Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]([OH:7])([CH2:5]Cl)[CH2:3][OH:4].[H-].[Na+].[CH3:10][O:11][C:12]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:13]=1[CH2:14][Li].COC1C(C)=C(C)C(OC)=C(C)C=1C>O1CCCC1.O>[CH3:1][C@:2]([OH:7])([CH2:5][CH2:21][C:18]1[C:19]([CH3:20])=[C:12]([O:11][CH3:10])[C:13]([CH3:14])=[C:16]([CH3:24])[C:17]=1[O:22][CH3:23])[CH2:3][OH:4]
Reactant: C[C@@](O)(CO)CCl
Reactant: [Li]Cc1c(C)c(OC)c(C)c(C)c1OC
Agent: COc1c(C)c(C)c(OC)c(C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A solution of 9.78 g (80 mmol) of (2R)-2-methyl-3-chloropropane-1,2-diol in 100 ml of tetrahydrofuran was reacted with 4.3 g (180 mmol) of sodium hydride at room temperature by the portionwise addition while stirring for 1 hour. To the suspension obtained there was added dropwise, while stirring at room temperature, a solution of 88 mmol of 2,5-dimethoxy-3,4,6-trimethylbenzyl lithium (obtained by reacting 17.2 g (88 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene in 20 ml of n-pentane with 88 mmol of tert.butyl lithium at room temperature) and the mixture was subsequently stirred at room temperature for an additional 16 hours. The mixture was then treated with 50 ml of water while stirring, the volatile constituents were removed by distillation in a vacuum (~15 mbar) and the separated material was removed by filtration and washed with water. The filter residue was recrystallized from ether/hexane and there were obtained 23 g of (2S)-2-methyl-4-(2,5 -dimethoxy-3,4,6-trimethylphenyl)-1,2-butanediol in the form of white crystals with a melting point of 83°-85° C. and [α]D20 =+2.86° (c=1.5% in CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH2:30][C@H:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][C:28]=1[Cl:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:22][C:23]1[CH:24]=[C:25]([CH2:30][C@H:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:27][C:28]=1[Cl:29])=[O:21])[C@H:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](C)Cc1ccc(Cl)c(N)c1
Reactant: C[C@H]([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H](C)Cc1ccc(Cl)c(NC(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H](C)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (purity 76%, about 3.14 mmol) of (3R)—N-[(benzyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 0.91 g (3.76 mmol) of (+)-ethyl (2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate were dissolved in a mixture of 10 ml of DMF and 4 ml of pyridine, and 1.55 g (4.08 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were then washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The resulting solid was stirred in a mixture of cyclohexane and diethyl ether (about 3:1), filtered off with suction and dried under high vacuum. This gave 0.99 g of the target product (59.9% of theory, diastereomer ratio about 7:1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4].[CH3:20][O:21][C:22]1[C:33]([CH2:34][CH:35]=O)=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[O:28][CH2:29][C:24]=2[CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:20][O:21][C:22]1[C:33]([CH2:34][CH2:35][N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[C:12]4[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:13]=4)[CH:9]=[CH:10]3)[CH2:15][CH2:16]2)=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[O:28][CH2:29][C:24]=2[CH:23]=1
Reactant: COc1cc2c(cc1CC=O)N(C)C(=O)OC2
Reactant: CNC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4cc5c(cc4OC)COC(=O)N5C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
80 mg of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide and 83 mg of (6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl)acetaldehyde were dissolved in 6 ml of methylene chloride. Thereafter, 0.04 ml of acetic acid and 99 mg of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate), so as to obtain 141 mg of the subject compound.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:26][CH2:27][C:28]([F:32])([F:31])[CH2:29][CH2:30]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.0244 g, 0.123 mmol), 1-[5-chloro-8-(4,4-difluoropiperidin-1-yl)quinolin-7-yl]ethanamine (0.020 g, 0.061 mmol), and N,N-diisopropylethylamine (0.021 mL, 0.12 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H21ClF2N7 (M+H)+: m/z=444.1; Found: 444.0.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:41])[C@@H:35](O)[CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:34]([OH:41])=[O:33])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)CC(C)C
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Product: CC(C)C[C@@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and (S)-(−)-hydroxyisocaproic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 81-83° C.; MS m/e 645 (M−H)+;
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CCCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of hex-5-en-1-ol (20.0 g, 200 mmol) in CH2Cl2 (350 mL, 0.57 M) at 0° C. was added triethylamine (33.7 mL, 240 mmol, 1.2 equiv), DMAP (1.22 g, 10 mmol, 0.05 equiv) and then 4-Nitrobenzoyl chloride (39 g, 210 mmol, 1.05 equiv.). The reaction was stirred at rt for 2 h. The reaction mixture was quenched with a saturated NH4Cl solution and extracted 3 times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The product was purified by combi-flash 2×120 g silica gel cartridge using gradient (0-5% in 5 min, 5-25% in 30 min, 25-40% EA/Hex in 10 min) to afford the desired product (35 g, Yield=70%) as a yellowish oil. 1H NMR (500 MHz, acetone-d6): δ 8.36 (d, 2H), 8.26 (d, 2H), 5.87-5.79 (m, 1H), 5.03 (d, 1H), 4.94 (d, 1H), 4.38 (t, 2H), 2.14 (m, 2H), 1.84-1.78 (m, 2H), 1.60-1.54 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[C:13](=[O:18])[NH:14][N:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[C:13](=[O:18])[N:14]([CH3:28])[N:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1[C@@H](CC(=O)c1ccn[nH]c1=O)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1[C@@H](CC(=O)c1ccnn(C)c1=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of (S)-4-(3-(4-bromophenyl)-3-o-tolylpropanoyl)pyridazin-3(2H)-one (293 mg, 679 μmol) in N,N-dimethylacetamide (4 mL) was added iodomethane (101 mg, 712 μmol) followed by potassium carbonate (103 mg, 746 μmol). The reaction mixture was stirred for 5½ h at room temperature and then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2, gradient heptane to heptane/ethyl acetate 1:1) produced the title compound (251 mg, 90%). White solid, MS: 411.2 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6]([OH:9])(=[S:8])[CH3:7]>C(O)C.C(N(CC)CC)C>[C:6]([S:8]/[CH:3]=[CH:2]\[C:1]([OH:5])=[O:4])(=[O:9])[CH3:7]
Reactant: C#CC(=O)O
Reactant: CC(O)=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)S/C=C\C(=O)O
Reaction time: 0.08 h
Yield: 117.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 1.0 ml (0.01625 mol) of propiolic acid in 12 ml of absolute ethanol under nitrogen was added 0.22 ml (0.0016 mol) of triethylamine. After 5 min, 1.45 ml (0.0203 mol) of thioacetic acid was added. After 20 h at 0° C. the reaction mixture was stripped of solvents to give 2.8 g of cis-3-(acetylthio)propenoic acid as a waxy solid. This product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Br.Br[CH:7]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]1=O.[OH-].[Na+]>>[O:3]1[C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:1]=[C:2]1[NH2:4]
Reactant: O=C1CCNCCC1Br
Reactant: NC(N)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2c(o1)CCNCC2
Temperature: 70 °C
Yield: 23.8 %

Procedure:
6.6 g urea was added to 6 g 5-bromo-azepan-4-one hydrobromide and heated 24 h at 70° C. 4 M aqueous sodium hydroxide was added and the mixture was extracted with chloroform and ethyl acetate. The combined organic layers were evaporated to give 800 mg of the desired product.
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:26][CH:25]=2)[C:8]2[C:9]([CH2:21][CH3:22])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:43]I>CN(C)C(=O)C>[CH:1]1([CH:7]([N:23]([CH3:43])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:26][CH:25]=2)[C:8]2[C:9]([CH2:21][CH3:22])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cn(-c3cccc(OC)c3)nc2CC)C2CCCCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(N(C)C(c2cn(-c3cccc(OC)c3)nc2CC)C2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of ethyl 3-[{[4-({cyclohexyl[3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1.1 g) synthesized in Example 78(4) in N,N-dimethylacetamide (5 mL) was added sodium hydride (0.16 g) under ice-cooling and, after stirring for 30 min, methyl iodide (0.37 mL) was added. The ice bath was removed, the reaction mixture was stirred at room temperature overnight, saturated aqueous ammonium chloride solution was added and the mixture was extracted with diethyl ether. The extract was washed with brine to give ethyl 3-[({4-[{cyclohexyl[3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl]methyl}(methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (0.23 g, 75%) as a pale-yellow oil. This was dissolved in ethanol (3.0 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1, volume ratio) to give the title object compound (0.10 g, 10%) as a pale-yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[N:13][C:6]2[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH2:41][CH2:42][NH:43][CH2:44][CH:45]=2)=[CH:36][CH:35]=1>C(#N)CC.O>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH2:45][CH2:44][N:43]([CH2:2][C:3]3[CH:14]=[N:13][C:6]4[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:42][CH:41]=2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CN1CC(=O)Nc2cc(CO)cnc21
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CC(=O)Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (103.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (30.2 mg, 19%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.51 (s, 1H), 7.64 (s, 1H), 7.41-7.47 (m, 2H), 7.34-7.40 (m, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.18 (s, 1H), 3.93 (s, 2H), 3.41 (s, 2H), 3.01 (br. s., 2H), 2.91 (s, 3H), 2.60 (br. s., 2H), 2.39-2.47 (m, J=7.3 Hz, 2H). [M+H] calc'd for C20H21ClN4O, 369; found, 369.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]2[S:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].I[CH3:19]>C1COCC1.CO>[CH3:19][NH:3][C:4]1[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][C:7]2[CH:12]=[CH:11][S:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1nc2ccsc2nc1NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a stirred suspension of neat NaH (0.82 g, 3.40 mmol) in 10 ml THF at -78° C. was canulated a cold (-78° C.) 20 ml THF solution of ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.690 g, 3.09 mmol). The reaction mixture was allowed to warm to rt, stir for 2 h and was then treated with iodomethane (0.460 g, 3.24 mmol). After stirring for 12 h at rt, the mixture was diluted with 5 ml MeOH and concentrated. Purification by column chromatography on silica gel eluting first with 10:1 then 5:1 hexanes:ethyl acetate gave the title compound (0.610 g, 84%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.40 (t, 3H), 3.60 (d, 3H), 4.36 (q, 2H), 7.48 (br s, 2H), 8.54 (d, 1H), 8.57 (d, 1H). MS (DCI/NH3) m/e 238 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:45][C:46]([CH3:48])=[O:47]>C1COCC1>[OH:47][C:46]([CH:3]1[C:2](=[O:1])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1)([CH3:48])[CH3:45]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)CC3)cc1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)C(C(C)(C)O)C3)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 7-(6-oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid (step 2) (100 mg, 0.219 mmol) in THF (5 ml) under a nitrogen atmosphere was treated dropwise with lithium bis trimethylsilylamide (1M in THF, 0.546 ml, 0.546 mmol). The mixture was stirred at −78° C. for 10 minutes and treated with acetone (0.100 ml, 0.546 mmol) in THF (2 ml) maintaining the internal temperature below −65° C. Once addition was complete, the reaction was quenched with sat. NH4Cl (aq). The organic portion was separated and the aqueous was extracted with ethyl acetate (×2). The combined organic extracts were concentrated under reduced pressure and the crude product was purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the titled compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:32]N1C(=O)CCC1=O>>[Br:32][CH2:25][C:13]1[C:12]([C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Reference Example 5, 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methyl-3-valerylquinoline was brominated with N-bromosuccinimide (NBS) to give 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 150°-151° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>>[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1sc(Cl)cc1Br

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 3-bromo-5-chlorothiophene-2-sulfonyl chloride to obtain, the title compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J=2.1 & 10.5 Hz, 1H), 7.35 (br m, 2H), 7.31 (dd, J=2.1 & 4.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.08 (dd, J=9.0 & 17.4 Hz, 1H), 6.02(dt, J=2.1, 8.4 & 17.1 Hz, 1H), 5.59 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2cnc(Br)cn2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of 2,5-dibromopyrazine (100 mg, 0.4 mmol) in toluene (6 mL) and ethanol (3 mL) was added (4-fluorophenyl)boronic acid (29 mg, 0.2 mmol) and 2M sodium carbonate solution (2.84 mL). The solution was purged with argon for 15 min, Pd(PPh3)4 (4 mg, 0.004 mmol) was added, and the reaction mixture was purged with argon for 15 min. The resulting mixture was heated to 40° C. and stirred for 1 h. The reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (10 mL), and dried over Na2SO4 and concentration in vacuo. The crude product was purified by flash chromatography (60-120μ, 5% ethyl acetate in hexane) to afford 2-bromo-5-(4-fluorophenyl)pyrazine as off-white solid (60 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.88 (s, 1H), 8.18-8.15 (m, 2H), 7.37 (dd, 2H); LC-MS m/z calculated for [M+H]+ 252.97. found 253.0.
Reaction SMILES: [C:1]([C:3]1([NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].O.S(=O)(=O)(O)[OH:26]>C(O)CO>[C:1]([C:3]1([NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:11])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:26])[CH3:2]
Reactant: C#CC1(NS(=O)(=O)Cc2ccc(S(C)(=O)=O)cc2)CCCCC1
Reactant: O=S(=O)(O)O
Solvent: OCCO
Solvent: O
Product: CC(=O)C1(NS(=O)(=O)Cc2ccc(S(C)(=O)=O)cc2)CCCCC1
Temperature: 175 °C

Procedure:
N-(1-Ethynylcyclohexyl)-4-methanesulfonyl-phenylmethane sulfonamide (19.6 g, 55 mmol) was suspended in ethylene glycol (250 ml). 10 ml Water, 2 g HgO and 2 ml conc. sulfuric acid were added and the mixture was heated at 175° C. for 3 hours, then poured warm into 1 l crushed ice, decanted from mercury salts, stirred and the precipitate was filtered off, washed with water and dried under vacuum at 70° C. to yield N-(1-acetylcyclohexyl)-4-methanesulfonyl-phenylmethanesulfonamide, shown below, as a solid (14.4 g, 70%). 1H-NMR (CDCl3) δ 7.95 (d, 2H), 7.68 (d, 2 H), 4.68 (s, 1 H), 4.42 (s, 2 H), 3.06 (s, 3 H), 2.29 (s, 3 H), 2.00-1.25 (m, 10 H); MS (IS): 372.1 [M−H]−