Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[S:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][O:26][C:25]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20][CH:19]=1)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]2[O:26][C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([S:14](=[O:16])(=[O:17])[NH2:15])=[CH:23][CH:22]=3)[CH:28]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)c1occc1-c1ccc(S(N)(=O)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1oc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 150 °C
Yield: 9.8 %

Procedure:
1-Bromo-4-chlorobenzene (0.214 g, 1.11 mmol) and potassium acetate (0.199 g, 2.03 mmol) were added to a solution of ethyl 3-(4-sulfamoylphenyl)furan-2-carboxylate (60a, 0.3 g, 1.01 mmol) in dimethyl acetamide (5 ml) at 25° C. in a tube. A nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added palladium (II) acetate (0.023 gm, 0.102 mmol) under nitrogen atmosphere and the tube was sealed. The reaction mixture was then heated at 150° C. for 20 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure. The residue so obtained was dissolved in ethyl acetate (30 ml). The solution so obtained was then washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.040 gm, 9.70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C=O)cc2)C1)c1cc(F)cc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(CN3CCCC3)cc2)C1)c1cc(F)cc(F)c1
Reaction time: 20 h
Yield: 51.1 %

Procedure:
0.75 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine and then 0.68 g of sodium triacetoxyborohydride are added to a solution of 0.10 g of pyrrolidine in 20 cm3 of 1,2-dichloroethane. After 20 hours at room temperature, 2 cm3 of 1 N sodium hydroxide are added, the product is extracted with 100 cm3 of dichloromethane, the organic phase is washed twice with 50 cm3 of water and then 50 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of 0.5 bar with acetate as eluent and collecting 20 cm3 fractions. Fractions 10 to 18 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.39 g of (RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 1.65 (4H, m, 2CH2), 2.40 (4H, m, 2NCH2), 3.02 (3H, s, SCH3), 3.50 (2H, s, NCH2Ph), 3.85 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), between 7.15 and 7.40 (9H, m, 9CH arom.), 7.48 (2H, d, J=7 Hz, 2CH arom.)].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][C:16]([C:20](O)=O)=[CH:17][CH:18]=2)[NH:13][C:12](=[O:23])[CH2:11]1.N>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C(O)C>[CH3:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][C:16]([C:20]3[NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[N:8]=3)=[CH:17][CH:18]=2)[NH:13][C:12](=[O:23])[CH2:11]1
Reactant: CC1(C)CC(=O)Nc2cc(C(=O)O)ccc21
Reactant: Nc1ccccc1N
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc(-c3nc4ccccc4[nH]3)ccc21
Yield: 37.2 %

Procedure:
One stirs ortho-phenylenediamine (1.30 g, 12.0 mmol) and 4,4-dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid (2.60 g, 12.0 mmol; preparation see DE-A-3,818,830) in a mixture of polyphosphoric acid (50 g) and diphosphorus pentoxide (10 g) for 3 hours at 160° C. One allows to cool to 80°-90° C., carefully adds ice and water thereto and filters off the precipitate with suction. One takes up in water (200 ml), adds conc. ammonia thereto, filters off with suction, dissolves the residue in hot ethanol, filters and allows to crystallise. One dries the colourless crystals at 120° C. in a vacuum and obtains 1.30 g (37%) of the title compound with the m.p. 314°-316° C. which, per mole, still has adhering a half mol of water.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([N:13]1[C:17]([OH:18])=[C:16]([C:19](=[O:39])[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:21]=2[CH3:38])[CH:15]=[N:14]1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:12][C:10]([N:13]1[C:17]([O:18][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:16]([C:19](=[O:39])[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:21]=2[CH3:38])[CH:15]=[N:14]1)([CH3:9])[CH3:11]
Reactant: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3O)c2C)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3OCc3ccccc3)c2C)cc1
Reaction time: 8 h

Procedure:
Benzyl chloride (1.1 mL) was added with stirring under nitrogen to a mixture of 2.0 g (4.5 mmol) of 1-(1,1-dimethylethyl)-5-hydroxy-4-(2-methyl-4-methylsulfonyl-3-(4-methoxyphenyl)benzoyl)pyrazole and 1.3 g of sodium carbonate in about 20 mL of dry N,N-dimethylformamide and the resulting mixture was allowed to stir overnight. Ethyl acetate was then added and the resulting mixture was washed with water several times, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residual orange oil was chromatographed on silica eluting with an 80:20 mixture and then a 60:40 mixture of hexane and ethyl acetate. The product fractions were combined and concentrated by evaporation under reduced pressure and dried to obtain 1.73 g (72 percent of theory) of the title compound as a yellow glass.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:2].Cl.C(OCC)(=O)C>[Pd].C(O)C>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2c(n1CC#N)CCCC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(n1CCN)CCCC2
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A 200-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 1.28 g dry weight), 101c (3.00 g, 12.9 mmol), 12% hydrochloric acid (6.5 mL, 25 mmol), ethyl acetate (60 mL) and ethanol (40 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 6 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. diatomaceous earth filter agent (CELITE®, Imerys Minerals California, Inc.) CELITE® 521 (4.0 g) was added, and the mixture was filtered through a pad of CELITE® 521. The filter cake was washed with ethanol (2×20 mL), and the combined filtrates were concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (150 mL) and 10% aqueous potassium carbonate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ethanol (5 mL) to afford a 71% yield (1.71 g) of ethyl 1-(2-aminoethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101d as a white solid: mp 102-104° C.; 1H NMR (500 MHz, DMSO-d6) δ 6.61 (s, 1H), 6.22 (br, 2H), 4.15 (m, 4H), 2.77 (m, 2H), 2.59 (t, 2H, J=6.5 Hz), 2.42 (t, 2H, J=6.5 Hz), 1.70 (m, 2H), 1.62 (m, 2H), 1.23 (t, 3H, J=7.0 Hz); MS (APCI+) m/z 237.2 (M+H)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.O.[CH2:7]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[CH3:8]>CO>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([CH:2]([C:14]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:7][CH3:8])[CH:15]=2)[C:1]([OH:5])=[O:4])=[CH:15][C:9]=1[CH2:7][CH3:8]
Reactant: CCc1ccccc1N
Reactant: O=CC(=O)O
Solvent: O
Solvent: CO
Product: CCc1cc(C(C(=O)O)c2ccc(N)c(CC)c2)ccc1N
Temperature: 25 °C

Procedure:
A mixture of glyoxylic acid 50% w/v (3.05 parts), water (20 parts) and methanol (10 parts) was stirred at ambient temperature. 2-ethylaniline (5.0 parts) was added and the mixture was stirred under reflux for 2 hours. After cooling to ambient temperature, the product was isolated by filtration, washed with a little water (50 parts) and dried to yield di(4-amino-3-ethylphenyl)acetic acid (5.5 parts).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:14])[NH:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:51]2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NCC(O)CN1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (300 mg, 1.3 mmol) in DCM (8 mL) was added EDCI (383 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), Et3N (263 mg, 2.6 mmol), 1-amino-3-(isoindolin-2-yl)propan-2-ol (499 mg, 2.6 mmol), and the mixture was stirred at 25° C. for 16 h. The crude reaction mixture was washed with water and extracted with DCM. The combined organic layers were concentrated, and the residue was purified by column chromatography (DCM:MeOH=10:1). (260 mg, yield 49%) MS (ESI+) e/z: 412.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.87 (s, 1H), 7.58-7.50 (m, 1H), 7.45-7.38 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.14 (m, 4H), 4.08-3.96 (m, 5H), 3.63-3.53 (m, 1H), 3.45-3.37 (m, 1H), 2.94-2.80 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:26])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[O:27][C@@H:28]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[N:37]1[N:41]=[CH:40][CH:39]=[N:38]1)[CH3:29].Cl>CO>[F:36][C:34]1[CH:33]=[CH:32][C:31]([N:37]2[N:38]=[CH:39][CH:40]=[N:41]2)=[C:30]([C@H:28]([O:27][C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[C:9]([CH3:26])=[N:10][N:11]([CH:13]4[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]4)[CH:12]=3)[CH:4]=2)[CH3:29])[CH:35]=1
Reactant: Cc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(O[C@H](C)c2cc(F)ccc2-n2nccn2)c1
Agent: Cl
Solvent: CO
Product: Cc1nn(C2CCNCC2)cc1-c1cnc(N)c(O[C@H](C)c2cc(F)ccc2-n2nccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of tert-butyl 4-[4-(6-amino-5-{(1R)-1-[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]ethoxy}pyridin-3-yl)-3-methyl-1H-pyrazol-1-yl]piperidine-1-carboxylate (86 mg) in MeOH (1 mL) was added HCl (4N in dioxane, 0.73 mL). The mixture was stirred at RT for 1 hr. The mixture was concentrated and the residue purified by reverse phase prep-HPLC. The desired fractions were lyophillized to give the title compound (46 mg)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)#N.Cl.CC[O:23]CC>C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:23]
Reactant: Cc1ccnc(C#N)c1
Reactant: c1ccoc1
Reactant: CCOCC
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Product: Cc1ccnc(C(=O)c2ccco2)c1
Temperature: -20 °C
Yield: 51 %

Procedure:
75 gr of freshly distilled furan dissolved in 180 ml of anhydrous ether are placed in a four-liter reactor and 800 ml of a 1,3 N ethereal solution of freshly prepared butyl-lithium are slowly added under a nitrogen atmosphere, keeping the temperature at -20° C. The reaction mixture is then allowed to reach room temperature, following which it is boiled to reflux for seven hours. It is then cooled to -20° C. and 116 gr of 2-cyano-4-methylpyridine dissolved in one liter of anhydrous benzene are added drop by drop. Upon completion of the addition, the mixture is boiled to reflux for two and a half hours, following which it is cooled and 6 N hydrochloric acid is carefully added until an acid pH is reached. The organic layer is removed by decanting, said layer is washed with 6 N hydrochloric acid, the aqueous layers are collected, the residual ether is removed by distilling and once 100° C. are reached the mixture is boiled to reflux for one and a half hours. Following this, the reactor is cooled externally, 50% sodium hydroxide is added until a basic pH is reached and the resulting solution is extracted with chloroform. After being dried once over anhydrous magnesium sulphate and evaporated to dryness, the organic layer is purified by chromatography on silica gel in a continuous flow column using benzene as eluent, providing 93 gr of 2-(2-furoyl)-4-methylpyridine (II) (Yield 51%). An analytical sample recrystallized from ether has a melting point of 111-2° C. Analysis calculated for C11H9NO2 : C: 70.58; H: 4.81; N: 7.48. Found: C: 70.48; H: 5.11; N: 7.20.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20]>C1COCC1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.7 g, 17.5 mmol) is added to a solution of 1-pentanol (5 ml) in dry THF (25 ml). After stirring at room temperature for 30 min, 3.50 g (16.7 mmole) of 1-fluoro-4-nitro-2-trifluoromethylbenzene is added, and stirring is continued at room temperature overnight. The reaction is quenched with water and extracted with ethylacetate, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluted with 33% dichloromethane/hexane. Removal of solvent provides 4-nitro-1-pentyloxy-2-trifluoromethyl-benzene as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)=[N:13][CH:12]=[CH:11][N+:10]=2[O-])[CH:5]=[C:6]([CH3:8])[CH:7]=1.P(Cl)(Cl)([Cl:26])=O>O>[Cl:26][C:12]1[N:13]=[C:14]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[N:10][CH:11]=1
Reactant: Cc1cc(C)cc(-c2ncc[n+]([O-])c2-c2cc(C)cc(C)c2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C)cc(-c2ncc(Cl)nc2-c2cc(C)cc(C)c2)c1
Reaction time: 1 h
Yield: 90 %

Procedure:
Then, to 7.0 g of 2,3-bis(3,5-dimethylphenyl)pyrazine-1-oxide was added phosphoryl chloride, and stirring was performed at 100° C. for 1 hour. The reaction solution was poured into water and extracted with chloroform. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water, and then brine, dried with magnesium sulfate, filtered, and concentrated to give 5-chloro-2,3-bis(3,5-dimethylphenyl)pyrazine as gray powder in 90% yield.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([N:51]4[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]4)=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO.C1COCC1.[Pd]>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([N:51]1[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]1)[CH:33]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2N)C[C@@H](N)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(4-methylpiperazin-1-yl)quinolin-3-yl]carbamate (8.0 mg, 0.01 mmol) in MeOH (0.4 mL) and THF (0.4 mL), 10% Pd on carbon (4 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was filtered and concentrated under reduced pressure to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.1 mL, 0.4 mmol) with stirring at room temperature for 30 min., then concentrated under reduced pressure. The residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (3.0 mg, 54%). LCMS calc. for C28H36N11O (M+H)+: m/z=542.3. Found: 542.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([C:31]2[S:32][C:33]([CH3:36])=[N:34][N:35]=2)[CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)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>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[S:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: Cc1nnc(-c2cccc(I)c2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)s4)c3)CCC(=O)CC2)cc1OC1CCCC1
Reaction time: 15 h
Yield: 82.2 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 2-(3-iodophenyl)-5-methyl-[1,3,4]thiadiazole (0.097 g, 0.32 mmol) in dry triethylamine (2.5 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenylphosphine (a small crystal) at 70° C. for 1 h and at 25° C. for 15 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and cold dilute hydrochloric acid. The organic phase was chromatographed (silica, 10 to 20% ethyl acetate in methylene chloride) and the pure fractions were combined, concentrated in vacuo and dried at 50° C. in vacuo and the brittle resin ground to afford the titled compound as a yellow powder (0.128 g, 79%). Anal. (C29H3ON2)3S.H2O) calcd: C 69.02, H 6.39, N 5.55, found: C 68.91, H 6.21, N 5.35. 1H-NMR (400 MHz, CDCl3) δ 8.06 (t, J=1.6 Hz, 1H), 7.88 (d-t, J=1.4 Hz, J=8.1 Hz, 1H), 7.58 (d-d, J=1.2 Hz, J=9.0 Hz, 1H), 7.45 (t, J=7.8 Hz), 7.21 (d, J=2.2, 1H), 7.14 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 6.88 (d, J=8.5, 1H), 4.82 (p, J=4.1 Hz, 1H), 3.86 (s, 3H), 3.04 (d-t, J=6.1 Hz, J=14.2, 2H), 2.84 (s, 3H), 2.50 (d,br, J=14.9, 2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8 Hz, J=14.2 Hz, 2H), 2.00-1.5 (m, 12H with H2O).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH2:14]([N:16]([CH2:19]C)CC)[CH3:15].CS(Cl)(=O)=[O:23]>C(Cl)Cl>[OH:23][CH2:15][CH2:14][N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:19]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)cc(CN(C)CCO)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. 2-Methoxy-N-methyleneamine (0.354 mL, 3.3 mmol) is added to the filtrate and stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (50% ethyl acetate/hexanes) provides the title compound. ESI MS m/z 238 [M+H]+.