Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1)([CH3:10])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21](N=C=NCCCN(C)C)C.CO>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:21][O:18][C:17]([C:15]1[N:16]=[C:12]([S:11][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:10])[CH3:9])[S:13][CH:14]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)O)cs1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-tert-Butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid was dissolved in methylene chloride (1200 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191.70 g), 4-dimethylaminopyridine (5.86 g) and methanol (19.47 mL) were added and the mixture was stirred at room temperature overnight. The mixture was washed with dilute hydrochloric acid (about 0.5 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 500 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved again in ethyl acetate (700 mL), washed successively with dilute hydrochloric acid (about 0.2 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 300 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained solid was washed with a mixed solvent (10:1, about 500 mL) of hexane and ethyl acetate, and the solid was collected by filtration. The solvent was evaporated from the filtrate and the residue was purified by silica gel column chromatography (using 500 g of Fuji Silysia BW-300, elution solvent: hexane/ethyl acetate=3/1). The obtained solid was washed with hexane and combined with the solid obtained earlier to give 2-(1-tert-butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid methyl ester (94.6 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[C:23]=1[NH2:38])([CH3:21])[CH3:20]>C1(C)C=CC=C(C)C=1>[CH:19]([C:22]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[C:23]=1[N:38]1[CH2:2][CH2:3][N:4]=[C:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:21])[CH3:20]
Reactant: O=C(NCCCl)c1ccccc1
Reactant: CC(C)c1cc(C(C)C)c2oc3ccccc3c2c1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)c1cc(C(C)C)c2oc3ccccc3c2c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
N-(2-chloroethyl)benzamide (2.1 g, 11.2 mmol), PCl5 (3.5 g, 16.8 mmol) were dissolved in m-Xylene (100 mL) and refluxed for 2 h. After cooling down the reaction flask to room temperature, 2,4-diisopropyldibenzo[b,d]furan-1-amine (3.3 g, 12.3 mmol) was added to it and the reaction mixture was refluxed overnight. From the cooled reaction mixture white precipitate was filtered out. Precipitate was dissolved in ethylacetate and partitioned between ethylacetate and aqueous Na2CO3. Organic phase was extracted out and dried under vacuum. Target compound (4 g, 90% yield) was used in next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:1]1[CH2:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1coc(CCc2ccncc2)c1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C1=C(CCc2ccco2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 1-(pyridin-4-yl)-2-(furan-2-yl)ethane (2 g, 11.6 mmol) in anhydrous dimethylformamide (5 ml) was treated with benzyl bromide (1.5 ml, 12.7 mmol) and the reaction stirred at room temperature for one hour. The reaction was diluted with ethanol (50 ml), treated with sodium borohydride (0.55 g, 14.5 mmol) and heated at reflux for one hour. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic was separated, dried (Na2SO4) and evaporated to give crude product as a yellow oil. This material was triturated with diethyl ether to afford the title compound (2.3 g, 68%) as a colourless solid; δH (DMSO-d6) 1.92-2.10 (2H, m, tetrahydropyridinyl CH2), 2.14-2.30 (2H, m, CH2), 2.36-2.50 (2H, m, CH2), 2.60-2.82 (2H, m, tetrahydropyridinyl CH2), 2.84-2.90 (2H, m, tetrahydropyridinyl CH2), 3.50 (2H, br s, PhCH2N), 5.32-5.44 (1H, m, tetrahydropyridinyl 5-H), 6.02-6.10 (1H, m, furanyl H), 6.30-6.36 (1H, m, furanyl H), 7.16-7.36 (5H, m, ArH), and 7.44-7.52 (1H, m, furanyl H); m/z (CI+, NH3) 268 (M+1)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>O1CCOCC1.CCOCC>[CH:1]1([C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[CH2:8][C@@H:9]([C:11]([O:13][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:12])[NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N[C@@H](Cc1ccccc1C1CCCC1)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1C1CCCC1
Yield: 100 %

Procedure:
According to example 54, 0.23 g of 2-cyclopentyl-L-phenylalanine.HCl was treated with 25 mL of isobutylene in 20 mL of 1,4-dioxane in the presence of 0.13 mL of conc. H2SO4. Work-up afforded a clear oil which was dissolved in 20 mL of ether. The solution was treated with 1 mL of 1 M ethereal HCl and concentrated in vacuo to dryness to afford 0.28 g (100%) of tert-butyl 2-cyclopentyl-L-phenylalaninate.HCl as a light yellow glass.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[N:23][C:22]=3[CH3:36])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 1 a], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was treated with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide in acetone for 14 h at reflux temperature to give the title compound as yellow liquid.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:25]#[C:26][CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:21]=3)[N:16]=[CH:15]2)=[CH:9][CH:8]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[N:28]1([CH2:27][C:26]#[C:25][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:34])=[O:5])=[CH:8][CH:9]=2)[C:23]3=[O:24])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cnc3ccc(C#CCN4CCOCC4)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2cnc3ccc(C#CCN4CCOCC4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[6-(3-Morpholin-4-yl-prop-1-ynyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid tert-butyl ester from the previous step was dissolved in 20 mL of trifluoroacetic acid (“TFA”), and stirred at room temperature for 30 minutes. The TFA was then evaporated in vacuum, and dissolved in dichloromethane. Hexane was then added, which precipitated 4-[6-(3-morpholin-4-yl-prop-1-ynyl)-4-oxo-4H-quinazolin-3-ylmethyl]-benzoic acid trifluoroacetic acid salt as a solid (150 mg). Mass Spec: 404 (M+1), 460 (M+1+TFA). 1H-NMR. DMSO: 3.2-4.4 (broad m, 6H), 5.27 (s, 2H), 7.4 (d, J=8.3 Hz, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.88-7.94 (m, 3H), 8.23 (d, J=1.4 Hz, 1H), 8.64 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([OH:13])[CH:3]=1.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16]>>[Cl:25][C:20]1[CH:19]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=1[O:13][C:4]1[CH:3]=[C:2]([F:1])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)COc1ccc(F)cc1O
Product: CS(=O)(=O)c1ccc(Oc2cc(F)ccc2OCC(=O)O)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 1 step (ii) using the product from step (ii) and the product from example 7 step (ii).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][CH2:10][C@H:9]1[NH2:13])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>ClCCCl>[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([NH:13][C@@H:9]3[CH2:10][O:11][CH2:12][C@H:8]3[NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:23][CH2:22]2)=[CH:18][CH:17]=1
Reactant: O=C1CCC(Cc2ccc(F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1COC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H]1COC[C@H]1NC1CCC(Cc2ccc(F)cc2)CC1
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a flame-dried round bottom flask under nitrogen containing (3S,4S)-3-aminotetrahydrofuran-4-yl carbamic acid tert-butyl ester (90 mg, 0.45 mmol) and 4-(4-fluorobenzyl)cyclohexanone (87 mg, 0.42 mmol) in 1,2-dichloroethane (6 mL) was added sodium triacetoxyborohydride (191 mg, 0.90 mmol). The resulting yellow mixture was stirred for 15 min and was then poured into 1N aqueous hydrogen chloride (50 mL). The aqueous layer was basified with 50% aqueous sodium hydroxide and washed with ethyl acetate (4×20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the resulting residue was purified by flash chromatography (5% methanol in dichloromethane) to yield the desired carbamic acid tert-butyl ester (94 mg, 53%) as a yellow oil. MS (ESI) 393 (M+H).
Reaction SMILES: C(O)=O.OS(O)(=O)=O.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][N:18]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:17](=[O:28])[C:16]=2[CH:29]=1)([O-:11])=[O:10]>O>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][N:18]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17](=[O:28])[C:16]=2[CH:29]=1)([O-:11])=[O:10]
Reactant: CCOC(=O)CCCn1sc2ccc([N+](=O)[O-])cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O=CO
Solvent: O
Product: O=C(O)CCCn1sc2ccc([N+](=O)[O-])cc2c1=O
Reaction time: 8 h

Procedure:
A mixture of 10 mL of formic acid and 25 uL of H2SO4 containing 0.25 the 5-nitro-2-(3-carbethoxypropyl)benzoisothiazol-3-one was heated in a 130° oil bath overnight. The reaction was cooled and then poured into 30 mL of water. After standing overnight, the mixture was filtered to yield 0.11 g of the title compound as a yellow solid, mp 183°-186° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[N:4]2[N:13]=[C:14]([C:16]([NH2:18])=O)[CH:15]=[C:3]12.S(Cl)(Cl)=O>CN(C)C=O>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[N:4]2[N:13]=[C:14]([C:16]#[N:18])[CH:15]=[C:3]12
Reactant: Cn1c2ccccc2c(=O)n2nc(C(N)=O)cc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cn1c2ccccc2c(=O)n2nc(C#N)cc12
Temperature: 57 °C

Procedure:
A mixture of 5.3 g of 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide, 5.2 g of thionyl chloride and 65 ml of dimethylformamide is stirred and heated at 57° C. for 18 hrs, then evaporated at reduced pressure. The residue is stirred with 600 ml of water and the resulting solid 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 307°-310° C., after crystallization from dimethylformamide/ethanol.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].[N+:19]([O-])([OH:21])=[O:20]>>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]
Reactant: Clc1ccc(-c2nc3n(c2Cl)CCCC3)c(Cl)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(-c2nc3n(c2Cl)CCCC3)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 1.1 g (3.85 mmol) sample of 3-chloro-2-(2,4-dichlorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine was added to 8.0 ml of a 1:1 mixture of concentrated sulfuric/nitric acid at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes followed by warming to 20° C. After pouring the reaction mixture onto ice/water, the resulting aqueous mixture was extracted with 400 ml of ethyl acetate. The separated organic layer was washed with water, brine, and dried over magnesium sulfate. The yellow oily solid residue obtained after evaporating in vacuo was flash chromatographed on silica gel (1:1 hexane/ethyl acetate) to provide 0.8 g of the title compound as a yellow solid (m.p. 111-112° C.). NMR (CDCl3, 200 MHz): δ1.95 (m, 2H), 2.05 (m, 2H), 2.91 (t, 2H), 3.92 (t, 2H), 7.66 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [K].[F:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=O)=O)=[CH:5][CH:4]=1>C1COCC1.[Cl-].[Ti+3].[Cl-].[Cl-]>[N:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]3[C:10](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:9][C:7]=2[C:6]2[CH:24]=[CH:25][C:3]([F:2])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccccc1C(=O)c1ccncc1)c1ccc(F)cc1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Product: Fc1ccc(-c2[nH]c3ccccc3c2-c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 0.42 h

Procedure:
Graphite (272 mg, 3.63 mmol) and potassium (100 mg, 0.33 mmol) were warmed to 150° C. under argon in a 250 mL round bottom flask with stirring for 25 min. THF (30 mL) was added via syringe to the hot bronze colored solid followed by a suspension of titanium (III) chloride (254 mg, 1.65 mmol) in THF (20 mL). The resultant black solution was allowed to reflux for 1 h. 4-(2-(4-fluoro-N-benzoylamino)benzoyl)pyridine (14) (100 mg, 0.33 mmol) and THF (20 mL) were then added to the hot (65° C.) reaction mixture over 5 min. After 1 h at 65° C., the reaction was cooled to 23° C. the filtered through a silica gel pad (20 g). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 3-(4-pyridyl)-2-(4-fluorophenyl)indole (3): Mass spectrum (CI) 289 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2].[C:28]([Si](Cl)(C)C)(C)(C)C.N1C=CN=C1.CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([N:16]([CH3:28])[C:17]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1cc2ccccc2s1)c1ccc(N2CCC(O)CC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl]benzo[b]thiophene-2-carboxamide (2.0 g) obtained in Example 12, tertiary butyldimethylsilyl chloride (0.9 g) and imidazole (0.4 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 12 hr. Then the reaction mixture was treated with water and the organic layer was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in dimethylformamide. Under ice-cooling, sodium hydride (60% contained, 0.2 g) (was added and the mixture was stirred for 1 hr and methyl iodide (0.6 g) was added. The mixture was further stirred for 1 hr. The reaction mixture was treated with water and the organic layer was extracted with toluene. The extract was washed with water and the solvent was evaporated under reduced pressure. To the residue were added tetrabutylammonium fluoride (0.93 g) and tetrahydrofuran(15 ml) and the mixture was stirred at 60° C. for 4.5 hr. Then the solvent was evaporated and the residue was separated and purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.8 g). melting point: 211-212° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[C:16]1(B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19][CH2:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=2[O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(C2=CCCC2)c(OCC2CC2)n1
Temperature: 100 °C
Yield: 82 %

Procedure:
The mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 1.0 g, 4 mmol), 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9, 0.86 g, 4 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 150 mg 0.18 mmol) and aqueous sodium carbonate solution (2N, 16 mL) was added to DMF (10 ml). The mixture was heated to 100° C. overnight; then the solution was diluted with water (15 mL), extracted with ethyl acetate (30 mL), the water layer was adjusted to pH=3.0 by hydrochloric acid (3N) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×100 mL) and brine (80 mL) and evaporated to dryness. The residue was purified by column chromatography (silica gel, 8 g, eluting with 15% ethyl acetate in petroleum ether) to obtain the product (0.85 g, 89%) as a white solid; MS (LC/MS): 260.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH3:13])=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:11][C:10]2[CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=[CH:8][C:9]=2[CH3:13])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Cc1ccc(-c2ccoc2)cc1N
Product: Cc1ccc(-c2ccoc2)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-(furan-3-yl)-2-methylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[F-].[Cs+].Cl[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:18]2[CH:26]=[C:25]3[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]3[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 102 °C
Yield: 74.5 %

Procedure:
840 mg of 4-trifluoromethoxyphenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 25, in 30 cm3 of dioxane. The reaction medium is then heated at about 102° C. for 20 hours and allowed to return to room temperature, and is diluted with 75 cm3 of ethyl acetate, filtered through a sinter funnel packed with Celite and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41 described previously. 1 g of N-[6-[4-(trifluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][CH:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)=[CH:18][C:12]=3[N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][Si:31]([CH3:38])([CH3:37])[CH2:32][CH2:33][O:34][CH2:35]Cl.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[N:14]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:38])([CH3:37])[CH3:30])[C:13]3[CH:15]=[CH:16][C:17]([N:19]4[CH2:20][CH2:21][CH:22]([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)=[CH:18][C:12]=3[N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C1CCN(c2ccc3[nH]c(C(=O)c4ccnc(Br)c4)nc3c2)CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc3c(c2)nc(C(=O)c2ccnc(Br)c2)n3COCC[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
(2-Bromo-pyridin-4-yl)-[5-(4-dimethylamino-piperidin-1-yl)-1H-benzoimidazol-2-yl]-methanone (11.9 g, 27.8 mmol) was dissolved in 200 mL of dry THF. This solution was cooled at 0° C. and NaH 60% dispersion (1.34 g, 33.3 mmol) was added in portions. The mixture stirred at 0° C. for 30 minutes and then the 2-(trimethylsilyl)ethoxymethyl chloride (5.56 g, 33.3 mmol) was added dropwise. The mixture was allowed to warm at room temperature while stirring overnight. 2M Aqueous HCl (300 mL) was carefully added and then the aqueous mixture was washed with EtOAc (3×100 mL). The aqueous phase was then neutralised with saturated aqueous NaHCO3 and then extracted with CHCl3/iPrOH (3:1; 3×250 mL). The combined CHCl3/i-PrOH fractions were dried (Na2SO4) and then evaporated to dryness. Purification by SiO2 chromatography (dichloromethane/NH3 2.0M in MeOH; 98:2 to 90:10) gave the title compound as a dark red oil (11.2 g, yield 72%; as a mixture of two regioisomers). MS(ESI) m/z 558, 560.2 (M+H)+.