Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:5][C:6]=1[CH2:7][S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2.O.[C:31]([OH:35])(=[O:34])[CH:32]=O>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[S:5][C:6]=1[CH2:7][S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[C:14](=[CH:32][C:31]([OH:35])=[O:34])[CH2:13][CH2:12]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCCC2=O
Reactant: O=CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A slurry of 6-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-naphthalen-1-one (2.0 g, 4.6 mmol) in glyoxylic acid monohydrate (2.0 g, 22 mmol), under nitrogen atmosphere, was warmed to 160° C. and stirred for 1 h. The reaction mixture was cooled to room temperature, dissolved in EtOAc (100 mL) and filtered. The filtrate was washed with water (50 mL×3) and brine. The organic phase was dried over magnesium sulfate, concentrated under vacuum, and purified by recrystallization in ethanol to give 1.02 g (45%) of yellow solid. Analyzed for C24H18NO3S2: Calcd: C, 58.89%; H, 3.71%; N, 2.86%; Found: C, 58.715; H, 3.56%; N, 2.77.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]#[N:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[CH:3]=1.[N:34]([Si](C)(C)C)=[N+:35]=[N-:36].C([Sn](=O)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:36][N:35]=[N:34][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CC#N)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Yield: 74 %

Procedure:
To 8.7 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(cyanomethyl)-3,4-dimethoxybenzenesulfonamide (compound 211), obtained in Example 18, dissolved in 100 ml of THF are added, at room temperature, 10 g of azidotrimethylsilane and 2.29 g of dibutyltin oxide, and the mixture is refluxed for 8 hours. The reaction medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 7 g of the expected product.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.O[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.Cl.C(OCC)(=O)C>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([O:13][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH2:15][CH2:16]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
N-(1-Methyl-4-piperidyloxy)phthalimide may be obtained in the following manner: diethyl azodicarboxylate (53.8 g) is added in the course of 90 minutes at a temperature in the region of 0° C. to a suspension of 4-hydroxy-1-methylpiperidine (30.6 g), N-hydroxyphthalimide (43.7 g) and triphenylphosphine (68.3 g) in tetrahydrofuran (450 cc). The suspension obtained is stirred at a temperature in the region of 20° C. for 18 hours and the reaction mixture is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The product obtained is taken up with ethyl acetate (500 cc) and the suspension obtained is filtered. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The product obtained is redissolved in N aqueous hydrochloric acid solution (500 cc). The suspension obtained is filtered and the filtrate is extracted 3 times with ethyl ether (300 cc in total) and brought to a pH in the range of 10 by adding N aqueous sodium hydroxide solution (500 cc) The crystals which appear are separated by filtration, washed 3 times with distilled water (300 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 20° C. N-(1-Methyl-4-piperidyloxy)phthalimide (19 g) is thereby obtained in the form of beige crystals, m.p. 90° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH2:11][NH2:16])[S:9][CH:10]=1
Reactant: N
Reactant: O=Cc1cc(Oc2cccc(F)c2)cs1
Agent: [Ni]
Solvent: CO
Product: NCc1cc(Oc2cccc(F)c2)cs1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
4-(3-Fluorophenoxy)thiophene-2-carbaldehyde described in Preparation Example 34 (210 mg, 0.95 mmol) was dissolved in 7N ammonia/methanol (30 mL), Raney nickel (500 mg) was added thereto, followed by stirring for 19 hours under hydrogen atmosphere at room temperature. The reaction mixture was filtered through Celite pad, Raney nickel was removed, silica gel was added to the filtrate, then, the solvent was evaporated in vacuo, for adsorption on silica gel, purification by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol=4:1) was carried out, and the title compound (70 mg, 0.32 mmol) was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Br:11][C:12]1[CH:16]=[N:15][N:14]([CH3:17])[C:13]=1[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]([CH3:32])([N+:29]([O-])=O)[CH3:28])[NH2:21].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:29][C:27]([CH3:32])([CH3:28])[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:20]([NH:21][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)=[CH:19][C:18]=1[C:13]1[N:14]([CH3:17])[N:15]=[CH:16][C:12]=1[Br:11]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(Br)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-Bromobenzoyl chloride (12 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (24 mg, 91%) as a TFA-salt. LCMS m/z (%)=525.5 (M+H 81Br2 34.2%), 523.3 (M+H 79Br 81Br 100.0%), 521.4 (M+H 79Br212.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (s, 3H), 1.18 (s, 3H), 3.67 (s, 3H), 3.83 (d, J=9.60 Hz, 1H), 3.99 (d, J=9.60 Hz, 1H), 7.29 (d, J=9.09 Hz, 1H), 7.51 (t, J=7.83 Hz, 1H), 7.67 (s, 1H), 7.69 (d, J=2.53 Hz, 1H), 7.78-7.84 (m, 1H), 7.84-7.92 (m, 3H), 7.92-7.98 (m, 2H), 8.14 (t, J=1.77 Hz, 1H), 10.44 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[I-:29].[K+]>CC(C)=O>[I:29][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(CI)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
A mixture of 2-chlorometyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (0.5 g) and potassium iodide (1 g) in acetone (5 ml) is stirred at room temperature for 24 hours, then it is filtered, concentrated under reduced pressure and the residue purified by column chromatography on silica gel (20 g, eluent: hexane/AcOEt 80/20) to give 0.22 g of 2-iodomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]([CH3:15])[C:10]([O:12]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH2:24][Mg+].[Br-]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([C:10]1([OH:12])[CH2:24][CH2:23]1)[CH3:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC[Mg+]
Reactant: CCOC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@H](N(Cc1ccccc1)Cc1ccccc1)C1(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 26 (8.80 g, 29.5 mmol) and titanium tetraisopropoxide (1.28 g, 5.90 mmol) in dry THF (100 mL) was added EtMgBr (30 mL, 90 mmol, 3.0 N in THF) at 0° C. After stirring at RT overnight, the mixture was cooled to 0° C. and quenched with NH4Cl solution. The solid was filtered off and filtrate was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1) to afford 7.5 g (90%) of 7.5 g (90%) of (S)-1-(1-(dibenzylamino)ethyl)cyclopropanol (28). LCMS (ESI) m/z: 282.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[CH2:19]([N:21]1[C:25]([NH2:26])=[CH:24][CH:23]=[N:22]1)[CH3:20].C(O)(=O)C>CN(C=O)C>[CH2:19]([N:21]1[C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([NH2:18])=[O:17])=[CH:24][CH:23]=[N:22]1)[CH3:20]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: CCn1nccc1N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCn1nccc1Nc1c(C(N)=O)cnc2cc(OC)c(OC)cc12
Temperature: 100 °C
Yield: 32.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 1-ethyl-5-aminopyrazol (0.030 g, 0.27 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 7.5 h. The DMF was evaporated under reduced pressure and the residue was dissolved in a mixture of MeCN and water (1:7) containing 0.1% trifluoroacetic acid. Preparative HPLC using a gradient (containing 0.1% trifluoroacetic acid) of 10→40% MeCN in water as eluent gave, after evaporation, the title compound as the trifluoroacetic acid salt. The product was suspended in saturated aqueous NaHCO3 and absorbed on a short SPE column [ISOLUTE™ C18 (EC)] pre-conditioned subsequently with methanol and water. The column was washed extensively with water until the pH of the eluent was neutral. The product was then eluted with methanol, the solvent evaporated and the residue crystallized from ethanol to give the title compound (19 mg, 32%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][CH:11]([OH:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].C1(=O)CCCCC1>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:11](=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
For example, a solution of (3R,5R)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methylenecyclohexanol (compound 9) in toluene is made to react with aluminum isopropoxide and cyclohexanone to produce (3R,5R)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methylenecyclohexanone (compound 10).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][O:43][Si](C(C)(C)C)(C)C)([CH2:12][O:13]2)[C:10]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=4)[CH:26]=3)[O:24][C@@:11]([CH2:42][OH:43])([CH2:12][O:13]2)[C:10]1=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO[Si](C)(C)C(C)(C)C)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of (1R,3R,4R,5S)-3,4-dibenzyloxy-1-[(tert-butyl(dimethyl)silyl)oxymethyl]-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-2-one 28f (15.9 g, 21.8 mmol) in tetrahydrofuran (40 mL) was added tetrabutylammonium fluoride (48 mL, 43.6 mmol, 1 M in tetrahydrofuran) at room temperature. The mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate (100 mL×2). The combined organic phases were washed with water (100 mL×3) and then saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28g as colorless oil (13.4 g, 100%). The crude product was used for next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ (ppm): 7.31 (d, 2H), 7.29-7.22 (m, 6H), 7.13 (m, 1H), 7.07 (m, 2H), 6.98 (d, 2H), 6.75 (d, 2H), 6.68 (d, 2H), 5.28 (s, 1H), 4.93 (d, 1H), 4.59 (d, 1H), 4.31 (m, 2H), 4.10 (d, 1H), 3.99 (m, 2H), 3.96-3.92 (m, 3H), 3.88 (m, 3H), 1.31 (t, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH2:30]([O:32][C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)=[O:34])[CH3:31]>>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([NH:21][C:4]1[C:3]([CH3:29])=[C:2]([C:39]2[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=2)[C:33]([O:32][CH2:30][CH3:31])=[O:34])[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]=1[CH3:20])=[O:28]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 63 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and 3-(ethoxycarbonyl)phenylboronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 63%. Melting point: 175-177° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[H-].[Na+].[C:35]([O:39][CH3:40])(=[O:38])[CH2:36][SH:37].CN(C=O)C>CO>[CH3:40][O:39][C:35](=[O:38])[CH2:36][S:37][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Yield: 15 %

Procedure:
A mixture of the title compound from Example 250 (0.26 grams), sodium hydride (0.08 grams, 60% in mineral oil), methyl thioglycolate (0.19 mL) and anhydrous DMF (15 mL) was stirred while being irradiated with a 200 W lamp for 16 hours. The mixture was diluted with MeOH, concentrated in vacuo, diluted with CH2Cl2 and water, and washed with 1N aqueous NaOH and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo and the residue purified by preparative plate chromatography (silica gel) using 3% MeOH—CH2Cl2 to afford the title compound (0.05 grams, 15%, MH+ 534).
Reaction SMILES: [NH2:1][C:2](=[N:8]O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C)C(C)=CC=CC=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[C:19]#[CH:20]>C(N(CC)CC)C>[CH2:6]([O:5][C:3]([C:2]1[NH:8][CH:20]=[C:19]([C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:1]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(N)=NO
Reactant: C#CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C(=O)OC(C)(C)C)c[nH]1

Procedure:
tert-Butyl 2-ethoxycarbonyl imidazole-4-carboxylate can be prepared as follows: the procedure is as in Example 1 but starting from 15 g of ethyl α-aminooximinoacetate, 500 ml of xylene, 19.1 of triethylamine and 14.3 ml of tert-butyl propiolate. The crude product (19 g) is chromatographed on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume) to give 5 g of tert-butyl 2-ethoxycarbonylimidazole-4-carboxylate, employed as such in the subsequent syntheses.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]#[C:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]3[CH2:25][CH2:24]3)=[C:18]([Cl:26])[CH:17]=2)[N:13]=[CH:12][N:11]=1)[C:3]([O:5][CH3:6])=[O:4].[BH4-].[Na+]>CO.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:26][C:18]1[CH:17]=[C:16]([C:14]2[N:13]=[CH:12][N:11]=[C:10]([CH:9]3[NH:1][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:7][CH2:8]3)[CH:15]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH:23]1[CH2:25][CH2:24]1
Reactant: COC(=O)[C@@H](N)CC#Cc1cc(-c2ccc(OC3CC3)c(Cl)c2)ncn1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [BH4-]
Solvent: CO
Product: COC(=O)C1CCC(c2cc(-c3ccc(OC4CC4)c(Cl)c3)ncn2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
Silver triflate (0.17 g, 0.67 mmol) was added portion wise to a stirred solution of methyl (2S)-2-amino-5-[6-(3-chloro-4-cyclopropoxyphenyl)pyrimidin-4-yl]pent-4-ynoate (0.5 g, 1.3 mmol) in methanol (10 ml) and the mixture was stirred at room temperature overnight. After this time the solid precipitate was removed by filtration and the filtrate concentrated. The resulting residue was dissolved in methanol (5 ml), cooled to 0° C., treated with sodium borohydride (0.2 g, 5.0 mmol) and stirred at 0° C. for 2 hours. After this time the reaction mixture was quenched by the careful addition of saturated sodium bicarbonate (1 ml), the mixture was concentrated and the resulting residue partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was removed, dried (MgSO4), filtered and concentrated. The residue was purified by prep HPLC to give the title compound (0.03 g, 5% yield) as a brown oil. Tr=2.22 min m/z (ES+) (M+H+) 373.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:23]=1[C:24]([Sn](CCCC)(CCCC)CCCC)=[N:25][NH:26]2>CN(C=O)C.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>[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:23]=1[C:24]([C:2]1[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=1)=[N:25][NH:26]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)cc(F)c12
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
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
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)cc(F)c34)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.56 g, 4.38 mmol) and 4,6-difluoro-3-tributylstannanyl-1H-indazole (1.94 g, 4.38 mmol) were dissolved in DMF (40 mL) and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.22 mmol) and copper(I) iodide (167 mg, 0.88 mmol) were added. The reaction mixture was purged with argon, stirred at room temperature for 4 h, then heated at 80° C. for 1 h. The reaction was cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 1.89 g of 2-(4,6-difluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a brown solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[N:13]([CH:25]=[N:26][N:27]=2)[C:14](SC)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[CH2:28]([C@H:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([C@@H:35]1[NH:36][CH2:37][CH2:38][N:39]([C:14]2[N:13]3[CH:25]=[N:26][N:27]=[C:12]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[N:15]=2)[CH2:40]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c2nncn12
Solvent: CN(C)C=O
Product: c1ccc(C[C@H]2CN(c3nc(-c4ccncc4)c(-c4ccc5ccccc5c4)c4nncn34)CCN2)cc1
Temperature: 100 °C

Procedure:
8-(2-naphthyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (200 mg, 0.54 mmol), K3CO3 (100 mg) and (S)-2-benzylpiperazine (170 mg, 0.97 mmol) were combined in dry DMF (ca. 4 mL) and the mixture was heated at 100° C. for 48 h. The reaction was cooled to RT, and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (2-8% MeOH/NH3:CH2Cl2) to provide the product as a tan solid; MS (m/z) 498.3 (M+H)+; C31H27N7 requir. 497.59.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([CH:11]=[C:12]([CH3:14])[CH3:13])[C:8]([CH:15]=[C:16]([CH3:18])[CH3:17])=[N:7][CH:6]=1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:8]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(C=C(C)C)c(C=C(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(CC(C)C)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.8 %

Procedure:
5,6-Di(2-methyl-propenyl)-nicotinic acid ethyl ester (52 mg, 0.3 mmol) is dissolved in THF (10 mL), Pd/C (20 mg, 10% Pd) is added and the mixture is stirred under 1 atm H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated to give 5,6-diisobutyl-nicotinic acid ethyl ester (52 mg) as an oil; LC-MS: tR=1.12 min, [M+1]+=264.19.