Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N([SiH3:18])C(C)C)(C)C>>[SiH3:18][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1]
Reactant: CC1Cc2ccccc2N1
Reactant: CC(C)N([SiH3])C(C)C
Product: CC1Cc2ccccc2N1[SiH3]
Reaction time: 24 h

Procedure:
In a 500 ml Schlenk flask, 62.5 g (0.5 mol) 2-methylindoline and 131 g (1.0 mol) di-isopropylaminosilane were stirred at ambient temperature under a nitrogen atmosphere for 24 hours. The relatively lower boiling point by-product di-isopropylamine was removed with vacuum at a pressure of 20 mmHg and room temperature (25° C.). The reaction mixture was stirred for another 24 hours. The end-product N-silyl-2-methylindoline was obtained by vacuum distillation. The compound was characterized by mass spectroscopy (MS). The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 4 and shows, among other things, peaks at 163, 162, 148, 132, 117, 105, 91, and 77. The molecular weight of the N-silyl-2-methylindoline was 163.29.
Reaction SMILES: Cl[C@@H:2]1[C@H:19]2[O:20][C@:18]32[C@:13]([CH3:28])([CH2:14][CH2:15][C@H:16]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17]3)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:29])[C@H:6]2[CH2:30][C@@H:5]12>C(O)(=O)C.O1CCCC1.[Zn]>[OH:20][C@@:18]12[CH2:17][C@@H:16]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:15][CH2:14][C@:13]1([CH3:28])[C@@H:12]1[C@H:3]([C@H:4]3[C@@:8]([CH2:10][CH2:11]1)([CH3:9])[C:7](=[O:29])[C@H:6]1[CH2:30][C@@H:5]31)[CH:2]=[CH:19]2
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3C=C[C@]2(O)C1
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A solution of 196 g of 7α-chloro-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one in 500 ml of acetic acid and 800 ml of tetrahydrofuran is combined at 70° C. with 392 g of zinc dust in two portions at an interval of 30 minutes, and stirred for one hour at this temperature. After cooling, the zinc is filtered off over "Celite" and washed with 5 l of methylene chloride. The combined filtrates are mixed with 1.5 l of water and neutralized under agitation by the addition of solid sodium bicarbonate. The organic phase is then washed with water, dried over sodium sulfate, and concentrated under vacuum. By trituration of the thus-obtained solid with ethyl acetate, 134.7 g of 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one is produced, mp 243° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[S:18][C:6]2[CH2:7][NH:8][CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CCOCC>[ClH:1].[CH3:2][C:3]1[S:18][C:6]2[CH2:7][N:8]([CH3:19])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: Cc1cc2c(s1)CNCC2c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: Cc1cc2c(s1)CN(C)CC2c1ccc(Br)cc1
Yield: 90.6 %

Procedure:
3.45 gm (0.01 mole) of 2-methyl-4-(p-bromophenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride, m.p. 282°-283° C., 50 ml of ether, 2.8 gm (0.02 mol) of potassium carbonate and 1.5 gm (0.01 mol) of methyl iodide were admixed, and the mixture was heated for 2 hours on a water bath. The inorganic salts were separated by suction filtration, the solvent was evaporated out of the filtrate, and the hydrochloride was precipitated from the residue with ethereal hydrochloric acid, and recrystallized from isopropanol. 3.25 gm (91% of theory) of 2,6-dimethyl-4-(p-bromophenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride, m.p. 258°-260° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:1][C:2]1[C:7]([Cl:18])=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1nc(Br)cc(N)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(Br)c(Cl)c(N)c1OC

Procedure:
To methyl 4-amino-6-bromo-3-methoxypyridine-2-carboxylate (1.45 g, 5.56 mmol) in 10 mL of acetonitrile was added sulfuryl chloride, in excess, via pipette until the solution remained yellow. The solution was heated to reflux for 5 min. The reaction mixture was added to saturated sodium bicarbonate and aqueous phase was extracted with diethyl ether (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid. Solid was washed in 10% diethyl ether/petroleum ether and solid filtered to give 0.580 g of a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:35]([C:29]3[N:30]([CH3:34])[C:31]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=4)=[O:36])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cn1c(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)cc2cc(F)ccc21

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 5-fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=508.1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:6][O:5][C:3]([C:2]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:4]
Reactant: COC(=O)CBr
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(OC)cc2o1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl bromoacetate (1.53 g, 10 mmol), 2-hydroxy-4-methoxybenzaldehyde (1.52 g, 10 mmol) and Cs2CO3 (6.5 g, 20 mmol) in DMF (100 mL) was stirred vigorously at 50° C. for 3 hrs and then at 150° C. for 5 min. The reaction was cooled, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to give essentially pure 6-methoxy-benzofuran-2-carboxylic acid methyl ester as a solid.
Reaction SMILES: [NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:9]([N:4]1[CH2:3][C:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1(N)CN(Cc2ccccc2)CC12CC2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (7.3 g) was dissolved in toluene (30 mL). t-Butyl dicarbonate (9.3 mL) and 1N aqueous sodium hydroxide (10 mL) were added to the solution, followed by stirring for 15 hours at room temperature and then for 4 hours at 50° C. After completion of reaction, the toluene layer was separated and washed with water, followed by drying with sodium sulfate. The desiccant was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel chromatography (hexane:ethyl acetate), to thereby yield the title product (8.745 g, yield: 820). Notably, when optically active 7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane is treated in accordance with the above-described procedure, the corresponding optically active target product can be yielded without decreasing optical purity.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40]C(=O)C(F)(F)F)[O:13][C@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[NH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C@H:14]1[O:13][C@@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:15]1[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CO[C@@H]1O[C@H](COCCCCCNC(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CO[C@@H]1O[C@H](COCCCCCN)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
To a stirred solution of methyl 2,3,4-tri-O-benzyl-6-O-(N-trifluoroacetyl-5-aminopentyl)-β-D-glucopyranoside (799 mg, theoretically 1.71 mmol, structure (13) from Example 4) in 10 mL of ethanol at room temperature was added a solution of 5M (3 mL, 15 mmol). The solution was heated to reflux for 2 hours. The solvents were removed under reduced pressure. The reaction mixture was diluted with dichloromethane (70 mL) and washed with aqueous HCl (25 mL, 15 mmol). The water layer was re-extracted with dichloromethane (3×50 mL), and the combined organic layers were washed with saturated aqueous NaCl (1×75 mL) and dried over magnesium sulfate. Concentration and crystallization from ethyl acetate/petroleum ether provided pure analog having structure (8), methyl 6-O-(5-aminopentyl)-2,3,4-tri-O-benzyl-β-D-glucopyranoside, (675 mg, 72% from methyl 2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-β-D-glucopyranoside) as a white solid: m.p. 95°-95.5° C.; RF 0.19 (6% methanol in dichloromethane); 1H NMR (500 MHz, CDCl3) δ 7.35-7.24 (m, 15H), 4.92 (d, J=7.5 Hz 1H), 4.90 (d, J=7.6 Hz, 1H), 4.85 (d, J=11.0 Hz, 1H), 4.78 (d, J=11.0 Hz, 1H), 4.70 (d, J=11.0 Hz, 1H), 4.60 (d, J=11.0 Hz, 1H), 4.32 (7.8, 1H), 3.66-3.59 (m, 3H), 3.56 (s, 3H), 3.48-3.36 (m, 3H), 2.94 (dd, J=12.5, 2.1 Hz, 1H), 2.68 (dd, J=12.0, 6.8 Hz, 1H), 2.64-2.53 (m, 2H), 1.71 (s, 2H), 1.59-1.53 (m, 2H), 1.51-1.45 (m, 2H), 1.42-1.36 (m, 2H), 13C NMR (500 MHz, CDCl3) δ 138.55, 138.47, 138.17, 128.39, 128.33, 128.03, 127.95, 127.85, 127.77, 127.60, 127.57, 104.72, 84.56, 82.45, 79.74, 75.66, 75.02, 74.74, 74.16, 62.62, 57.20, 50.69, 49.72, 32.49, 29.65, 23.37; IR (thin film) 3280 (m), 3095 (w), 3065 (w), 3035 (w), 2935 (s), 2915 (s), 2860 (s), 1496 (w), 1454 (m), 1404 (w), 1393 (w), 1358 (m), 1214 (m), 1115 (s), 1072 (s), 1037 (m), 1027 (m), 1009 (m), 911 (w), 826 (s), 747 (s), 696 (s) cm-1 ; HRMS m/e calc'd for C33H43O6N (M+H) : 550.3168, found 550.3179; [α]D20 +9.3° (c=0.15, acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][CH2:27][CH:28]([NH2:31])[CH2:29][CH3:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[NH:31][CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: CCC(N)CC
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC(CC)CC)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and pentan-3-amine as a pale-yellow solid (78%). 1H NMR (400 MHz, DMSO-d6) δ 0.68 (t, J=8.0 Hz, 6H), 1.27 (s, 6H), 1.31 (t, J=8.0 Hz, 3H), 1.37-1.42 (m, 4H), 2.54 (s, 3H), 3.56-3.61 (m, 1H), 4.16 (s, 2H), 4.30 (q, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.06 (s, 2H). MS 416 (MH+).
Reaction SMILES: [Na].[CH2:2]([SH:8])[CH2:3][S:4][CH2:5][CH2:6][SH:7].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][S:8][CH2:2][CH2:3][S:4][CH2:5][CH2:6][S:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: SCCSCCS
Reactant: CCCCCCl
Agent: [Na]
Solvent: CCO
Product: CCCCCSCCSCCSCCCCC
Reaction time: 0.5 h
Yield: 62 %

Procedure:
(Compound 1) of formula: ##STR11## 150 ml of absolute ethanol are introduced into a 500 ml three-necked flask, under argon, which is equipped with a thermometer, a condenser and a dropping funnel. Into it are dissolved 4.6 g of sodium (0.20 mole) and heating takes place to 45° C. This is followed by the slow addition of 15.43 g of an ethanolic 3-thia-1,5-pentane dithiol solution (0.10 mole). After stirring for 30 min., slow addition takes place of 25.58 g of an ethanolic 1-chloropentane solution (0.24 mole) and refluxing takes place for 4 hours. The reaction mixture is brought to ambient temperature, followed by filtering. This gives 28.8 g of crude product which is solubilized in 200 ml of dichloromethane and this is all washed with 2×100 ml of distilled water. Drying takes place on MgSO4, followed by filtration. After evaporating the solvent, recrystallization takes place twice in ethanol giving 18.21 g of 6,9,12-trithiaheptadecane, which corresponds to a 62% yield. The said thioether has the following characteristics:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:10]=2[CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:4][CH:3]=1.[F:41]C1C=CC(N)=CC=1>>[F:41][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:10]=2[CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(C(F)(F)F)ccc1Nc1ccc(Cl)cc1
Reactant: Nc1ccc(F)cc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(C(F)(F)F)ccc1Nc1ccc(F)cc1

Procedure:
The compound of example 19, 4-{3-[2-(4-chlorophenylamino)-5-trifluoromethylbenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (molecular weight 580.11 (C27H19ClF6N4O2); retention time Rt=3.21 min. [C]; MS (ESI): 581.18 (MH+) was prepared like the compound of example 17 with the difference that, in the second stage of the synthesis, instead of 4-fluoroaniline,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=2[CH3:33])=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:36])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 4-(3-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([O:19]C)=[O:18])=[O:12].Cl>C1COCC1.[OH-].[Na+].O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([OH:19])=[O:18])=[O:12]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2sc3nccnc3c2N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1NC(=O)c1sc2nccnc2c1N
Yield: 100.1 %

Procedure:
A solution of methyl 3-(7-aminothieno[2,3-b]pyrazine-6-carboxamido)-4-methylbenzoate 108 (0.803 mmol, 275 mg) in THF (10 mL) and 2N NaOH (10 mL) stirred for 4 h. The red solution was diluted with water, acidified with 2N HCl solution pH 5-6 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to give 3-(7-aminothieno[2,3-b]pyrazine-6-carboxamido)-4-methylbenzoic acid 109 (264 mg, 100%). NMR (400 MHz, DMSO-d6) 2.31 (s, 3H), 7.08 (s, 2H), 7.41 (d, J=8.2 Hz, 1H), 7.75 (dd, J=7.8 Hz and 1.6 Hz, 1H), 7.93 (d, J=1.2 Hz), 8.78 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 9.53 (s, 1H), 12.91 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[C:17]12([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:30][CH2:29][C:28]([NH:27][C:17]23[CH2:24][CH:23]4[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]4)[CH2:18]2)[CH2:26]3)=[O:31])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)NC23CC4CC(CC(C4)C2)C3)cc(C(C)(C)C)c1O

Procedure:
Following the method of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole), the title compound of Example 5 (1.03 g, 0.005 mole) and triethylamine (0.5 ml) were stirred in methanol (100 ml) for 12 hours at room temperature under argon. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica, recrystallized from ethyl aceate/hexane, filtered and dried in vacuo, m.p. ca 172.5°-173.5° C. Analysis calc. for C27H41NO2S(443.69):
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[N:6]([CH3:8])[CH3:7])C.[OH-].[K+].O.Cl>CN(C=O)C>[Br:15][C:11]1[CH:10]=[C:9]([CH:5]([N:6]([CH3:8])[CH3:7])[C:4]([OH:16])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(c1cccc(Br)c1)N(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(C(=O)O)c1cccc(Br)c1
Yield: 93.6 %

Procedure:
To a solution of (3-bromo-phenyl)-dimethylamino-acetic acid ethyl ester (350 mg, 1.2 mmol) in DMF was added potassium hydroxide (4 mL, 50% in water) and water (50 mL). The resulting mixture was refluxed for 25 hours. The mixture was neutralized to pH 7 with concentrated hydrochloric acid and extracted with ethyl acetate (50 mL×4). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford (3-Bromo-phenyl)-dimethylamino-acetic acid (290 mg, 94%). MS: m/z 258 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([C:32]#[C:33]C4CCOC4)=[C:17]([NH:20][C:21]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:22])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(NC2C3C(=CC(C#C[C@@H:61]4[CH2:65][CH2:64][CH2:63][O:62]4)=C(N)C=3)N=CN=2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([C:32]#[C:33][C@@H:61]4[CH2:65][CH2:64][CH2:63][O:62]4)=[C:17]([NH:20][C:21]([CH2:23][P:24](=[O:31])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])=[O:22])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#C[C@@H]1CCCO1
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#CC1CCOC1)OCC
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#C[C@@H]1CCCO1)OCC

Procedure:
Compound 2.4 was prepared with the same procedure as the preparation of Compound 1.3, using Compound 2.3 instead of Compound 1.2. MS (ESI) m/z=562 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[C:11]([O:18][CH3:19])[CH:10]=1.C(N(CC)CC)C>ClCCl>[C:2]1([NH:1][C:15](=[O:16])[C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[O:18][CH3:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(Br)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Reaction time: 3 h
Yield: 73.5 %

Procedure:
Aniline(1.24 mL, 13.62 mmol) was added slowly to a mixture of 4-bromo-2-methoxy-1-benzenecarbonyl chloride (3.24 g, 12.98 mmol) and triethyl amine (2.7 mL, 19.48 mmol) in dichloromethane (130 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-phenyl-4-bromo-2-methoxybenzamide (2.92 g, 74%). 1H NMR (DMSO-d6) δ 3.92 (s, 3H), 7.09 (s, 1H), 7.27 (m, 1H), 7.33 (m, 2H), 7.39 (s, 1H), 7.55 (d, J=8.15 Hz, 1H), 7.71 (m, 2H), 10.10 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[CH2:22][C:23]#[N:24])[CH2:19]2>O>[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[CH2:22][CH2:23][NH2:24])[CH2:19]2
Reactant: N#CCC1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
0.051 Mole of lithium aluminum hydride is dissolved in 200 ml. of anhydrous ethyl ether at 0° C, under nitrogen. 0.0571 Mole of adamant-2-yl acetonitrile in 100 ml. of anhydrous ethyl ether is added dropwise with stirring and the mixture is allowed to warm to room temperature and stirred for one hour. 10 Ml. of water is added dropwise and the mixture then filtered. The filtrate is dried over potassium hydroxide pellets and then filtered. The filtrate is distilled to remove the solvent affording 2-(adamant-2-yl)ethylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:28]([CH3:27])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CNc1ccccc1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Product: COc1ccc(-c2nc(CN(C)c3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 56, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline was reacted with N-methylaniline to give 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(N-methyl-N-phenylaminomethyl)quinazoline. This compound was recrystallized from ethanol. Colorless needles, mp. 141°-143° C.