Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25](O)=[O:26])=[CH:18][C:17]=3[CH:28]=2)=[CH:9][CH:8]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:33][N:34]([CH2:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1)[CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1.CN(C=O)C.O>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:23])(=[O:24])[CH2:21][CH2:20][C:19]([C:25]([NH:46][C:45]4[CH:44]=[CH:43][C:42]([CH2:41][N:34]([CH3:33])[CH:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:48][CH:47]=4)=[O:26])=[CH:18][C:17]=3[CH:28]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
In THF (72 ml) was dissolved 7-[4-(2-ethoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (3.6 g). To the mixture were added under ice-cooling thionyl chloride (0.93 ml) and DMF (three drops), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (2.23 g) and triethylamine (5.0 ml) in THF (67 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 84) (2.4 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>O1CCCC1>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[O:22])=[O:18])[CH3:21]
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
In a flame-dried, three-necked round-bottomed reaction flask equipped with reflux condenser, magnetic stirring bar and addition funnel, there were placed 1.72 g (0.00535 mole) of 4-chloro-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline (the product of Preparation C) dissolved in 15 mL of dry tetrahydrofuran. Stirring was commenced and the resulting organic solution was then treated dropwise with a solution consisting of 573 mg (0.00535 mole) of o-toluidine (available from the Aldrich Chemical Company, Inc. of Milwaukee, Wis.) dissolved in 15 mL of dry tetrahydrofuran. The resulting reaction mixture was then stirred and heated to 60° C. and thereafter kept at that temperature for a period of approximately 16 hours (i.e., overnight). Upon completion of this step, the final reaction mixture was slowly allowed to cool to ambient temperatures (ca. 20° C.) and the yellow precipitate which resulted was subsequently collected by means of suction filtration and air-dried on the filter funnel to constant weight. Recrystallization of the latter crude salt material from methylene chloride/ethyl acetate/petroleum ether then gave 1.75 g (76%) of pure 3-(3-ethoxycarbonylpropionyl)-8-methoxy-4-(2-methylphenylamino)quinoline as the hydrochloride salt, m.p. 210°-211° C. The pure product was further characterized by means of mass spectrum (MS) analysis and nuclear magnetic resonance (NMR) data, in addition to elemental analysis.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH2:9]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18])[CH:10]=[CH2:11].[CH3:19][O:20]C(Cl)Cl>C(Cl)Cl>[CH2:9]([N:12]1[CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=[C:13]1[C:17]#[N:18])[CH:10]=[CH2:11]
Reactant: C=CCn1cccc1C#N
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: C=CCn1cc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a 100 mL flask charged with AlCl3 (3.3 g, 25 mmol, 2.5 equiv.) and 35 mL of dry CH2Cl2 was added 2 mL of nitromethane. The mixture was cooled to 0° C. and a solution of 1-allyl-1H-pyrrole-2-carbonitrile (1.3 g, 10 mmol, 1 equiv.) in 5 mL of CH2Cl2 was added followed by a solution of dichloromethyl methyl ether in 10 mL of CH2Cl2 dropwise. After 30 minutes, the reaction was warmed to room temperature, stirred for 1.5 hours, poured over 100 mL of ice water, and the organic layer was separated. The organic layers were washed with 30 mL of 3M HCl, 30 mL of water, 18% aqueous sodium sulfite, filtered through CELITE® filter aid and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc-hexanes (5-40% gradient) to provide 1.25 g (78%) of 1-allyl-4-formyl-1H-pyrrole-2-carbonitrile as a yellow oil.
Reaction SMILES: [NH:1]([C:105]([O:107][C:108]([CH3:111])([CH3:110])[CH3:109])=[O:106])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@H:55]([C:63]([NH:65][C@H:66]([C:73]([NH:75][C@H:76]([C:83]([NH:85][C@H:86]([C:96]([O:98]C1C=CC=CC=1)=[O:97])[CH2:87][CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:84])[CH2:77][O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:74])[CH2:67][O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:64])[C@@H:56]([CH3:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:53])[CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].OO.[OH-].[Na+].Cl>O>[NH:1]([C:105]([O:107][C:108]([CH3:109])([CH3:110])[CH3:111])=[O:106])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:40]([NH:42][C@H:43]([C:52]([NH:54][C@H:55]([C:63]([NH:65][C@H:66]([C:73]([NH:75][C@H:76]([C:83]([NH:85][C@H:86]([C:96]([OH:98])=[O:97])[CH2:87][CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:84])[CH2:77][O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:74])[CH2:67][O:68][C:69]([CH3:70])([CH3:71])[CH3:72])=[O:64])[C@@H:56]([CH3:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:53])[CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:41])[CH:37]([CH3:38])[CH3:39])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:10])[CH2:3][O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C)C(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)[C@@H](C)OC(C)(C)C)C(C)C

Procedure:
A solution of Boc-Ser(tBu)-Asp(OtBu)-Ala-Val-Val-Asp(OtBu)-Thr(tBu)-Ser(tBu)-Ser(tBu)-Glu(OtBu)-OC6H5 (452 mg, 0.29 mmol) in TFE:H2O (5.2-0.4 mL) was treated with 3% H2O2 (0.31 mL, 0.30 mmol, 1.0 eq) with stirring (magnetic). The reaction mixture was adjusted to pH 10.5 by addition of 1N NaOH (triggered by an autotitrator) and maintained at that pH for 3 h. The reaction mixture was adjusted to pH ~1 with 1M HCl, refrigerated, filtered and washed with H2O and CH3OH and dried in vacuo. Yield: 423 mg (98.4%); mp ~245° dec; [α]D25 -13.28° (c 1, TFE); Rf 0.41 (CHCl3 :MeOH:AcOH; 80-2-0.4). Anal. calc. for C70H127N10O23.H2O (1494.87): C, 56.24; H, 8.69; N, 9.37. Found: C, 56.33; H, 8.32; N, 9.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH3:29])=[N+:20]([O-])[C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:38].[K+].[K+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH2:29][OH:38])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2CO)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was also prepared as follows: A solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (770 mg, 1.50 mmol) in trifluoroacetic anhydride (7 mL) and CH2Cl2 (7 mL) in a sealed tube was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in methanol (14 mL), and 1.0 M aqueous K2CO3 solution (7 mL, 7 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, then concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (50 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was purified using a silica gel cartridge (80 g) eluted with a gradient of ethyl acetate (50-100%) in hexanes to afford 660 mg (86%, 2 steps) of the title compound as a yellow foam. HPLC/MS: retention time=2.68 min, [M+H]+=512.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:4].OO.C([O-])(O)=[O:18].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([OH:18])=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cccc2cccnc12
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2cc(O)cnc12
Yield: 44 %

Procedure:
To a solution of the intermediate 8-Quinolinecarboxylic acid methyl ester (2.89 mmol) in AcOH (4 ml) was added 30% H2O2 (0.6 ml). The reaction mixture was heated at 85 degrees for 7.5 hr. The reaction mixture was treated with sat NaHCO3, and extracted six times with CHCl3. Organic layer was dried over anhydrous MgSO4, and concentrated. Crude residue was triturated with CHCl3/Toluene to provide compound 313 (256 mg, 44%, in 2 steps).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]1([C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1>>[CH3:2][C:3]1[C:4]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:33][CH2:32][C:29]3[CH:30]=[N:31][C:26]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[CH:27][CH:28]=3)[CH2:17][CH2:16]2)=[CH:5][CH:6]=[C:7]2[C:11]=1[CH2:10][O:9][C:8]2=[O:12]
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: O=CCc1ccc(-n2cnnn2)nc1
Agent: Cl
Product: Cc1c(CCN2CCN(CCc3ccc(-n4cnnn4)nc3)CC2)ccc2c1COC2=O

Procedure:
4-Methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetaldehyde. LC-MS (IE, m/z): 406.1 [(M+1)+−28]. (0.61 μm)
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:26])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CO.[OH-].[Na+]>O>[CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)NCC(=O)OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)NCC(=O)O)c(C)c1
Yield: 69.4 %

Procedure:
A mixture of methyl (4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-2-methylbenzoylamino)acetate (0.43 g, 0.89 mmol), CH3OH (10 ml), NaOH (0.18 g, 4.46 mmol), and H2O (1 mL) is refluxed for 2 h. The reaction is concentrated, diluted with H2O (5 ml), acidified (pH 3-4) with 0.1 M HCl and extracted with EtOAc (3×15 mL). The combined organic layers are MgSO4 dried, and concentrated to give the title compound (0.29 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].CN(C)C=O.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([C:16]([CH3:22])([C:15]([O:14][CH2:12][CH3:13])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
A mixture of 50.0 g (0.31 mol) of 2,4-difluoronitrobenzene II, 56.1 g (0.32 mol) of diethylmethylmalonate and 400 ml of dimethylformamide are vigorously stirred. To the stirring mixture is added 13.1 g (0.33 mol) sodium hydroxide in one portion at 25° C., cooling with ice to keep the temperature of the reaction mixture at 25°-30° C. during the first hour. Thereafter, stirring is maintained for 3.5 hours, then 800 ml of water is added, the organic layers removed, and the aqueous layer extracted with three 180-ml portions of ethyl acetate-water.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:9]([C:13]1[O:14][C:15]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:16]=2[C:17]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:10][CH2:11][CH3:12].Cl[CH2:35][CH2:36][CH2:37][OH:38]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:9]([C:13]1[O:14][C:15]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:16]=2[C:17]=1[C:18]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:35][CH2:36][CH2:37][OH:38])=[CH:23][CH:24]=1)=[O:26])[CH2:10][CH2:11][CH3:12]
Reactant: OCCCCl
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCCO)cc1
Temperature: 45 °C
Reaction time: 4.5 h
Yield: 69.5 %

Procedure:
312 g (2.26 moles) of potassium carbonate, 11 g (0.066 moles) of potassium iodide and 11 g (0.034 moles) of tetrabutylammonium bromide are added to a solution of 222 g (0.655 moles) of 2-butyl-3-(4-hydroxybenzoyl)-5-nitro-benzofuran (formula (V)) in 1780 ml of DMF. The reaction mixture is heated to 50° C. and after approximately 30 minutes 100 g of 3-chloro-1-propanol are added dropwise. At the end of the dropwise addition, the reaction mixture is brought to 80-85° C. and left under stirring for 4-5 hours. Once the reaction is complete, the mixture is cooled to 40-50° C. and the inorganic salts are removed by filtering. The organic solvent is distilled at reduced pressure, maintaining the temperature around 60-70° C., and the residue is dissolved in 2220 ml of toluene. After performing three washing operations on the organic phase, each with 1130 ml of deionised water, the toluene is concentrated to residue. The crude product is dissolved with approximately 100 ml of ethyl acetate and the mixture is left under cooling at 0-4° C. for approximately 12 hours. The solid is filtered, the wet product is washed with a little ethyl acetate pre-cooled to 0-5° C. and it is dried under a vacuum at 40° C. for 6-7 hours. 181 g of 3-{4-[(2-butyl-5-nitro-1-benzofuran-3-yl)carbonyl]phenoxyl}propan-1-ol (formula (II)) are obtained.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:5]=1)(=[O:3])[NH2:2].[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CCOC(C)=O.CN(C)C=O>[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][N:33]([C:17]([C:13]2[CH:14]=[CH:15][C:16]3[C:8]4[N:7]=[C:6]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=5)[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]=4[NH:10][C:11]=3[CH:12]=2)=[O:18])[CH2:32]1
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)O)ccc4c3n2)cc1F
Reactant: CN(C)C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CC[C@H](N(C)C)C5)ccc4c3n2)cc1F
Reaction time: 0.17 h
Yield: 44.3 %

Procedure:
Dimethylformamide (5 mL) was added to a mixture of 4-carbamoyl-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid (70 mg, 0.19 mmol), (3S)-(+3-(dimethylamino)pyrrolidine (0.070 mL, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (106 mg, 0.554 mmol), and 1-hydroxybenzotriazole hydrate (75 mg, 0.55 mmol). After stirring for a few minutes, triethylamine (0.077 mL, 0.55 mmol) was added and the reaction was left stirring overnight. It was diluted with EtOAc, washed with water, dried with sodium sulfate and the solvent was removed. The residue was suspended in DCM at 40° C. for 10 min and then filtered to gave (S)-7-(3-(dimethylamino)pyrrolidine-1-carbonyl)-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (40 mg) as a yellow solid. MS (ESI) m/z 476.2 (M+H). 1H NMR (DMSO-d6) δ ppm 11.71 (1H, br. s.), 8.62 (1H, br. s.), 8.47 (1H, s), 8.30 (1H, dd, J=7.48, 4.43 Hz), 8.09-8.21 (2H, m), 7.92 (2H, m), 7.42 (1H, m), 7.36 (1H, m), 3.95 (3H, s), 3.64-3.82 (1H, m), 3.47-3.63 (2H, m), 3.36 (1H, m), 2.61-2.83 (1H, m), 2.22 (3H, s), 2.11 (3H, s), 2.03 (1 H, br. s.), 1.68-1.85 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12.[CH3:11][OH:12].C[O-].[Na+]>CCOC(C)=O.Cl>[CH3:11][O:12][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12
Reactant: Clc1ccnc2c1CCC2
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccnc2c1CCC2
Temperature: 110 °C
Yield: 44 %

Procedure:
A mixture of 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (2.8 g, 18 mmol), MeOH (20 mL) and sodium methoxide (3.0 g, 56 mmol) was sealed in a pressurized flask and heated at 110° C. for 18 h. The mixture was diluted with EtOAc and neutralized with HCl to pH=1. The organic solvent was removed under reduced pressure. The resulting mixture was washed with ether twice, and then neutralized with Na2CO3 solution. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound (1.20 g, 44%). LCMS calc. for C9H12NO (M+H)+: m/z=150.1. Found: 150.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)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.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([C:21]#[C:20][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc(C#Cc2ccccc2)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.12 mmol) was dissolved in 140 μl tetrahydrofuran and 160 μl triethylamine. Ethynylbenzene (16 μl, 0.15 mmol), bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.01 mmol) and copper(I) iodide (5 mg, 0.02 mmol) were added and the mixture was stirred at room temperature during 2 h. The reaction was poured into a 4% aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 15%, hexane-ethyl acetate) to give 45 mg (95% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[C:4]([O:12][CH3:13])[C:5]([C:8](=[CH2:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1.[F:15][C:16]([F:25])([F:24])[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl.FC(F)(F)CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][CH3:10])[CH2:11][C@:17]([OH:23])([C:16]([F:24])([F:25])[F:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([O:12][CH3:13])[C:3]=1[CH3:14]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C(CC)c1ccc(F)c(C)c1OC
Agent: [Pd]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@](O)(CC(CC)c1ccc(F)c(C)c1OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
5.7 g (29.3 mmol) of 3-fluoro-2-methyl-6-(1-methylenepropyl)anisole, 7.7 ml (170 mmol) of ethyl trifluoropyruvate and 15 g of molecular sieve are admixed dropwise at 0° C. over 30 minutes with 0.76 g (0.88 mmol) of [Cu(R,R)-2,2-bis(4,5-dihydro-4-tert-butyloxazolin-2-yl)propane)(H2O)2]((SbF6)2, in 38 ml of dichloromethane. The reaction mixture is stirred at 0° C. for 16 hours and the reaction mixture is purified by means of column chromatography on silica gel (hexane/ethyl acetate 0-20%). This gives 8.7 g of ethyl (R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hex-4-enoate as an E/Z mixture with an enantiomeric excess of greater than 80%, and in this way 13.9 of crude E/Z-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-(trifluoromethyl)hex-4-ene-1,2-diol. 4.0 g (11 mmol) of ethyl (2R,4E/Z)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hex-4-enoate are dissolved in 180 ml of 2,2,2-trifluoroethanol and the solution is admixed with 400 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at 100 bar until reaction is complete. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The concentrated crude product is purified by column chromatography on silica gel (hexane/ethyl acetate 15%) to give 3.7 g (10 mmol) of ethyl (2R,4R/S)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanoate as a diastereomer mixture. 3.7 g (10 mmol) of ethyl (2R,4R/S)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanoate are cooled to −15° C. in 132 ml of diethyl ether and admixed over 10 minutes with solid lithium aluminum hydride, 1.03 g (27.3 mmol), in portions. The mixture is stirred at −10° C. for 3 hours, and ethyl acetate and water are added cautiously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate.