Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[C@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][C:10]([O:23][Si](C(C)C)(C(C)C)C(C)C)=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)C>O1CCCC1.CCCCCCC>[O:23]=[C:10]1[CH2:9][C@H:8]([NH:7][C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11]1
Reactant: CC(C)[Si](OC1=C[C@@H](NC(=O)OC(C)(C)C)[C@H](c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CC[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1 h

Procedure:
To a round-bottomed flask (500 mL) containing trans tert-butyl(6-(2,4,5-trifluorophenyl)-3-[(triisopropylsilyl)oxy]cyclohex-2-en-1-yl)carbamate (10.7 g) dissolved in tetrahydrofuran (100 mL), tetrabutylammonium fluoride (1M in tetrahydrofuran, 26 mL) was added and the mixture was stirred for 1 h. The solution was concentrated to a dark brown oil and purified by chromatography (silica gel, gradient 20%-40% ethyl acetate in hexane) to yield the product as a mixture of enantiomers. HPLC using a chiral AD column (12% isopropanol in heptane) gave the title compound as the slower eluting isomer. LC/MS 227.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)c2ccccc21
Yield: 26 %

Procedure:
The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 26% of theory; LC (method 4): tR=2.02 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: S([O-])(=O)(=O)C.[CH3:6][CH2:7][CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:17]([I:25])=[CH:18][C:19]([I:24])=[C:20](O)[C:21]=1[I:22].C(=O)([O-])[O-].[K+].[K+].IC1C=C(I)C=C(I)C=1OC(CCCCCCCCCCCCC)C>CN(C=O)C>[I:22][C:21]1[CH:20]=[C:19]([I:24])[CH:18]=[C:17]([I:25])[C:16]=1[O:15][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH3:6]
Reactant: CCCCCCC(O)CC
Reactant: Oc1c(I)cc(I)cc1I
Agent: CCCCCCCCCCCCCC(C)Oc1c(I)cc(I)cc1I
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCC(CC)Oc1c(I)cc(I)cc1I
Yield: 67.3 %

Procedure:
The mesylate of 3-nonanol (11.5 g, 51.9 mmol), triiodophenol (24.5 g, 51.9 mmol) and potassium carbonate (7.18 g, 51.9 mmol) were reacted in dry DMF (200 ml) as per 2-(2,4,6-triiodophenoxy)-pentadecane except at an oil bath temperature of 87° C. for 16 hrs. The reaction was processed as for 2-(2,4,6-triiodophenoxy)-pentadecane to provide a light brown oil. Flash column chromatography (silica, hexanes) provided 3-(2,4,6-Triiodophenoxy)-nonane (20.9 g, 67%) as a clear viscous oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:16]2[CH2:20][C@H:19]([CH2:21][N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[N:23]3)[O:18][C:17]2=[O:28])[CH:6]=[C:7]([F:15])[C:8]=1[C:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=1.N1C=CC=CC=1.[CH3:35][C:36]1([CH3:44])[O:40][C@H:39]([C:41](Cl)=[O:42])[CH2:38][O:37]1.O>ClCCl>[CH3:35][C:36]1([CH3:44])[O:40][C@H:39]([C:41]([N:12]2[CH2:11][CH:10]=[C:9]([C:8]3[C:7]([F:15])=[CH:6][C:5]([N:16]4[CH2:20][C@H:19]([CH2:21][N:22]5[CH:26]=[C:25]([CH3:27])[N:24]=[N:23]5)[O:18][C:17]4=[O:28])=[CH:4][C:3]=3[F:2])[CH2:14][CH2:13]2)=[O:42])[CH2:38][O:37]1
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCNCC4)c(F)c3)C(=O)O2)nn1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
(5R)-3-[3,5-Difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one hydrochloride (Intermediate 53) (1.13 g, 2.75 mmol) was suspended in dichloromethane (20 ml). Pyridine (2.22 ml, 27.50 mmol) was added and the solution was cooled to 0° C. A solution of (4S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl chloride (WO 01/81350, 0.89 g, 5.43 mmol) in dichloromethane (10 ml) was added. After 2 hours, the solution was poured into water, the organic phase was washed with brine, dried over magnesium sulfate and concentrated under vacuum. Chromatography on silica gel with ethyl acetate gave 542 mg of the title product.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]1[N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:7][CH:8]=2)[C:16](=[O:15])[CH2:17][CH2:20][CH2:21]1
Reactant: COc1cccc(OC)c1C=O
Reactant: NCc1ccc(N2CCCC2)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(N2CCCC2)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (4-(pyrrolidin-1-yl)phenyl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.62 min.; [M+H]+: 395.25 g/mol.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[CH3:32][C:22]1[CH:21]=[C:20]([O:19][CH2:18]/[CH:17]=[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)\[C:13]2[CH:14]=[CH:15][C:10]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:11][CH:12]=2)[CH:31]=[CH:30][C:23]=1[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: C#CCN1CCCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-Propargylpyrrolidine (250 mg, 2.29 mmol) was added under nitrogen atmosphere to a degassed solution of the above ester (400 mg, 0.68 mmol) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 96 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: FC(F)(F)CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(F)(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Reaction time: 8 h

Procedure:
The mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol), 3-bromo-1,1,1-trifluoropropane (85.0 uL, 0.60 mmol) and triethylamine (102.0 uL, 0.60 mmol) in 2 mL of DMF was stirred overnight. The reaction mixture was purified by preparative RP-HPLC to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. ESMS m/z 512.2 (M+H+).
Reaction SMILES: Cl.Cl.[CH2:3]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][N:4]1[C@H:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:5][N:4]([C@H:12]4[C:20]5[C:15](=[CH:16][C:17]([C:21]6[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=6)=[CH:18][CH:19]=5)[CH2:14][CH2:13]4)[CH2:3]3)[CH2:7][CH2:8]2)=[O:40])=[N:36][CH:37]=1
Reactant: NC(=O)c1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cn1
Reactant: COc1ccc(CC(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5cnc(C(N)=O)cn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyrazine-2-carboxylic acid amide (10-1c, 28 mg, 0.08 mmol) in 3 mL of DMF was added (5-methoxy-pyridin-2-yl)-acetic acid (SM-1aa, 13.0 mg, 0.08 mmol), HBTU (33.0 mg, 0.09 mmol) and triethylamine (0.06 mL, 0.46 mmol). The solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and coevaporated with toluene. The residue was partitioned between 10 mL of dichloromethane and 10 mL of 1N NaOH solution. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified by Biotage reverse phase column chromatography (Biotage, Inc.) using 100-60% water in acetonitrile to give the desired product 12.0 mg (27%). MS (ES+) 513.4 (M+H)+. 1H NMR (CD3OD) δ 1.56-1.81 (m, 4H), 1.81-2.09 (m, 1H), 2.11-2.35 (m, 1H), 2.93 (d, 1H), 3.12 (d, 1H), 3.20-3.27 (m, 2H), 3.31-3.41 (m, 1H), 3.43-3.66 (m, 4H), 3.69-3.89 (m, 5H), 4.06 (dd, 1H), 4.54-4.81 (m, 2H), 7.25 (d, 1H), 7.34 (dd, 1H), 7.50 (d, 1H), 7.97 (dd, 1H), 8.04 (s, 1H), 8.13 (d, 1H), 9.12 (d, 1H), 9.22 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.I.O.CO>C(O)(=O)C>[Cl:1][C:2]1[C:15]2[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Agent: I
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Clc1cccc2c1Cc1cccc(Cl)c1C2
Temperature: 25 °C

Procedure:
A mixture of 1,5-dichloro anthraquinone (49, 10 g, 36 mmol), red phosphorous (4.5 g, 145 mmol) and hydroiodic acid (47+%, 70 ml) in 470 ml of glacial acetic acid was refluxed under N2 for 4 days. The resulting mixture was cooled to room temperature and poured into 1 L of water to precipitate a violet colored solid. The solid was collected by filtration, dissolved in 800 ml of CH2Cl2, and filtered again. The filtrate was washed once with 100 ml of H2O, dried over Na2SO4 and concentrated under vacuum to yield the yellow colored, crude solid product. Methanol (100 ml) was added to this solid product and filtered again to collect white needles of the desired product (7.2 g, 80%). 1H NMR (300 MHz, CDCl3): δ 4.10 (s, 4H), 7.12-7.25 (m, 6H). 13C NMR (300 MHz, CDCl3): δ 32.93, 126.50, 127.13, 127.20, 133.15, 137.16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH:18]=O.O>N1CCCCC1.CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:18]\[C:17]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:12]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1nc[nH]c1C=O
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(Br)cc21
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-1,3-dihydro-2H-indol-2-one (0.3 g, 1.41 mmol) (Starting Material 6), and excess 4-methyl-5-imidazolecarboxaldehyde (0.25 g, 2.27 mmol) (Aldrich) in 1% piperidine in 2-propanol (6 mL) was heated at 90° C. for 4 h. Hot water (6 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.44 g, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3C=CC=CC=3)[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28]([O-])([O-])=O.[K+].[K+].IC(C)C>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:28])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1
Agent: [Pd]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)I
Product: CCOC(=O)c1cc2cc(O[C@H]3CCN(C(C)C)C3)ccc2[nH]1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 18 g (49 mmol) 5-((S)-1-benzyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester, 28.3 ml acetic acid and 2 g Pd/C 10% was hydrogenated with H2 at room temperature during 16 h. The mixture was filtered and the filtrate evaporated to dryness. The residue was taken up in 500 ml DMF and 34.1 g (247 mmol) K2CO3 and 42 g (247 mmol) 2-iodopropane was added and the mixture was stirred for 4 h at 50° C. After filtration and evaporation the residue was purified on silica eluting with a gradient formed from DCM/MeOH (2N NH3) 98/2 to 92/8 to yield after evaporation of the product fractions 60% of the title compound as light brown solid. MS (m/e): 317.3 (MH+, 100%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:42]1([CH:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:49][NH2:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.C(Cl)Cl.CCOCC>[NH2:8][C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:50][CH2:49][CH:48]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N[C@H](Cc1ccccc1)C(=O)NCC(c1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 111 %

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-D-phenylalanine (11.0 g, 41.5 mmol) in chloroform (125 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.95 g, 41.5 mmol) and 1-hydroxybenzotriazole (5.60 g, 41.4 mmol). After 5 minutes, 2,2-diphenylethylamine (7.44 g, 37.7 mmol) was added. The reaction was stirred for 2 hours, diluted with chloroform (100 mL) and washed with aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford an off-white solid. Trituration with ether afforded the crude amide. This material was taken up in methylene chloride (100 mL) and treated with trifluoroacetic acid (45 mL, 580 mmol). After stirring for 15 minutes, the reaction was concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried (sodium sulfate) and concentrated to afford 12.4 g (111% yield inflated by entrained residual solvent) of product as a colorless gum: 1H NMR (CDCl3) δ 7.34-6.95 (m, 15H), 4.10 (t, J=8.2, 1H), 3.88-3.79 (m, 2H), 3.68-3.61 (m, 1H), 3.49 (br s, 2H), 3.13-3.03 (m, 1H), 2.70-2.59 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:11][C@:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[NH:8][O:9][CH2:10][C@@H:6]2[CH2:5]1)[CH3:2].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[NH2:8][C@@:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:11][C@H:4]([O:3][CH2:1][CH3:2])[CH2:5][C@H:6]1[CH2:10][OH:9]
Reactant: CCO[C@@H]1C[C@H]2CON[C@@]2(c2ccccc2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCO[C@@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Zinc (3.68 g) was added to a solution of (3aR*,5R*,6aS*)-5-ethoxy-6a-(2-fluorophenyl)hexahydrocyclopenta[c]isoxazole (540 mg) in acetic acid (15 mL), and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and zinc was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (540 mg).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:18]1([C:4]2[C:5]3[S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cccc3c2sc2ccccc23)cc1
Yield: 82.4 %

Procedure:
10 g (41.6 mmol) 4-dibenzothiophene boronic acid, 6.25 g (39.6 mmol) bromobenzene, 366 mg (0.39 mmol) Pd2 (dba)3, 656 mg (1.6 mmol) S-phose, 25.4 g (120 mmol) K3PO4, 180 mL toluene and 20 mL water were charged in a 500 mL flask. The mixture was heated up to reflux under nitrogen for overnight. The reaction mixture was purified by silica gel column chromatography with pure hexane as elute. ˜8.5 g (83%) white solid was obtained as product which was confirmed by MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[N+]([O-])(O)=O.[CH3:49][C:50]1[CH:54]=[C:53]([CH3:55])[N:52]([C:56](=[NH:58])[NH2:57])[N:51]=1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[NH2:58][C:56]([N:52]1[C:53]([CH3:55])=[CH:54][C:50]([CH3:49])=[N:51]1)=[N:57][C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[F:9])=[O:21]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: O=C(O)c1ccc2nccc(-c3c(F)cc(F)cc3F)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)n(C(N)=NC(=O)c2ccc3nccc(-c4c(F)cc(F)cc4F)c3c2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A mixture of 4-(2,4,6-trifluorophenyl)quinoline-6-carboxylic acid (118 mg), WSC hydrochloride (112 mg), HOBt (37 mg), and DMF (4 mL) was stirred at room temperature for 5 minutes, and then 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate (94 mg) and DIPEA (76 mg) were added thereto, followed by stirring for an additional 24 hours. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain N-[1-amino(3,5-dimethyl-1H-pyrazol-1-yl)methylene]-4-(2,4,6-trifluorophenyl)quinoline-6-carboxamide (140 mg).
Reaction SMILES: CN1CCC(=O)CC1.BrC1C2C(=CC=CC=2)C=CN=1.C([Li])CCC.[ClH:25].[CH3:26][N:27]1[CH2:32][CH2:31][C:30]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][N:35]=2)([O-:33])[CH2:29][CH2:28]1.[Li+]>O.CCOCC>[ClH:25].[ClH:25].[CH3:26][N:27]1[CH2:28][CH2:29][C:30]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][N:35]=2)([OH:33])[CH2:31][CH2:32]1
Reactant: CN1CCC([O-])(c2nccc3ccccc23)CC1
Agent: Brc1nccc2ccccc12
Agent: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CN1CCC(O)(c2nccc3ccccc23)CC1
Reaction time: 2 h

Procedure:
A solution of 11.3 g. of 1-methylpiperidin-4-one in 120 ml. of ether is added dropwise to a stirred isoquinolyl-1-lithium solution, freshly prepared from 20.8 g. of 1-bromoisoquinoline and n-butyllithium in 400 ml. of ether, at 0°, under dry nitrogen. The mixture is stirred for 2 hours more at 0°. Water (50 ml.) and then 100 ml. of 5% hydrochloric acid are added dropwise to decompose the lithium 1-methyl-4-(1-isoquinolyl)-piperidin-4-olate formed. The mixture is worked up in the customary manner to give 1-methyl-4-(1-isoquinolyl)-piperidin-4-ol, dihydrochloride, m.p. 265°-266°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C@H:11]([C:12]([OH:14])=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)C(Br)C(=O)O
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
Following the procedure of Example 17, N-(2-fluoro-4-chlorophenyl)valine (0.79 g) is reacted with α-ethynyl-m-phenoxybenzyl bromide (0.39 g) to yield the α-ethynyl-m-phenoxybenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 451 (M+). N-(2-fluoro-4-chlorophenyl)valine is prepared from 2-fluoro-4-chloroaniline and α-bromoisovaleric acid using the procedure of Example 17.