Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C(O)C.[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]2[N:6]=[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]3=[CH:9][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1C=O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(CN2CCc3nc4ccccc4cc3C2)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 10% potassium hydroxide/ethanol solution (120 ml) was added dropwise to a solution of 2-aminobenzaldehyde (26 g, 0.21 mol) and 1-benzyl-4-piperidone (40 g, 0.21 mol) in absolute ethanol (430 ml) over a period of 1 hour. After stirring overnight, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate, and the extract solution was washed with water and then dried over anhydrous sodium sulfate. The organic solvent was removed by concentration under reduced pressure, and the residue was recrystallized from ethyl acetate-isopropyl ether to obtain the desired compound (37 g, 63%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)O)[CH:8]=2)[N:3]=1.C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-].[Pd]>[CH2:25]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(C(O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(Cc2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reaction time: 72 h

Procedure:
A mixture of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanol (0.245 g, 0.576 mmol) and palladium hydroxide, 20 wt % Pd (dry basis) on carbon, wet (0.380 g, 2.71 mmol) in ethanol (15 mL) and ethyl acetate (5.0 mL) was stirred under H2 balloon overnight. 400 mg more Pd(OH)2 was added and stirred for 72 h. The product mixture was filtered through a pad of celite. The filtrate was concentrated and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford 6-(2-benzyl-6-methylphenyl)-3-morpholinoquinolin-2-amine as white solid. MS (ESI, pos. ion) m/z: 410 (M+1).
Reaction SMILES: Cl.C(O)C.C([O:7][C:8](=[O:34])[CH2:9][C:10]1[S:11][C:12]2[C:13]([O:32]C)=[CH:14][C:15]3[CH:31]=[CH:30][CH:29]=[CH:28][C:16]=3[C:17](O)([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:18]=2[CH:19]=1)C.[OH-].[Na+]>O>[CH3:26][N:23]1[CH2:22][CH2:21][C:20](=[C:17]2[C:16]3[CH:28]=[CH:29][CH:30]=[CH:31][C:15]=3[CH2:14][C:13](=[O:32])[C:12]3[S:11][C:10]([CH2:9][C:8]([OH:34])=[O:7])=[CH:19][C:18]2=3)[CH2:25][CH2:24]1
Reactant: CCOC(=O)Cc1cc2c(s1)C(OC)=Cc1ccccc1C2(O)C1CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCC(=C2c3ccccc3CC(=O)c3sc(CC(=O)O)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Hydrochloric acid (8 mL) was added to an ethanol (24 mL) solution of the compound obtained in Example 16 (2.0 g, 4.7 mmol), and the mixture was refluxed while heating overnight. The solvents were distilled off, water (20 mL) and sodium hydroxide (0.8 g, 20 mmol) were then added to the residue, and the mixture was stirred at room temperature overnight. The property of the solution is adjusted to a pH of 6.5 with hydrochloric acid, and the precipitated crystals were separated by filtration and dried, to give 0.68 g (39%) of the captioned compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=1>>[O:23]=[S:22]1(=[O:24])[C:8]2[C:7]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:33]=3)=[N:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[CH2:19][CH2:20][CH2:21]1
Reactant: O=S1(=O)CCCc2nc(-c3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 77.1 %

Procedure:
Following general procedure G, 5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (1.0 g, 2.46 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.527 g, 2.94 mmol) to afford the desired product (0.83 g, 77%) as a light yellow solid. MW=437.51. 1H NMR (DMSO-d6, 500 MHz) δ 8.77 (s, 1H), 8.28-8.24 (m, 2H), 7.64-7.49 (m, 5H), 7.34 (d, J=8.5 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.76-3.72 (m, 2H), 3.70 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H), 1.20 (t, J=7.0 Hz, 3H); APCI MS m/z 438 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[O:15]1[CH2:20][CH2:19][O:18][C:17]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:16]2[O:15][CH2:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc4c(c3)OCCO4)cc12
Temperature: 100 °C
Yield: 10.2 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg, 0.14 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (27.4 mg, 0.152 mmol) and 2N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N2, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N2. The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 50.0% H2O/50.0% MeCN in 10.5 min, 50.0% H2O/50.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to afford the title compound (4.7 mg, 10% yield). MS (ES+) 331.1 (M+H)+. Retention time=2.62 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:28])[CH:6]([S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.O[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][S:18][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=3)=[O:16])=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:28])=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CS(=O)(=O)Oc1ccc(CO)cc1
Product: CS(=O)(=O)Oc1ccc(COC(=O)Cc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethyl-phenyl)-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid 2,2,2-trichloro-ethyl ester (30 mg, 0.01 mmol) and methanesulfonic acid 4-hydroxymethyl-phenyl ester (14 mg, 0.067 mmol) in the same manner as described for example 1. The crude product was purified by HPLC (yield: 0.47 mg, 1.4%). Mass Spectrum: M−H+ 545.50.
Reaction SMILES: Br[C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]3[CH:16](Br)[C:6]1([C:7]1[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=13)[CH2:5][N:4]([CH3:22])[C:3]2=[O:23].C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[CH3:22][N:4]1[CH2:5][C:6]23[CH2:16][CH:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:2]2[C:3]1=[O:23])[C:8]1[CH:18]=[CH:19][CH:20]=[CH:21][C:7]3=1
Reactant: CN1CC23c4ccccc4C(c4ccccc4C2(Br)C1=O)C3Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CN1CC23CC(c4ccccc4C2C1=O)c1ccccc13
Yield: 70.8 %

Procedure:
A mixture of 8.07 g of 1a, 17.2 g of freshly distilled tributyltin hydride and 50 ml of anhydrous benzene is heated under reflux under nitrogen for 3 days. Most of the benzene is removed and the residue is distilled through a short-path column (to 125° bath temperature, 1 micron). The pot residue is crystallized from isopropyl alcohol to give 3,63 g (71% yield) of 2-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrol-1-one (1b), mp 141°-146°. A sample crystallized once from isopropyl alcohol has mp 147°-157°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:22][C:20](=[O:21])[C@@H:19]([NH:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 118.4 %

Procedure:
4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid (0.801 g), (S)-2-amino-3-(4-iodophenyl)propanamide (Example 1, step (ii), 0.947 g) and N-ethyl-N-isopropylpropan-2-amine (1.422 mL) were dissolved in DMF (10 mL) and to the solution was added TBTU (1.573 g). The reaction mixture was stirred, at room temperature, for 2 days. The reaction mixture was evaporated to dryness dissolved in dichloromethane (20 mL) and evaporated onto silica. The silica was put on the top of a silica column and eluted with 20% ethyl acetate in isohexane then 50% ethyl acetate in isohexane then 100% ethyl acetate followed by 10% then 20% methanol in ethyl acetate to afford the sub-titled compound (2.00 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cn1
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
A solution of 6-methoxy-3-pyridine carboxaldehyde (100 mg, 0.73 mmol) in ethanol (2 mL) and acetic acid (0.2 mL) at room temperature was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 1.82 mmol, 339 mg) and stirred for 5 minutes. Sodium cyanoborohydride (0.95 eq, 0.69 mmol, 44 mg) was added portionwise and the reaction then stirred for 16 h. Concentration in vacuo and preparative tlc purification (EtOAc) gave the product (168 mg, 75%) as a colourless oil; δH (500 MHz, CDCl3) 1.47 (s, 9H, C(CH3)3), 2.00 (s, br, 2H, piperazine NCH2), 2.39 (t, J=4.7 Hz, 2H, piperazine NCH2), 3.43 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.45 (s, 2H, CH2), 3.94 (s, 3H, OCH3), 6.73 (d, J=8.4 Hz, 1H, methoxypyridine H-5), 7.57 (dd, J=8.5, 2.4 Hz, 1H, methoxypyridine H-4), 8.05 (d, br, J=2.3 Hz, 1H, methoxypyridine H-2);
Reaction SMILES: N1C=CC=CC=1.C(O[C:11](=[O:13])[CH3:12])(=O)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:11](=[O:13])[CH3:12])=[CH:17][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)cc1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Pyridine (551 mg, 5.8 mmol) and acetic anhydride (650 mg, 0.6 mL, 6.4 mmol) were added to a cold solution (at 0° C.) of 4-bromo-phenylamine (1 g, 5.8 mmol) in DCM (10 mL) and stirring was continued at ambient temperature for 2 hrs. The reaction mixture was diluted with DCM and washed the organic layer with water followed by brine solution. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure to afford 900 mg (69.5% yield) of N-(4-bromo-phenyl)-acetamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([O:16][CH:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[Cl:27])[CH3:18])[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl[CH2:29][P:30](=[O:33])([CH3:32])[CH3:31]>>[CH3:29][P:30]([CH2:32][N:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([O:16][CH:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=3[Cl:27])[CH3:18])[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:7][CH:8]=1)[CH2:29][P:30]([CH3:32])([CH3:31])=[O:33])([CH3:31])=[O:33]
Reactant: CP(C)(=O)CCl
Reactant: CC(Oc1cc(-c2ccc(CN)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1cc(-c2ccc(CN(CP(C)(C)=O)CP(C)(C)=O)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
the title compound (di-alkylation product) was prepared from 5-[4-(aminomethyl)phenyl]-3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridin-2-amine and chloromethyl-dimethyl-phosphine oxide following the same procedure as Example 2. ESMS: m/z 584 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].O>ClC1C=CC=CC=1Cl>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(Br)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Temperature: 160 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.33 g) and 2-bromo-4-methylphenol (2.5 ml) were dissolved in o-dichlorobenzene (3 ml), and the solution was stirred at 160° C. for 5 hr. The reaction solution was cooled to room temperature, and water was then added to the reaction solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give the title compound (1.83 g, yield 82%).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[N:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[H-].[Na+]>O1CCOCC1>[CH2:24]([NH:23][C:21](=[O:22])[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]#[C:12][C:9]2[CH:8]=[N:7][C:6]([O:4][CH2:3][CH2:2][F:1])=[N:11][CH:10]=2)=[CH:19][CH:18]=1)[CH3:26])[CH3:25]
Reactant: CCNC(=O)C(C)c1ccc(C#Cc2cnc(Cl)nc2)cc1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(C#Cc2cnc(OCCF)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 13 mg (0.21 mmol) 2-fluoro-ethanol in 0.5 mL 1,4-dioxane are added 34 mg (0.10 mmol) 2-[4-(2-chloro-pyrimidin-5-ylethynyl)-phenyl]-N-ethyl-propionamide (XVIII.1) in 1 mL 1,4-dioxane, followed by 12 mg (0.30 mmol) sodium hydride (60% in mineral oil). The mixture is stirred at rt for 12 h. After that time, the solvent is evaporated and the residue s purified by HPLC (preparative column: Sunfire, eluent A: water+0.1% TFA, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.FC(F)(C(F)(F)F)C([O:32][C:33](=O)[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=O>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:16][C:33](=[O:32])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)C(F)(F)C(F)(F)F
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of (R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (15 mg, 0.038 mmol), prepared by method described in Procedures 5, 6 and 7, in anhydrous DCM (0.5 mL), was added pyridine (1 drop) and 2,2,3,3,3-pentafluoropropanoic anhydride (14 mg, 0.040 mmol) at room temperature. The reaction mixture was stirred for 5 mins and the solvents removed under a stream of nitrogen. The resulting residue was diluted with MeOH (0.5 mL) and purified by preparative HPLC (YMC Sunfire 30×100 mm column, eluting with 10-90% MeOH/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm); (R)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2,2,3,3,3-pentafluoropropanamide (13.4 mg, 65% yield) was isolated as a colorless oil at a retention time of 12.44 min. LCMS: RT=2.12 min [M+H] 541.21 (LCMS Method 2); HPLC: RT=4.28 min, Purity 98% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 9.60 ppm, 1 H, s; 8.36 ppm, 1 H, s; 7.75 ppm, 1H, d, J=8.0 Hz; 7.44 ppm, 1H, s; 7.34 ppm, 1H, d, J=8.0Hz; 7.30 ppm, 1H, d, J=8.0 Hz; 7.09 ppm, 4 H, m; 6.53 ppm, 2H, d, J=4.0 Hz; 3.38 ppm, 1H, d, J=12.0 Hz; 3.65 ppm, 1H, d, J=12.0 Hz.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28](O)=[O:29])=[CH:22][C:21]=1[Cl:31])([CH3:19])([CH3:18])[CH3:17].CN1CCOCC1>C1COCC1>[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:29])=[CH:22][C:21]=1[Cl:31])([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ncc(OCC(=O)O)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ncc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1Cl
Yield: 30.6 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (192 mg, 0.751 mmol) was reacted with (6-tert-butyl-5-chloro-pyridin-3-yloxy)-acetic acid (183 mg) DMTMM (1.1 eq, 229 mg) and NMM (1.2 eq, 100 μl) in THF to give the title compound (102 mg, 30.6%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CCOCC>[CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC1(C)COC(c2cccs2)=N1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1C1=NC(C)(C)CO1
Temperature: -70 °C
Yield: 134.1 %

Procedure:
To a solution of 5.0 g of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole in 20 ml of ether is added dropwise 18.75 ml of butyl lithium while maintaining the temperature at -70° C. with stirring under nitrogen. The reaction mixture is stirred at -70° C. for 15 minutes and 30 minutes at 0° C. The reaction mixture is cooled to -70° C. and 10.0 g of tributyl tin chloride added. The reaction mixture is quenched with water and extracted with ether. The organic layer is washed with water (2×100 ml), dried and evaporated in vacuo to give 17.4 g of residue which is purified by chromatography on silica gel by elution with 7:1 hexane:ethyl acetate to give 12.4 g of a yellowish oil. MS(M+H=472) the next step is example 19.
Reaction SMILES: O.[OH-].[Na+].[N:4]1([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:33][CH2:32][CH2:31][C@H:5]1[C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([O:29]C)=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].Cl>CO>[N:4]1([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:33][CH2:32][CH2:31][C@H:5]1[C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([OH:29])=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
35 ml of water and 5.0 ml of 1N sodium hydroxide solution are added to 1.92 g of Z-Pro-Phe-His-OMe (H. Derwald et al., J. Med. Chem. 7, 50 [1964]) dissolved in 50 ml of methanol. The solution is stirred for 45 minutes at 25° and then neutralised with 5.0 ml of 1N hydrochloric acid. The solvent is removed and the residue is flash-chromatographed over 10 g of silica gel (eluant: chloroform/methanol/concentrated aqueous ammonia solution [5:3:1]; fractions of approximately 15 ml). Fractions 6-13 are combined, concentrated by evaporation and the residue is dissolved in 70 ml of water. After neutralisation to a pH value of 5.0 by the addition of dilute hydrochloric acid, extraction is carried out twice with n-butanol and the combined butanol phases are washed with water and concentrated by evaporation. After drying the residue in a high vacuum, Z-Pro-Phe-His-OH is obtained in the form of a colourless powder; Rf (I)=0.23.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:24][CH:21]3[CH2:23][CH2:22]3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NC1CC1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NC1CC1
Yield: 85.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and cyclopropylamine (50 μL, 0.5 mmol) to give 143 mg of the title compound (86%): mp 265°~268° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 bs, 1H), 8.04 (d, 1H, J=4 Hz), 7.20 (d, 1H, J=2 Hz), 7.14 (d, 1H, J=2 Hz), 5.05~5.14 (m, 1H), 2.97 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.77 (dm, 1H, J=17.1 Hz), 2.54~2.64 (m, 2H), 2.35 (dd, 1H, J=16.2, 4.5 Hz), 2.25 (dd, 1H, J=16.2, 11.7 Hz), 2.00 (dm, 1H, J=13.5 Hz), 1.73~1.87 (m, 1H), 0.56~0.64 (m, 2H), 0.32~0.41 (m, 2H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19]>OS(O)(=O)=O>[CH3:17][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:12]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-p-tolyl-3-trifluoromethyl-pyridine (8.4 mmol) in H2SO4 (6 mL) cautiously add fuming HNO3 (2 ml). Stir the mixture for 60 minutes at room temperature. Pour the mixture onto ice-water (30 mL), extract with EtOAc, neutralize with 1 N NaOH, dry over Na2SO4, and concentrate under vacuum to obtain 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.