Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCOC(C)=O>O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: OCCOCCO
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COCCOCCO
Reaction time: 0.5 h

Procedure:
A solution of 53 g of 2-hydroxyethyl ether (0.5 mol) in 200 mL of tetrahydrofuran was prepared, and the solution cooled in an ice-water bath. The solution was placed under a slow stream of argon. Sodium bis(trimethylsilyl)amide (125 mL, 0.125 mol, 1 M in tetrahydrofuran) was added dropwise over a 30 minute period. The mixture was stirred an additional 30 minutes, then 24.4 g of tert-butyl 2-bromoacetate (0.125 mol) was added. The mixture was then stirred for 1 hour. The ice-water bath was removed, and the mixture transferred to a separatory funnel using 250 mL of 1 M NaH2PO4. The mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were dried over sodium sulfate, filtered, and the solvent removed by rotary evaporator to give a clear yellow liquid. The liquid was purified by chromatography using 500 mL of silica gel and eluting with ethyl acetate/hexanes 1:1. The product was isolated as a clear, gold liquid. Obtained 5.49 g TLC Rf 0.50 (EtOAc). NMR (DMSO-d6)δ 1.42 (s, 9H), 3.42 and 3.54 (m, 8H), 3.98 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[S:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:3]=12.[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:16])[CH:7]=1
Reactant: COC(=O)c1cc2c(Br)cnc(O)c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Br)cn(C)c(=O)c2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-bromo-7-hydroxythieno[2,3-c]pyridine-2-carboxylate (300 mg, 1.04 mmol) stirred at 0° C. in DMF (6.6 mL) under an atmosphere of nitrogen was added K2CO3 (358 mg, 2.6 mmol). After stirring at 0° C. for 15 min, methyl iodide (177 mg, 1.3 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 20 min, 50° C. for 2 h, and rt for 10 h. The reaction mixture was treated with water (8 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (284 mg, 90%) as a white solid. LCMS (M+H)+=303.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:21])[C:11]([CH3:20])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([OH:30])(=[O:29])[C:23]([CH2:25][C:26](O)=[O:27])=[CH2:24]>C(OCC)(=O)C>[CH2:1]([NH:9][C:10](=[O:21])[C:11]([CH3:20])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH:23]([C:22]([OH:30])=[O:29])[CH2:25][C:26]2=[O:27])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)C(C)=Cc1cccc(N)c1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)C(C)=Cc1cccc(N2CC(C(=O)O)CC2=O)c1

Procedure:
A mixture of 4.3 g. of N-octyl-2-methyl-3-(3-aminophenyl)propenamide and 2.0 g. of itaconic acid was heated at ca. 140° C. for 1.25 hours. The reaction mixture was allowed to cool somewhat and then a small volume of ethyl acetate was added. This gave a clear solution. The solution was diluted to ca. 75 ml. with further ethyl acetate, and then it was extracted with 1 N potassium hydroxide. The potassium hydroxide solution was washed with ethyl acetate and then it was acidified using concentrated hydrochloric acid. This caused a gum to precipitate. The gum was extracted into ethyl acetate, and the ethyl acetate solution was dried using sodium sulfate. The dried solution was evaporated in vacuo to give 4.5 g. of an oil. The oil was triturated under ether causing formation of a solid. The solid was collected by filtration to give 2.5 g. of a solid, which was recrystallized from ethyl acetate-cyclohexane and then from acetonitrile. This afforded 1.3 g. of the title compound, m.p. 120°-121° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:27])[CH:8]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.C(O)(=O)C>CN1CCCC1=O.CN(C)C1C=CN=CC=1>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:2]2[N:11]=[C:10]([NH:12][C@H:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:27])[CH:8]=3)[N:3]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of 4.00 g of tert-butyl (1R,2S)-2-[(2-chloro-6-methylquinazolin-4-yl)amino]cyclohexylcarbamate and 5.91 g of 4-methoxybenzylamine in 30 ml of N-methyl-2-pyrrolidone, 100 mg of 4-dimethylaminopyridine was added, and then the mixture was stirred at 110° C. for 24 hours. The reaction solvent was mixed with an aqueous 5% acetic acid solution and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 5.10 g of the desirable compound.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(Cl)C(C1C=CC=CC=1)(C)C.[Mg].[CH3:25][Si:26](Cl)([Cl:28])[Cl:27]>C1COCC1>[CH2:1]([CH2:25][SiH:26]([Cl:28])[Cl:27])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: C[Si](Cl)(Cl)Cl
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Agent: CC(C)(CCl)c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CC[SiH](Cl)Cl)c1ccccc1
Yield: 65 %

Procedure:
In accord with the procedure of Example 1, neophylmagnesium chloride was prepared from 674 g (4 mol) of neophyl chloride and 105 g (4.4 mol) of magnesium turnings in 1.5 liters of dry THF. The neophylmagnesium chloride was added to 598 g (4 mol) of methyltrichlorosilane and 2 g of cuprous cyanide in 500 ml of THF. 640 g (65% of theory) of neophylmethyldichlorosilane was obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[S:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)O1.Br[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)[C:23]([C:35]#[C:36][Si](C)(C)C)=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH:32]1([C:30]2[NH:29][N:28]=[C:27]([NH:26][C:24]3[C:23]([C:35]#[CH:36])=[CH:22][N:21]=[C:20]([C:9]4[S:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=4)[N:25]=3)[CH:31]=2)[CH2:34][CH2:33]1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)s2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C#Cc1cnc(-c2ccc(S(C)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 49.9 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(5-(methylsulfonyl)thiophen-2-yl)-1,3,2-dioxaborolane (550 mg, 1.92 mmol, 1.5 eq), 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (480 mg, 1.28 mmol, 1.0 eq), PdCl2(dppf)CH2Cl2 (106.1 mg, 0.13 mmol, 0.1 eq), K2CO3 (529.0 mg, 3.84 mmol, 3.0 equiv.), dioxane (20 mL) and water (2 mL) was heated for 1 h at 90° C. under nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel chromatography (PE/EtOAc=4:12:1 as eluant) to yield N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-ethynyl-2-(5-(methyl sulfonyl) thiophen-2-yl)pyrimidin-4-amine (Compound 255) (246 mg, 50%). LC-MS (m/z)=386 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.73-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.93-1.99 (m, 1H), 3.41 (s, 3H), 4.91 (s, 1H), 6.42 (s, 1H), 7.87 (dd, J1=4.0 Hz, J2=7.2 Hz, 2H), 8.54 (s, 1H), 8.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
First, 70 mg of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.25 ml of N,N-dimethylformamide, to which 36 mg of potassium carbonate and 27 mg of propargyl bromide were added, and the mixture was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 76 mg (yield, 96%) of 3-[4-chloro-2-fluoro-5-(propargyloxy)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-156; m.p., 106.9-107.1° C.).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[CH:9][C:10]([Cl:36])=[C:11]([CH2:18][N:19]([C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][CH:24]=3)[CH2:20][C:21]#[CH:22])[CH:12]=2)[N:7]=1)(=O)C.[OH-].[Na+].O>O1CCCC1>[Cl:36][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:17])[N:15]([CH3:16])[C:6]([CH2:5][OH:4])=[N:7]2)=[CH:12][C:11]=1[CH2:18][N:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[CH:34][CH:35]=1)[CH2:20][C:21]#[CH:22]
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COC(C)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(Cc1cc2c(=O)n(C)c(CO)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[N-[2-acetoxymethyl-7-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.47 g, 0.92 mmol) in tetrahydrofuran (18 ml), was slowly added 1N aqueous NaOH (1.84 ml, 1.84 mmol) followed by water (1.5 ml). The slightly cloudy solution was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was treated with water (35 ml). The pH was adjusted to 4.5 with 1N HCl and the mixture was extracted with ethyl acetate (3×60 ml). The organics were combined, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 50% ethyl acetate in dichloromethane, afforded a white solid which was reprecipitated from dichioromethane (minimum amount)/hexanes. The solid was collected by filtration and dried in vacuo over P2O5 (0.345 g, 80%), mp 109-111° C.; 1H-NMR (DMSO-d6); 1.49 (s, 9H, CO2But), 3.50 (s, 3H, N3-Me), 3.25 (s (poorly resolved triplet), 1H, C≡CH), 4.40 (s, 2H, CH2C≡C), 4.57 (d, J=5.70 Hz, 2H, 2-CH2OH), 4.80 (s, 2H, 6-CH2), 5.67 (t, J=6.4 Hz, 1H, CH2OH), 6.78 (d, J=8.80 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.44 Hz, 2H, 2′,6′-Ar), 7.82, 7.87 (2×s, 2H, 5-H, 8-H); MS (FAB, m/z) 467, 469 (M+, 95%, 45% respectively; Cl isotopic pattern).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[O:18][CH:19]1[CH2:22][NH:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:21]2[CH2:22][CH:19]([O:18][C:17]3[CH:23]=[CH:24][CH:25]=[C:15]([C:14]([F:13])([F:27])[F:26])[CH:16]=3)[CH2:20]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 67.4 %

Procedure:
The title compound (D79) (110 mg) was prepared according to the experimental procedure described in Description 62 starting from Methyl 2,5-dichloronicotinate (87 mg, 0.422 mmol) and 3-(3-(trifluoromethyl)phenoxy)azetidine (D53) (110 mg, 0.506 mmol)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[N:20]1([CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:27]([CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: c1cc(NCCN2CCCC2)ccn1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(N(CCN2CCCC2)c2ccncc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-[2-(pyrrolidin-1-yl)ethylamino]pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)-pteridine 3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[C:13]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:32]=2)=[CH:14][CH:15]=[C:16]([C:18]2[S:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[N:22]=2)[CH:17]=1)=[O:11]>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[C:13]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=2)=[CH:14][CH:15]=[C:16]([C:18]2[S:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[N:22]=2)[CH:17]=1)=[O:11]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Trifluoroacetic acid (8.3 mL, 108 mmol) was added to a solution of 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 4′-tert-butyl ester 2-methyl ester (which may be prepared as described for Intermediate 7; 5.8 g, 10.7 mmol) in CH2Cl2 (25 mL) at 0-5° C. The mixture was allowed to warm to room temperature and stir for 3 h. The resulting solution was concentrated under a stream of nitrogen and then dried under high vacuum to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (5.1 g, 98%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (br s, 1H), ppm 8.49 (s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.02 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].C([O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br)C.O>CC(C)=O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH2:25][CH2:24][CH2:23][C:22]([OH:27])=[O:21])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(SCCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
Potassium hydroxide flakes (2.52 g, 0.045 mole) were added to a clear solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.57 g, 0.015 mole) and ethyl-4-bromobutyrate (3.23 g, 0.0165 mole) in acetone (10 ml). Water (20 ml) was added and the solution stirred for 1.5 hours, the solvent removed on a rotary evaporator and water (50 ml) added and extracted with ethyl ether (3×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl ether (2×50 ml), washed with water (50 ml), dried over sodium sulfate, filtered and the solvents removed, leaving an oil, which was purified by chromatography on silica, recrystallized from ethyl ether/Skellysolve B, filtered and the product dried in vacuo at room temperature for 12 hours, m.p. ca. 112°-113.5° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[C:14]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18](Cl)[CH:17]=1)#[N:15]>CN1CCCC1=O>[C:14]([C:16]1[CH:21]=[C:20]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=2)[N:19]=[C:18]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:3])([F:12])[F:13])[CH:6]=2)[CH:17]=1)#[N:15]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(Oc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C

Procedure:
Sodium hydride (0.31 g (ca. 60% in mineral oil), 0.0035×2.2 mol) was suspended in 20 ml of N-methyl-2-pyrrolidinone, then meta-trifluoromethyl phenol (1.24 g, 0.0035×2.2 mol) was added thereto, and the resultant solution was heated to about 60° C. and stirred for several minutes. After allowed to cool to room temperature, to the reaction solution was added 4-cyano-2,6-dichloropyridine (0.60 g, 0.0035 mol), and then the mixture was allowed to react for 1 hour at about 90° C.
Reaction SMILES: [CH3:1][N:2]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4](OCC)=[O:5].[NH3:38]>CO>[CH3:1][N:2]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4](=[O:5])[NH2:38]
Reactant: N
Reactant: CCOC(=O)CN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC(N)=O)c3ccccc32)cc1
Temperature: 100 °C

Procedure:
5-(N-Methyl-N-ethoxycarbonylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) is dissolved in saturated solution of ammonia in methanol (20 ml), and the mixture is heated at 100° C. for 8 hours in a sealed tube. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-(N-methyl-N-carbamoylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:27]4[CH2:28][CH2:29][CH2:30][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CN1CCCNCC1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CN1CCCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (4.1, 100 mg, 0.22 mmol), N-methylhomopiperazine (140 μL, 1.1 mmol), CuI (42 mg, 0.22 mmol), ethylene glycol (25 μL, 0.44 mmol), potassium phosphate (93 mg, 0.44 mmol) in 2 mL isopropanol in a sealed tube was stirred for 16 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C20H23ClN6OS (M+H)+ 431.1, 433.1 (Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6]2.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)CCC2
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC2

Procedure:
50 g (0.34 mole) of 5-methoxyindane are reacted with 75 ml of chlorosulfonic acid analogously to Example 1a to give 6-chlorosulfonyl-5-methoxyindane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1F.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>CCOC(C)=O>[F:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
A mixture of 1,2,3-trifluoro-5-nitrobenzene (3.54 g, 20.0 mmol), morpholine (2.0 mL, 23.0 mmol) and Et3N (8.5 mL, 61.0 mmol) in EtOAc (30 mL) was stirred at rt for 5 h. The mixture was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a yellow solid (4.76 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 30 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 3-nitro-1H-1,2,4-triazole (2 g, 17.54 mmol, 1.00 equiv) in dichloromethane (100 mL), 3-(trifluoromethyl)phenylboronic acid (6.66 g, 35.05 mmol, 2.00 equiv), Cu(OAc)2 (4.79 g, 26.32 mmol, 1.50 equiv), pyridine (2.77 g, 35.06 mmol, 2.00 equiv), and molecular sieves (5.2 g). The resulting solution was stirred overnight at 30° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:10) to give 2.2 g (49%) of product as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](OC)(OC)OC.Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[N:21]=[CH:22]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1NC1CCN(Cc2ccccc2)CC1
Reactant: COC(OC)OC
Agent: Cl
Product: c1ccc(CN2CCC(n3cnc4cccnc43)CC2)cc1

Procedure:
The title compound was prepared from 153 mg of 2-N-(1-benzyl-piperidin-4-yl)-pyridine-2,3-diamine (from Step B), 6 mL of trimethyl orthoformate, and) 0.2 mL of concentrated HCl, using a procedure analogous to that described in Example 95, Step B to provide 139 mg of the title compound as a yellow solid.