])[CH3:1])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:4][CH2:5]2)=[CH:14]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccccc2c1C[C@@H](C)CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Cc1c[nH]c2ccccc12)CC1(O)CCC(c2ccccc2)(N(C)C)CC1
Reaction time: 4 h

Procedure:
A solution of (R)-4-dimethylamino-1-[2-methyl-3-(2-(triethylsilyl)-1H-indol-3-yl)propyl]-4-phenylcyclohexanol (175 mg, 0.34 mmol) in anhydrous tetrahydrofuran (30 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (109 mg, 0.34 mmol) and stirred for 4 h with reflux. The reaction mixture was then concentrated to low volume in a vacuum and the residue was purified by flash chromatography (10 g, 20×1.5 cm) with ethyl acetate/methanol (95:5).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:3]=1.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)#[N:29].C([O-])([O-])=O.[K+].[K+]>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].CN(C=O)C>[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:3]=1)#[N:29]
Reactant: O=C(NCc1cccnc1)c1ccc(Cl)nc1NCCc1cccc(F)c1
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccnc2)c(NCCc2cccc(F)c2)n1
Temperature: 125 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (1.0 g, 2.6 mmol), 2-cyanophenyl boronic acid (460 mg, 3.12 mmol), PdCl2(dppf)2 (140 mg, 0.26 mmol), K2CO3 (1.08 g, 7.8 mmol) and anhydrous DMF (8 mL) was degassed with nitrogen for 10 min. The mixture was then stirred at 125° C. for 1 hr. The mixture was filtered through the silica gel pad and washed with EtOAc. The filtrate was concentrated to dryness and purified by silica gel flash chromatography to give the desired product 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide as a pale yellow solid (740 mg, 63%). LRMS (M+H+) m/z 452.1.