Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2/[CH:21]=[CH:20]/[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CCC(C=Cc2ccccc2O)CCCCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1

Procedure:
A solution of 1.70 g (3.38 mmol, 75% pure) of methyl 4-{7-cyano-3-[2-(2-hydroxyphenyl)vinyl]-heptyl}benzoate in 20 ml of dry acetonitrile is mixed with 1.53 g (7.76 mmol) of 4-(tert-butyl)benzyl bromide and 1.4 g (10.13 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The resulting crude product is taken up on silica gel and purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 1700 mg (3.12 mmol, 96% purity, 92% of theory) of an oil are obtained.
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[CH:4]([CH2:21][CH3:22])[CH:5]([C:11]1[CH:20]=[CH:19][C:14]2[N:15]=[C:16]([NH2:18])[S:17][C:13]=2[CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH2:1]([N:3]([CH3:23])[CH:4]([CH2:21][CH3:22])[CH:5]([C:11]1[CH:20]=[CH:19][C:14]2[N:15]=[C:16]([NH:18][C:24](=[O:26])[CH3:25])[S:17][C:13]=2[CH:12]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)CC
Solvent: C1CCOC1
Product: CCC(C(c1ccc2nc(NC(C)=O)sc2c1)n1ccnc1)N(C)CC
Temperature: 40 °C
Reaction time: 72 h

Procedure:
A mixture of 6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (50 mg, 0.151 mmol) and acetic anhydride (37 mg, 0.37 mmol) in THF (4 mL) was stirred at 40° C. over 3 days. The reaction was quenched with saturated sodium carbonate, extracted with 5% methanol in DCM. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC to afford N-(6-(2-(ethyl(methyl)amino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)acetamide. MS ESI: m/z 372.28 [M+1+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](Cl)=[N:4][N:3]=1.[NH2:13][NH2:14].O.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:13][NH2:14])=[N:4][N:3]=1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NNc1nnc(Cl)c2c1CCCC2
Temperature: 60 °C
Yield: 55.9 %

Procedure:
To 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (406 mg, 2.0 mmol) in 2 mL THF was added hydrazine (704 uL, 704 mm, 12 mmol) and the mixture heated at 60° C. for 5.5 hours. To the mixture was added 3 mL of water and 10 mL EtOAc. The resulting suspension was filtered, washed with water (3×5 mL) and concentrated to provide Compound 29A as a pale tan powder (222 mg, 56%). LC/MS (m/z)=199.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([CH3:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([CH3:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=[C:16]([NH2:21])[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(Cl)nc(N)n2)cc1)Oc1ccccc1
Reactant: C1CNCCN1
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCNCC3)nc(N)n2)cc1)Oc1ccccc1

Procedure:
3-[4-(2-Amino-6-chloro-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester and piperazine were reacted, as described in Example 2, Step G, to provide 3-[4-(2-Amino-6-piperazin-1-yl-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester, shown below, as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][C@H:5]1[O:8][C:7](=[O:9])[CH2:6]1.[OH-:19].[Na+]>C1COCC1.O>[OH:8][C@H:5]([CH2:4][CH:3]([O:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][C:7]([OH:19])=[O:9]
Reactant: CCCCCCCCCC(C[C@@H]1CC(=O)O1)OC
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C[C@@H](O)CC(=O)O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(ref. Gu, et al. Nature 459, 731-735 (2009)). To a solution of 6 (92.0 mg, 0.359 mmol, 1.0 equiv) in THF (1.5 mL) was added a solution of NaOH (15.7 mg, 0.394 mmol, 1.1 equiv) in water (1.5 mL). The reaction mixture was stirred at rt for 1 h. During this time, its appearance changed from turbid to clear (t=about 0.5 h). The solution was quenched by addition of 1 M HCl (1 mL) and extracted with ether (2×5 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried (Na2SO4) and concentrated in vacuo to afford a pale yellow oil. Purification of the crude product by chromatography on SiO2 (1:1 EtOAc/hexanes containing 0.5% AcOH) provided (3R)-1 (94.4 mg, 96%) as a colorless oil: ATR/IR 2920, 2851, 1709, 1413, 1187, 1079, 736 cm−1; 1H NMR (CDCl3) 4.35-4.20 (m, 1H), 3.55-3.45 (m, 1H), 3.38, 3.37 (2s, 3H), 2.56-2.50 (m, 2H), 1.80-1.35 (m, 3H), 1.35-1.25 (m, 14H), 0.90 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3) 176.4, 175.7, 68.1, 65.4, 56.7, 56.0, 41.6, 41.5, 39.7, 39.1, 32.9, 32.8, 31.9, 29.8, 29.6, 29.5, 29.3, 25.2, 24.5, 22.7, 14.1.
Reaction SMILES: [CH:1]([N:4]([CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)[CH3:5])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[O:23])[CH:17]=[CH:18][C:19]=1[CH3:20]>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([NH:12][C:9]2[S:10][CH:11]=[C:7]([CH2:6][N:4]([CH:1]([CH3:3])[CH3:2])[CH3:5])[N:8]=2)=[O:23])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: CC(C)N(C)Cc1csc(N)n1
Reactant: Cc1ccc(N=C=O)cc1Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2nc(CN(C)C(C)C)cs2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-((isopropyl(methyl)amino)methyl)thiazol-2-amine (18 mg, 0.1 mmol) in dichloromethane (0.5 mL) is added to 3-chloro-4-methylphenyl isocyanate (16.7 mg, 0.1 mmol) in dichloromethane (0.5 mL). The resulting reaction mixture is shaken at room temperature for 1 hour. The solvent is evaporated under vacuum. The residue is purified by preparative LC to yield a brown glass LCMS, retention time: 1.87 min, M+H+: 353. H1-NMR (DMSO, σ ppm): 10.82 (s, 1H), 9.51–9.41 (s, br, 1H), 9.31 (s, 1H), 7.70 (s, 1H), 7.33 (s, 1H), 7.18–7.30 (m, 2H), 4.11–4.39 (m, 2H), 2.69 (d, 3H), 2.28 (s, 3H), 1.29 (t, 6H)).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1[N:9]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 30 °C

Procedure:
To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 mL), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30° C. The reaction mixture was stirred for 30 min. and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After two hours stirring at room temperature and one hour at 45° C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.8g, 78%), m.p. 92°-95° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[F:24]>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.COCCOC>[Cl:13][C:3]1[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:24])[CH:17]=1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CS(=O)(=O)Nc1ccc(Br)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CS(=O)(=O)Nc1ccc(-c2ccc(Cl)c(F)c2)c(Cl)c1

Procedure:
N-(4-bromo-3-chlorophenyl)methanesulfonamide (B, 100.0 mg, 0.351 mmol), 4-chloro-3-fluorophenylboronic acid (73.4 mg, 0.421 mmol, L2 equiv.) and Pd(PPh3)4 (20.3 mg, 0.0176 mmol, 0.05 equiv.) was placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added 2M-Na1CO3 (1.0 mL, 2.0 mmol, 5.7 equiv.) and DME (4 mL) subsequently at ambient temperature. The mixture was heated under reflux conditions for 1 hours. The mixture was filtered through Celite (3 g) and the Celite was washed with EtOAc (70 mL). The solvent was removed under a reduced pressure. Obtained crude mixture was purified by column chromatography (SiO2=80 g, EtOAc/hexane=1:3˜1:1, Rf=0.4) to give the desired product as colorless crystals (compound 5 (designated PT-017).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:2]1
Reactant: OCCCC1CCCOC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCC1CCCOC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To the solution of 3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (10.35 g, 0.0719 mol) in CH2Cl2 (200 mL) was added Dess-Martin periodinane (61.24 g, 0.1438 mol). The mixture was stirred at rt. When the reaction was over, the solution was poured into Et2O (300 mL) and anhydrous K2CO3 (19.84 g, 0.1438 mol) was added. The mixture was filtered and the filtrate was dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give 3-(tetrahydro-2H-pyran-3-yl)propanal (8.25 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([F:11])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>CN(C)C=O.C(O[Pd]OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6](/[CH:26]=[CH:25]/[C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:5]([F:11])=[CH:4][N:3]=1
Reactant: OB(O)c1cc(Br)ncc1F
Reactant: C=Cc1ccc(F)cc1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(/C=C/c2cc(Br)ncc2F)cc1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a 25 mL round bottom flask was added 2-bromo-5-fluoropyridin-4-ylboronic acid (1440 mg, 6.55 mmol), sodium carbonate (1085 mg, 10.23 mmol), and 1-fluoro-4-vinylbenzene (500 mg, 4.09 mmol) in dimethylformamide (8 mL). The solution was stirred at room temperature and the flask was purged with oxygen for 3 min. To the purged flask was quickly added diacetoxypalladium (92 mg, 0.409 mmol) and the reaction flask was again sealed and purged with oxygen for 15 min. The reaction mixture was then stirred at room temperature overnight. The next day the reaction was quenched with water and diluted with ethylacetate (3×). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 0% EtOAc/100% hexanes to 25% EtOAc/85% hexanes affording (E)-2-bromo-5-fluoro-4-(4-fluorostyryl)pyridine (100 mg, 0.338 mmol, 8.25% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 8.25 (m, 1H), 7.58-7.57 (m, 2H), 7.36 (d, J=16.0, 1H), 7.15-7.11 (m, 2H), 7.04 (d, J=16.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.76 min. Mass=295.98 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=[O:14])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of (3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)methanol (7.05 g), activated manganese dioxide (20.09 g) and tetrahydrofuran (50 mL) was stirred overnight at room temperature. Manganese dioxide was removed by filtration, and the filtrate was concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (6.80 g, yield 96%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 142-143° C.
Reaction SMILES: C(#N)C.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[S:12][CH2:13][C:14]([F:17])([F:16])[F:15].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH3:4])=[C:6]([S:12][CH2:13][C:14]([F:15])([F:17])[F:16])[CH:7]=1
Reactant: Cc1ccc(O)cc1SCC(F)(F)F
Reactant: ClCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: Cc1ccc(OCCCCCCl)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To 100 ml of acetonitrile were added 2.5 g (11 mmol) of 4-methyl-3-(2,2,2-trifluoroethylthio)phenol, 2.5 g (13 mmol) of 1-bromo-5-chloropentane, 1.9 g (14 mmol) of potassium carbonate and 0.35 g (1.1 mmol) of tetra-n-butylammonium bromide. The mixture was refluxed for 5 hours under heating and then allowed to cool to room temperature. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 2.9 g (yield: 79%) of an intended product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[CH:13]=[CH:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C([Li])CCC.CN(C)[CH:27]=[O:28]>O1CCCC1>[CH3:12][O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH:13]=[CH:14][C:15]1[S:16][C:17]([CH:27]=[O:28])=[CH:18][CH:19]=1
Reactant: COc1cc(OC)c(C=Cc2cccs2)c(OC)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(OC)c(C=Cc2ccc(C=O)s2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
In a stream of argon, in 10 ml of tetrahydrofuran was dissolved 500 mg (1.80 mmol) of 2-[2-(2,4,6-trimethoxyphenyl) vinyl]thiophene, and 1.27 ml of n-butyllithium (1.6 M solution in hexane) (2.03 mmol) was added dropwise thereto under cooling. The mixture was stirred for 1 hour. To this mixture, 0.16 ml (2.00 mmol) of N,N-dimethylformamide was added dropwise and reacted. After reacted at gradually increasing temperature, the reaction mixture was stirred at room temperature for 12 hours. The mixture was poured into 50 ml of ice water and subjected to 3 times of extraction with 200 ml of chloroform. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography to give 380 mg (yield: 69%) of 5-[2-(2,4,6-trimethoxyphenyl)vinyl]thiophene-2-carbaldehyde as a light yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:17]([OH:19])=O)[C@H:14]([CH3:16])[OH:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:38]([O:42][NH2:43])([CH3:41])([CH3:40])[CH3:39].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:38]([O:42][NH:43][C:17](=[O:19])[C@H:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[C@H:14]([OH:15])[CH3:16])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](C)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)NOC(C)(C)C)[C@@H](C)O)cc1
Reaction time: 8 h

Procedure:
N-[4-methoxybenzenesulfonyl]-(D)-threonine (4.0 g, 13.84 mmol), 1-hydroxybenzotriazole (1.87 g, 13.84 mmol), 4-methylmorpholine (7.9 mL, 69.2 mmol), and O-t-butylhydroxylamine hydrochloride (5.22 g, 41.52 mmol) are dissolved in methylene chloride (100 mL). To this solution is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.45 g, 17.99 mmol), and the reaction is stirred overnight. The mixture is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product is purified by silica gel chromatography (ethyl acetate) to give N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-amino]-3(R)-hydroxybutanamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1.O1CCOCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:19][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NCc3ccc(Cl)cc3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Clc1ccc(CNc2ccc(C3CNCCO3)cc2)cc1
Temperature: 60 °C
Yield: 70.4 %

Procedure:
To a stirred solution of (RS)-2-[4-(4-chloro-benzylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (68 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.34 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford (RS)-(4-chloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine (36 mg, 70%) as a white solid. MS (ISP): 305.1 ([{37Cl}M+H]+), 303.2 ([{35Cl}M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:17]([NH2:19])=O.C([O-])=O.[NH4+]>>[Br:16][C:14]1[CH:13]=[CH:12][C:5]2[C:6]3[C:7](=[O:8])[NH:19][CH:17]=[N:1][C:2]=3[S:3][C:4]=2[CH:15]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2sc3cc(Br)ccc3c12
Temperature: 25 °C

Procedure:
Ethyl 2-amino-6-bromo-1-benzothiophene-3-carboxylate (9.0 g, 27 mmol), formamide (85 mL) and ammonium formate (2.7 g, 43 mmol) were heated in an oil bath at 135° C. overnight. The next morning the reaction mixture was a pastel blue slurry. The reaction mixture was allowed to cool to room temperature and was then filtered. The solid was washed with water, dried by filtration, and finally dried in a vacuum oven overnight at 45° C. to yield a light blue solid (7.8 g, quantitative). 1H NMR (DMSO-d6) δ 12.9 (br, 1H), 8.37 (s, 1H), 8.35 (d, 1H), 8.31 (s, 1H), 7.69 (d, 1H); LCMS RT=3.08 min, [M+H]+=281.1.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([CH3:24])[C:9]2[C:8]([OH:25])=[CH:7][CH:6]=[C:5]([F:26])[C:4]=2[N:3]=1.[C:27](B1OC(C)(C)C(C)(C)O1)([CH3:29])=[CH2:28].O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[F:26][C:5]1[C:4]2[N:3]=[C:2]([C:27]([CH3:29])=[CH2:28])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([CH3:24])[C:9]=2[C:8]([OH:25])=[CH:7][CH:6]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(Cl)nc2c(F)ccc(O)c12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1nc2c(F)ccc(O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Temperature: 90 °C

Procedure:
A mixture of 2-chloro-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.22 g), 2-isopropenyl-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0.23 mL), potassium phosphate monohydrate (0.68 g) and N,N-dimethylformamide (3.0 mL) was purged with argon for 20 minutes, and then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.048 g), and the mixture heated at 90° C. for 12 hours. The mixture was cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water (5.0 mL) and saturated aqueous sodium chloride solution (5.0 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume) gave title compound as a white solid (0.082 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([C:22]=1[I:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=[O:13].CCN(CC)CC>C(Cl)Cl.CS(C)=O>[O:7]=[CH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([C:22]=1[I:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=[O:13]
Reactant: O=C(NCCCO)c1[nH]c2ccc(F)cc2c1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (3.68 g, 30 mmol) in anhydrous CH2Cl2 (50 mL) at −40° C. is added DMSO (4.52 g, 57.9 mmol) drop-wise. The mixture is stirred at this temperature for 5 minutes. 5-Fluoro-3-iodo-1H-indole-2-carboxylic acid (3-hydroxy-propyl)-amide, prepared as in reference 12, (6.99 g, 19.3 mmol) is dissolved in CH2Cl2 (800 mL) with small amount of DMSO (10 mL) and added to the above-mentioned solution at −40° C. The reaction is stirred for additional 30 minutes before adding Et3N (11.7 g, 0.116 mol). The mixture is allowed to warm to room temperature and quenched with H2O (1 L). The organic layer is separated and washed with citric acid (10%, 500 mL), saturated NaHCO3 (500 mL) and brine (500 mL). It is dried with Na2SO4 to give 5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-oxo-propyl)-amide; 1H NMR (DMSO-d6) δ 2.75 (dt, 2H, J1=1.2 Hz, J2=6.0 Hz), 3.61 (q, 2H, J=5.2 Hz), 7.06-7.17 (m, 2H), 7.45 (dd, 1H, J1=4.8 Hz, J2=8.8 Hz), 8.11 (t, 1H, J=5.6 Hz), 9.74 (t, 1H, 1.2 Hz), 12.10 (s, 1H); m/z [M++1] 361.0.