Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH:17]([OH:20])[CH2:18]Cl)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6])[CH:2]=[CH2:3].[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].CC(C)=O.[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>CC(C)=O.CN(C)C=O.C(N(CC)CC)C>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[CH2:1]([N:4]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][N:31]3[CH2:32][CH2:33][CH:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)CCc2c(OCC(O)CCl)cccc21
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)CCc2c(OCC(O)CN3CCC(Cc4ccccc4)CC3)cccc21
Reaction time: 5 h
Yield: 82 %

Procedure:
2.6 Grams of 1-allyl-5-(2-hydroxy-3-chloropropoxy)-3,4-dihydrocarbostyril, 1.5 g of triethylamine and 2.0 g of 4-benzylpiperidine were mixed with 30 ml of dimethylformamide and the mixture was stirred at 80°-90° C. for 5 hours. The reaction mixture was poured into 80 ml of a 5%-sodium hydrogencarbonate aqueous solution and the organic layer was extracted with chloroform, and the chloroform layer was washed with water and dried. Then the chloroform was removed by distillation and the residue thus obtained was dissolved in 30 ml of acetone and further 5%-oxalic acid acetone solution was added to make the pH to 4.5 and the crystals formed were collected by filtration and washed with acetone. Recrystallization from ethanol to obtain 4.3 g (yield: 82%) of 1-allyl-5-[2-hydroxy-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril monooxalate as in the form of colorless needle-like crystals. Melting point: 178°-180° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with piperazine (Aldrich) to give [(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:28]2)=[O:21])[CH2:17][CH2:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 288 h
Yield: 88.4 %

Procedure:
A mixture of 2-[4-(2 tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182-A, 0.35 g, 0.79 mmol), ethyl chloro(oxo)acetate (140 mg, 1.02 mmol) and triethylamine (439 3.15 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 12 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 75:25 to 25:75) to give the title compound (0.33 g, 88%) as a white amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1cc(C)c2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 5,7-dimethyl-1H-indole-2,3-dione in tetrahydrofuran at 0° C. was added 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (40 mL). After stirred at room temperature overnight, a 5% HCl solution was added to the mixture and it was stirred 20 minutes. It was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and evaporated to dryness to afford the title compound as oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.C(=O)(O)[O-].[Na+].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].CN(C=O)C>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Nc1ccc(Br)cc1I
Reactant: C=CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cc(Br)ccc1N
Temperature: 80 °C
Yield: 55.8 %

Procedure:
To a microwave vial was added, 4-bromo-2-iodoaniline (1.70 g, 5.71 mmol), PdOAc2 (0.064 g, 0.285 mmol), sodium bicarbonate (1.198 g, 14.27 mmol), ethyl acrylate (0.651 ml, 5.99 mmol) and DMF (1.902 ml). The reaction was heated in microwave for 1 hour at 80° C. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.860 g of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate. m/z (ESI) 270.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])[CH:15]=O>>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[CH:15][C:14]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]([OH:20])=[C:12]([OH:11])[CH:13]=1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: N#CCC(=O)NCCCO
Product: N#CC(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)NCCCO
Yield: 52 %

Procedure:
The procedure described in Example 99 was repeated using N-(3-hydroxypropyl)cyanoacetamide and 3,4-dihydroxy-5-nitrobenzaldehyde. Yield 52%, m.p. 223°-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.CI.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: C1CNCCN1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CI
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Temperature: 130 °C
Yield: 41.6 %

Procedure:
A mixture of 8-chloro-10H-dibenzo[b,f][1,4]oxazepin-11-one (189JO29C) (17 mg, 0.069 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (16 mg, 0.040 mmol) in toluene (2 mL) was heated in capped tube using microwave assisted heating (130° C., 20 minutes). The reaction mixture was cooled to room temperature and MeI (18 μL, 0.29 mmol) was added and the resulting mixture was heated in capped tube using microwave assisted heating (120° C., 20 minutes). The mixture was concentrated and the residue was taken up in pyridine (2 mL) and piperazine (25 mg, 0.29 mmol) was added. The resulting mixture was heated in a capped tube at 130° C. over night then using microwave assisted heating (160° C., 30 minutes). The mixture was concentrated, diluted with EtOAc and washed with water. The organic phase was applied onto a SCX-2 ion exchange column. The column was washed with MeOH, and then the product was eluted with NH3 (7 N in MeOH) to give 9.0 mg (57%) of the title compound (189JO31). MS (ESI) 314 (MH+). Purity for MH+ (UV/MS) 92/100.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (753 mg) in 2-propanol (10 mL) were added N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-N,N-dimethyl-D-serinamide (770 mg) and piperidinium acetate (329 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (371 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22](F)(F)F)=[O:19])=[CH:14][C:13]=3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]O)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.[F:32]C1(F)N(C)CCN1C>C(#N)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][F:32])[CH:11]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CN1CCN(C)C1(F)F
Reactant: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(CCCCCO)c1
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(CCCCCF)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a suspension of N-cyclopropyl-1-(2-(5-hydroxypentyl)-4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide (50.0 mg, 0.13 mmol) obtained in Example 394 in acetonitrile (3.0 ml) was added 2,2-difluoro-1,3-dimethylimidazolidine (20 μl, 0.16 mmol) and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate/hexane=1/4 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (26.8 mg, 53%).
Reaction SMILES: C(N(CC)[P:4]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])C.[F:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:54])[CH2:26][N:27]2[CH:31]=[C:30]([NH:32][C:33]3[C:42]4[C:37](=[CH:38][C:39]([O:43][CH2:44][CH2:45][CH2:46][N:47]([CH2:51][CH2:52][OH:53])[CH2:48][CH2:49][CH3:50])=[CH:40][CH:41]=4)[N:36]=[CH:35][N:34]=3)[CH:29]=[N:28]2)[CH:21]=[CH:22][CH:23]=1.N1C=NN=N1.OO.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])O.[K+]>CC(N(C)C)=O.O>[P:4]([O:53][CH2:52][CH2:51][N:47]([CH2:46][CH2:45][CH2:44][O:43][C:39]1[CH:38]=[C:37]2[C:42]([C:33]([NH:32][C:30]3[CH:29]=[N:28][N:27]([CH2:26][C:25]([NH:24][C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=4)=[O:54])[CH:31]=3)=[N:34][CH:35]=[N:36]2)=[CH:41][CH:40]=1)[CH2:48][CH2:49][CH3:50])([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: CCCN(CCO)CCCOc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCN(CCCOc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2c1)CCOP(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-tert-butyl diethylphosphoramidite (747 mg, 3 mmol) was added slowly to a solution of N-(3-fluorophenyl)-2-{4-[(7-{3-[(2 hydroxyethyl)(propyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (390 mg, 0.75 mmol) and tetrazole (158 mg, 2.25 mmol) in dimethylacetamide (4 ml) under nitrogen. The mixture was stirred at ambient temperature for 1 hour. Hydrogen peroxide (383 μl, 3.38 mmol, 30% aqueous solution) was added slowly at 0° C. and the reaction mixture stirred for 1.5 hours at ambient temperature. An additional portion of hydrogen peroxide (42 μl, 0.37 mmol) was added to the solution to complete the oxidation. The mixture was cooled to 0° C. and a saturated solution of sodium metabisulphite (7 ml of 0.53 M solution) added slowly with vigorous stirring. The mixture was stirred at ambient temperature for 20 minutes, diluted with water and the pH adjusted to 7 with an aqueous solution of potassium hydrogen carbonate. The reaction mixture was extracted with dichloromethane (3×25 ml) and the combined organics dried and concentrated in vacuo. Purification by silica gel chromatography, eluting with dichloromethane followed by increased polarity to dichloromethane:methanol:ammonia (20:1:0.1 to 20:3:0.2) gave di-tert-butyl 2-[[3-({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)propyl](propyl)amino]ethyl phosphite as a pale yellow oil. This intermediate was dissolved in dioxane (10 ml) and a solution of 4.0 N hydrochloric acid in dioxane (1.12 ml, 4.5 mmol) added. The mixture was stirred at ambient temperature for 18 hours. The solid was filtered, washed with dichloromethane and diethyl ether and dried in vacuo for 18 hours (50° C., 0.1 mm Hg) to yield compound 255 in table 11 as the dihydrochloride salt (375 mg, 70% yield):
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:3].Cl.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][CH3:30])[CH2:24][CH2:23]1.Cl>O.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[N:29]([CH2:28][C@H:25]2[CH2:26][CH2:27][C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[CH2:23][CH2:24]2)[CH3:30])=[CH:6][CH:7]=1
Reactant: CNC[C@H]1CC[C@H](CCCCCBr)CC1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)C(=O)Oc1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
0.515 ml Diisopropyl-aethylamine, 0.674 g (3.00 mmol) 4-trifluoromethylphenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] and 0.828 mg potassium carbonate (dissolved in the minimal amount of water) were added to a suspension of 0.625 g (2.00 mmol) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-amine hydrochloride in 20.0 ml of tetrahydrofuran kept at −10° C. The reaction mixture was then intensively stirred for 1 hour at −10° C. and for 3 hour at room temperature. 0.200 g 4-trifluoromethylphenyl chloroformate were added and stirring at room temperature continued for additional 2 hours. The reaction mixture was subsequently acidified with dilute hydrogen chloride solution. It was then evaporated, poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 1:1 v/v mixture of hexane and dichloromethane as the eluent giving 0.90 g (96.9%) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 464 (MH+, 1Br).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[N:5]=1>C(OCC)(=O)C.[Zn]>[CH3:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[N:5]=1
Reactant: Cc1nc(S(C)(=O)=O)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: Cc1nc(S(C)(=O)=O)ccc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.5 %

Procedure:
To a suspension of zinc dust (146 g, 2.01 mol) and aqueous ammonium chloride solution (3 M, 800 ml) was added dropwise a solution of 2-methyl-6-(methylsulfonyl)-3-nitropyridine (87.0 g, 401 mmol) in ethyl acetate (500 mL) via an addition funnel at 0° C. The mixture was stirred at room temperature for 17 h and filtered through Celite™. The filtrate was then extracted with ethyl acetate. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from ethanol to give the title compound (34.7 g, 46%) as a solid. Exact mass calculated for C7H10N2O2S: 186.1. Found: LCMS m/z=187.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])(O)=O.[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2occc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a stirred solution of benzofuran-5-ol (5.2 g, 0.039 mol) in DMF (50 mL) was added imidazole (5.3 g, 0.078 mol) and TBSCl (6.1 g, 0.041 mol) at room temperature. The mixture was stirred at room temperature 20 hours. Then a solution of saturated NaHCO3 (150 mL) was added into the reaction and the mixture was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (3×100 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 100% PE) to obtain the title compound (7.8 g, 81%) as colorless oil. 1H-NMR (600 MHz, DMSO-d6) δ 7.94 (d, J=2.1 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.89-6.84 (m, 1H), 6.81 (dd, J=8.8, 2.5 Hz, 1H), 0.98 (s, 9H), 0.19 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:28][C:29]3[C:30]([F:40])=[C:31]([CH:37]=[CH:38][CH:39]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:7]([CH:25]3[CH2:27][CH2:26]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15](COCC[Si](C)(C)C)[CH:16]=2)=[CH:4][CH:3]=1.Cl.CCN(CC)CC.CCCCC>CCO>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:28][C:29]3[C:30]([F:40])=[C:31]([CH:37]=[CH:38][CH:39]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:7]([CH:25]3[CH2:26][CH2:27]3)[N:8]2[C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(COCC[Si](C)(C)C)c3)c3c(F)c(Cl)ccc23)c1F
Agent: Cl
Solvent: CCCCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cn[nH]c3)c3c(F)c(Cl)ccc23)c1F
Yield: 82.6 %

Procedure:
To a stirred solution of compound 3 (140 mg, 0.23 mmol) in EtOH (17 mL) was added 3 N HCl (4 mL) at RT and heated to reflux for 3 h. After completion of the reaction (TLC), the pH of the mixture was neutralized with Et3N (2 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. The crude was titurated with n-pentane, dried under reduced pressure to afford 4 (90 mg, 90%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): 13.21 (br s, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 7.60 (t, J=6.5 Hz, 1H), 7.21-7.11 (m, 3H), 6.84 (t, J=6.5 Hz, 1H), 4.34 (q, 2H), 1.81-1.76 (m, 1H), 1.32 (t, J=8.0 Hz, 3H), 0.93-0.90 (m, 2H), 0.84-0.79 (m, 2H); LC-MS (ESI): m/z 474.9 (M+H+).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=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.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CC(O)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (58.9 mg, 0.7 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 10 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 64 mg, 70%).
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:7])=[O:6].[Cl:10]N1C(=O)CCC1=O>S(Cl)(Cl)=O>[Cl:10][CH:4]([CH2:3][C:2]([Br:9])([Br:8])[Br:1])[C:5]([Cl:7])=[O:6]
Reactant: O=C(Cl)CCC(Br)(Br)Br
Reactant: O=C1CCC(=O)N1Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C(Cl)CC(Br)(Br)Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
343.2 g (1.0 mol) of 4,4,4-tribromobutyric acid chloride are dissolved in 600 g of thionyl chloride, and 266.0 g (2.0 mols) of N-chlorosuccinimide are added in portions at 60° C., whilst at the same time exposing the mixture to a high-pressure mercury lamp. After all of the N-chlorosuccinimide has been added, the resulting mixture is stirred for 5 hours at 60° C., with exposure to the said lamp. The thionyl chloride is then distilled off and the residue is rectified under a high vacuum. 309.7 g (82% of theory) of 2-chloro-4,4,4-tribromobutyric acid chloride with a boiling point of 59° to 63° C./0.05 mm Hg are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](Cl)=[O:24]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1)=[O:24]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2F)C1
Yield: 52 %

Procedure:
tert-Butyl 3-(2-(2-fluorophenyl)acetyl)-4-oxopiperidine-1-carboxylate (295 mg, 52%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 2-(2-fluorophenyl)acetyl chloride according to the general procedure for the preparation of diketones. MS (ES−) m/z 334.1(M−H)−