Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][O:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)O1.I[C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:37]=[C:38]([C:39]([F:42])([F:41])[F:40])[C:31]=12.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[F:40][C:39]([F:42])([F:41])[C:38]1[C:31]2[C:32](=[N:33][CH:34]=[CH:35][C:30]=2[C:9]2[CH:10]=[C:11]([C:15]3([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:16][O:17][CH2:18]3)[CH:12]=[CH:13][CH:14]=2)[N:36]([C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:37]=1
Reactant: CC(C)(C)OC(=O)NCC1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)COC1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2nccc(I)c12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1(c2cccc(-c3ccnc4c3c(C(F)(F)F)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)COC1
Temperature: 60 °C
Yield: 50.3 %

Procedure:
tert-Butyl N-[[3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]methyl]carbamate (65 mg, 0.1670 mmol) was dissolved in dioxane (3 mL) and 4-iodo-3-(trifluoromethyl)-1-trityl-pyrazolo[3,4-b]pyridine (92.74 mg, 0.1670 mmol) was added followed by sodium carbonate (250.5 μL of 2 M, 0.5010 mmol). The reaction was degassed and filled with nitrogen 5 times then Pd[P(tBu)3]2 (12.80 mg, 0.02505 mmol) was added. The reaction was heated at 60° C. overnight. After cooling, water was added followed by ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, the combined organics washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified on silica (Companion, 12 g) eluting with 2.5-50% EtOAc:Pet.ether to give tert-butyl N-[[3-[3-[3-(trifluoromethyl)-1-trityl-pyrazolo[3,4-b]pyridin-4-yl]phenyl]oxetan-3-yl]methyl]carbamate as a white foam (58 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Br:15]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(C)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(CBr)ccc2o1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of 583 (500 mg, 2.63 mmol), N-bromosuccinimide (561 mg, 3.15 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (Vazo) (63 mg, 0.26 mmol) in 15 ml of CCl4 was heated overnight under reflux. The mixture was cooled to room temperature, quenched by adding water and extracted with DCM. The organic layer was washed with brine and dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30% ethyl acetate/hexane) to afford the title compound 585 (680 mg, 96% yield). 1H NMR: (CDCl3) δ (ppm): 7.79 (s, 1H), 7.70-7.52 (m, 3H), 4.69 (s, 2H), 4.06 (s, 3H), 3.72 (s, 2H). LRMS: 268.2 (Calc.); 269.1 (found).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:28])[C:25](Cl)=[O:26].[OH2:30]>>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[C:9]([C:24](=[O:28])[C:25]([OH:30])=[O:26])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc(Cn2ccc3cc(-c4ccccc4)ccc32)cc1
Product: O=C(O)C(=O)c1cn(Cc2ccc(F)cc2)c2ccc(-c3ccccc3)cc12

Procedure:
The title compound was prepared from 1-(4-fluorobenzyl)-5-phenyl-1H-indole and oxalyl chloride in substantially the same manner, as described in Step 3 of Example 25. The product was obtained as a light brown solid, mp: 165-166° C. Mass spectrum (ESI, [M+H]+) m/z 374. 1HNMR (400 MHz, DMSO-d6): δ 13.54 (br s, 1H), 8.73 (s, 1H), 8.42 (s, 1H), 7.68 (d, 1H, J=8.5 Hz), 7.64 (d, 2H, J=7.5 Hz), 7.58 (dd, 1H, J=8.6 Hz and 1.7 Hz), 7.47 (t, 2H, J=7.6 Hz), 7.39 (d, 1H, J=8.6 Hz), 7.37 (d, 1H, J=8.2 Hz), 7.34 (t, 1H, J=7.4 Hz), and 5.61 ppm (s, 2H). Elemental Analysis for C23H16FNO3.0.4 H2O: Calculated: C, 72.59; H, 4.45; N, 3.68. Found: C, 72.58; H, 4.29; N, 3.62.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:16][CH2:17][O:18]C(=O)C)[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+].C(O)(=O)C>CN(C)C=O.CO>[OH:4][CH2:5][CH2:6][N:7]([CH2:16][CH2:17][OH:18])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: O=Cc1ccc(N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 293 g of 4-di-(2-acetoxyethyl) aminobenzaldehyde (see under Example 2b) in 500 ml of dimethyl formamide was added a solution of 54 g of sodium methanolate in 500 ml of methanol. After stirring for 30 minutes at room temperature the reaction mixture was neutralized with acetic acid and concentrated to a small volume. The residue was taken up in 500 ml of water and 500 ml of ethyl acetate. The water layer was separated and extracted six times, each time with a portion of 500 ml of ethyl acetate. The combined organic layers were dried on magnesium sulphate and evaporated. The residue was crystallized from 500 ml of ethyl acetate to yield 156 g of 4-di(2-hydroxyethyl)aminobenzaldehyde with a melting point of 63°-64° C.
Reaction SMILES: C(OC(=O)C([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:26])[NH:24][CH3:25])[CH:18]=2)=[O:15])=[N:10][CH:9]=1)C)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=[C:46]([CH2:48][C:49]([OH:51])=[O:50])N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(NC)=O)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[CH:28]1([CH2:27][N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:26])[NH:24][CH3:25])[CH:18]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:46][CH2:48][C:49]([OH:51])=[O:50])=[CH:9][N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)NC)c2)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: CNC(=O)c1cccc(NCC2CCCC2)c1
Product: CNC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-methyl-benzamide and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C(=O)N([I:42])C(=O)C1>FC(F)(F)C(O)=O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:42])[C:28]([F:31])=[CH:27][C:26]=2[CH3:32])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)c(I)cc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21

Procedure:
A solution of (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-2-methylphenyl)octahydropyrano[3,4-c]pyrrole (55.8 mg, 0.12 mmol) and NIS (53 mg, 0.23 mmol) in 2 mL trifluoroacetic acid was stirred at rt for 40 min. Volatiles were removed. The crude was purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25]>>[Br:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: BrCc1ccccc1Br
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccccc3Br)ccc12
Yield: 4.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (151 mg, 0.71 mmol) and 1-(bromo-methyl)-2-bromobenzene (214 mg, 0.86 mmol) to provide 469 (11 mg, 4% yield) as a white powder. LC-MS (M+H=381, obsd.=381). 1H NMR (400 MHz, DMSO-D6) δ 11.50 (m, 1H), 8.53 (m, 1H), 8.39 (m, 1H), 8.01 (d, J=8.9, 1H), 7.68 (s, 1H), 7.43 (m, 2H), 7.37 (s, 1H), 7.23 (s, 2H), 6.92 (m, 2H), 4.55 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A solution of 15 g of 2-bromoanisole in 50 ml of THF is cooled to −70° C., under nitrogen, a 1.6 M solution of n-butyllithium in THF is added dropwise and the mixture is kept stirring for 1 hour. The mixture is cooled to −70° C. and a solution of 15.2 g of 1-benzylpiperid-4-one in 50 ml of THF is added dropwise. The mixture is kept stirring while allowing the temperature to rise to RT and after 1 hour, the reaction mixture is concentrated under vacuum. The residue is taken up in AcOEt, the organic phase washed with water, with a saturated solution of NaCl, dried over MgSO4 and the solvent evaporated under vacuum. 14 g of the expected product are obtained after crystallization from the AcOEt/ether/heptane mixture.
Reaction SMILES: [C:1]1([C:7](=[N:17][OH:18])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:24](=O)=[O:25]>C1COCC1.CCCCCC>[OH:25][C:24]1[O:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1
Reactant: CSc1ccc(CC(=NO)c2ccccc2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2c(-c3ccccc3)noc2O)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a stirred solution of 1-phenyl-2-(4-methylsulfanylphenyl) ethanone oxime (2.0 g) in dry THF (20 mL), was added a solution of n-butyl lithium (0.98 M. 25 mL) in hexane at −70° C. over a period of 30 minutes. The reaction mixture was warmed to 20° C. over a period of 2 h. To this was added solid CO2 (25 g) and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with cold 1N HCl (20 mL) and extracted with ethyl acetate (3×50 mL). The organic extract was washed with water (100 mL); brine (100 mL), dried over sodium sulphate and evaporated under reduced pressure. The crude product was chromatographed over silicagel using 10% ethyl acetate in petroleum ether as eluent, yielding 1.2 g of pure product as a thick liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=O)[C:6]=2[CH:22]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[S:32])[C:6]=2[CH:22]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN(C)C(=S)c1cc(F)ccc1-2
Reaction time: 1 h

Procedure:
10.7 g (35.3 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 7.13 g (17.6 mmol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide in 100 ml of toluene are heated to boiling under reflux for 22 hours. The mixture is subsequently concentrated in vacuo until crystallisation begins and is then left to stand in an ice-bath for 1 hour. The crystallised-out material is filtered off under suction and washed with a small amount of toluene. The mixture is separated on silica gel with ethyl acetate/chloroform (1:9). After recrystallisation from ethyl acetate, there is obtained pure ethyl 8-fluoro-5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 157°-159° C.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CCNCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of crude (cis)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 0.3 g) in dichloromethane (10 mL) was added diisopropylethyl amine (0.337 g, 2.61 mmol) followed by a solution of ethyl chloroformate (0.119 g, 1.09 mmol) in dichloromethane (1 mL) dropwise over 30 minutes at 0° C. and the mixture stirred at this temperature for 2 h. The mixture was then quenched by ice and diluted with dichloromethane and aqueous phase was extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The residue was then purified by preparative LC/MS (high pH) to provide the title compound as an off white solid (60 mg, 18%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88 (s, 3H), 1.07-1.21 (m, 1H), 1.23 (t, J=7.03 Hz, 3H), 1.29-1.43 (m, 3H), 1.45-1.92 (m, 13H), 2.02-2.24 (m, 2H), 2.81-3.01 (m, 2H), 3.23-3.40 (m, 2H), 3.41-3.69 (m, 5H), 4.10 (q, J=7.29 Hz, 2H).
Reaction SMILES: [C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:36]1(/[CH:42]=[CH:43]/[C:44](Cl)=[O:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[C:44](=[O:45])/[CH:43]=[CH:42]/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)c(C(=O)OC)c2)cc1
Reactant: O=C(Cl)/C=C/c1ccccc1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)c(C(=O)OC)c2)C(=O)/C=C/c2ccccc2)cc1

Procedure:
The title compound was prepared following the procedure G using the hydrochloride salt of methyl 5-{[(4-dec-1-ynylbenzyl)amino]methyl}-2-(2-methoxy-2-oxoethoxy)benzoate and (2E)-3-phenylacryloyl chloride (purification by flash chromatography on SiO2, DCM/MeOH 98:2) as a pale yellow oil (82%). M+ (ESI): 610.0. HPLC, Rt: 6.0 min (purity: 99.5%). 1H NMR (CDCl3) δ: 7.85 (d, J=15.4 Hz, 1H), 7.70 (m, 1H), 7.47-7.12 (m, 10H), 6.86 (m, 2H), 4.74 (s, 2H), 4.61 (m, 4H), 3.90 (s, 3H), 3.81 (s, 3H), 2.41 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.45 (m, 2H), 1.30 (m, 8H), 0.89 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[C:10]([O:17][CH3:18])[CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[C:10]([O:17][CH3:18])[CH:9]=1
Reactant: CC(C)(N)CO
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C1=NC(C)(C)CO1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
80 g of 2-amino-2-methyl 1-propanol was dissolved in 350 ml of methylene chloride, and the solution was cooled to -5° C. 4-Chloro-2-methoxybenzoyl chloride was dissolved in 180 ml of methylene chloride and then slowly dropwise added to the cooled solution. After the dropwise addition, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the crystal was washed with methylene chloride. Dilute hydrochloric acid was added to the filtrate and then subjected to phase separation to get an organic phase. The organic phase was dried over anhydrous magnesium sulfate and then concentrated. 120 ml of thionyl chloride was slowly dripwise added at room temperature to 106 g of the resultant oleaginous substance. The mixture was stirred for an additional 1 hr and then concentrated. Water was added to the concentrate for dissolution, and an aqueous sodium hydroxide solution was added to the solution to adjust the pH value to 11. Chloroform was added thereto, and the mixture was extracted, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography (chloroform). The yield was 62.3 g.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:23]([O:27][C:28]([C@@:30]1([CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)[CH:34]([F:35])[C:33](=[O:36])[N:32]([C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(OCC)(=O)C>O1CCCC1>[C:23]([O:27][C:28]([C@@:30]1([CH2:45][CH2:46][OH:47])[CH:34]([F:35])[C:33](=[O:36])[N:32]([C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic acid (0.66 mL, 11.54 mmol) and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (8.3 mL, 8.3 mmol) were sequentially added to a solution of the crude (3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.44 g) in tetrahydrofuran in a nitrogen atmosphere at 0° C. After stirring at room temperature for 20 hours, the reaction solution was poured into a mixture of ethyl acetate (100 mL) and a saturated sodium bicarbonate solution (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL×2), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 2.06 g (91%, two steps) of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:17]O>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: Cc1c(O)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1C
Yield: 65.6 %

Procedure:
A solution of 17.98 g (0.118 mol) of 3-hydroxy-2-methylbenzoic acid in 200 mL of MeOH was treated with 2.0 mL of conc. H2SO4 and heated at reflux overnight. The solution was concentrated under reduced pressure and diluted with H2O. The product was collected and recrystallized from MeOH/H2O to give 12.85 g (65.6% yield) of a tan solid, mp 74-75° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 167 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][C:6]2[N:12]=[C:13]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4]1=[O:31])[CH3:2].[C:32]([O:36][C:37](=[O:55])[NH:38][C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][C:40]=1[CH3:54])([CH3:35])([CH3:34])[CH3:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([O:36][C:37](=[O:55])[NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:15]2[C:5]3[C:4](=[O:31])[N:3]([CH2:1][CH3:2])[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][C:6]=3[N:12]=[C:13]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[N:14]=2)=[CH:41][C:40]=1[CH3:54])([CH3:33])([CH3:34])[CH3:35]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: CCN1CC(C)(C)Oc2nc(N3CCOC[C@@H]3C)nc(OS(=O)(=O)C(F)(F)F)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN1CC(C)(C)Oc2nc(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)OC(C)(C)C)c(C)c3)c2C1=O
Temperature: 100 °C
Yield: 110.8 %

Procedure:
A mixture of 1 g (2.13 mmol) of trifluoromethanesulfonic acid 6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl ester, 711.35 mg (2.13 mmol) of [2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]carbamic acid tert-butyl ester, 906.25 mg (4.27 mmol) of tribasic potassium phosphate, 149.83 mg (213.47 μmol) of bis(triphenylphosphine)palladium(II) chloride in 10 ml of dioxane and 3 ml of water is heated in a Biotage microwave machine at 100° C. for 30 minutes. The reaction medium is diluted in 250 ml of ethyl acetate and filtered through Celite. The organic phase is dried over MgSO4. The filtrate is evaporated under reduced pressure. The residue is taken up in 30 ml of heptane, brought to reflux and filtered while hot to give 1.24 g of {4-[6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triaza benzocyclohepten-4-yl]-2-methylphenyl}carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1([O:41]C(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[CH:50]1[CH2:55][CH:54](F)[CH2:53][CH2:52][NH:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:51]3[CH2:52][CH2:53][CH:54]([OH:41])[CH2:55][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: FC1CCNC(F)C1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(O)CC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,4-difluoro piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.