Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([CH2:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:17]([C:16]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Cc1cccnc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1cc2cccnc2[nH]1
Yield: 115.9 %

Procedure:
A solution of 1-[2-(t-butoxycarbonylamino)pyridin-3-yl]hexan-2-one (42) (4.2 g) (prepared, e.g, as described in Preparation 29), in dichloromethane (25 ml) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The solution was concentrated under vacuum and the residue was partitioned between aqueous ammonium hydroxide and ether. The ether layer was washed with brine, dried, and the solvent was evaporated. The residue was further purified by silica gel chromatography, eluting with 30% ethyl acetate-hexane, to give 2-(n-butyl)-7-azaindole (2.9 g), a compound of Formula (43), as an oil, which crystallized on standing to a solid, m.p. 46°-47° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)s1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (400 mg, 1.3 mmol) and commercially available 5-bromothiophene-2-sulfonamide (338 mg, 1.3 mmol) according to general procedure II. Obtained as a white solid (90 mg, 14%). MS (ISP) 448.1 [(M+H)+]; mp 206–210° C.
Reaction SMILES: C([O:3][C:4](C1NC2C(C=1)=CC=CC=2)=[O:5])C.[N+:15]([C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:24]2)=[CH:20][CH:19]=1)([O-])=O.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>>[CH3:40][S:41]([NH:15][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:24]2[C:4]([OH:3])=[O:5])=[CH:20][CH:19]=1)(=[O:43])=[O:42]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Cn2cc(-c3ccccc3)c3ccccc32)cc1
Product: CS(=O)(=O)Nc1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3ccccc32)cc1

Procedure:
The title compound was prepared from 1-(4-nitro-benzyl)-3-phenyl-1H-indole indolecarboxylic acid ethyl ester and methanesulfonyl chloride followed the procedure of Example 3 Step 2 as an off-white solid: 1H NMR (DMSO-d6) δ 2.94 (s, 3H), 5.80 (s, 2H), 7.05-7.15 (m, 5H), 7.31-7.38 (m, 2H), 7.43-7.47 (m, 5H), 7.62 (d, J=8.4 Hz, 1H), 9.68 (br s, 1H), 12.87 (br s, 1H); MS (ESI) m/z 419 ([M−H]−); HRMS calcd for C23H19N2O4S: 419.1068; found (ESI−): 419.1074.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH3:46])[CH2:7][O:8][C@@H:9]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:20][N:21](C)[C:22](=O)OCC[Si](C)(C)C)=[O:17])[CH2:11]1)=[O:4].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48].[Cl:45][C:41]1[CH:40]=[C:39]([C@@H:9]([C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:17])[NH:18][C@H:19]([CH2:20][NH:21][CH3:22])[CH2:32][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:11]2)[O:8][CH2:7][CH:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH3:46])[CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)NC(C)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCC(C)NC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(2-(methoxycarbonylamino)propoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate and TFA (2 mL) in CH2Cl2 (5 mL) was stirred at rt for 3 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to give TFA salt of methyl 1-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)propan-2-ylcarbamate. MS ESI +ve m/z 539 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([O:34]C(=O)C)[CH2:29][O:30]C(=O)C)=[O:25])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17]C(=O)C)[CH2:12][O:13]C(=O)C)=[O:8].[C:39](Cl)(=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].C(OCC)(=O)C>ClCCl>[OH:17][CH:11]([CH2:12][OH:13])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[C:21]([I:22])=[C:2]([NH:1][C:39](=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([OH:34])[CH2:29][OH:30])=[O:25])[C:5]=1[I:23]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Amino,N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide (2.19 g, 2.5 mmol) and 10,12-tricosadiynoyl chloride (1.82 g, 5 mmol) were dissolved in 20 ml dichloromethane. The solution was stirred for 3 days at ambient temperature under a nitrogen atmosphere. TLC (ethyl acetate) indicated that the reaction was complete. The reaction mixture was evaporated and dissolved in a mixture of methanol (30 ml) and 1M sodium hydroxide solution (15 ml). After 1 hour TLC (methanol/chloroform) indicated that the reaction was complete. The solution was neutralized with concentrated hydrochloric acid. The residue was dissolved in chloroform and filtered. The solvent was removed and the reaction mixture was purified through silica gel with methanol/chloroform (1:3) to give the title compound. 1H NMR (300 MHz, DMSO): δ0.8 (CH3, t), 1.2-1.7 (17×CH2, m), 2.2-2.3 (2×CH2, t), 3.1-3.2 (2×CH2NH, m), 3.3-3.5 (2×CH2OH, m), 3.6-3.8 (2×CHOH), 4.4-4.7 (4×OH, m), 8.4-8.5 (2×CONH, m), 9.8 (2×ArNHCO, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[Cl:19][S:20](O)(=[O:22])=[O:21].S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][C:15]([S:20]([Cl:19])(=[O:22])=[O:21])=[C:16]([CH3:18])[N:17]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1c[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-methylimidazole (1.0 g, 0.0034 mol) was added portionwise to chlorosulphonic acid (3 ml) and the mixture was stirred and heated at 100° C. for 2 hours. After cooling thionyl chloride (0.2 ml) was added and the mixture was reheated to 100° C. for 2 hours. The mixture was added cautiously to ice (20 g), and extracted with ethyl acetate (2×20 ml). The combined extracts were washed with water (20 ml) dried over anhydrous sodium sulphate and evaporated to dryness. Recystallisation from a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.)(1:3) gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylimidazole-5-sulphonyl chloride (0.21 g), m.p. 227°-230° C. as an off-white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].S([O-])([O-])=O.[Na+].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39]Br>O.CN(C)C=O>[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4].[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)Cc3c(Cl)cccc3Cl)cc2c2cc[nH]c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
180 mg (0.55 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is added to a solution of 139 mg (1.1 mmol) of sodium sulfite and 78 mg (0.55 mmol) of dibasic sodium phosphate dissolved in 2.5 mL of water. The solution is heated at 60° C. for 20 hours then a solution of 132 mg (0.55) of 2,6-dichlorobenzyl bromide in 2.5 mL of dimethylformamide is added. Stirring is continued at 60° C. for 4 hours then the solution is filtered. The solid is triturated in hot methanol then filtered again to give 88 mg (35%) of 8-(2,6-dichlorophenylmethanesulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:21](Cl)=[O:22]>COCCOC>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:21]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:22]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1F

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g of 3-fluoro-4-(hexadecylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 3-fluoro-4-(hexadecylamino)benzoylmalonate.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=O.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C(O)C>C(Cl)(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH:8]=[N:31][C:28]2=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Cl)cc32)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
TFA (2.2 ml, 28 mmol) was added to a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.00 g, 9.38 mmol), 1-(4-chlorophenyl)hydrazine hydrochloride (1.68 g, 9.38 mmol) and ethanol (0.2 mL) in CHCl3 (200 mL) at about 0° C. The reaction mixture was then stirred at about 50° C. overnight. After cooling, the reaction was quenched by the addition of 10% NH4OH (20 mL) and ice (60 mL). The organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to yield tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate which was used in the next step without further purification (2.57 g, 85%). LCMS (APCI+) m/z 221, 223 [M+H−Boc]+; Rt=3.67 min.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C([Li])CCC.Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].O>O1CCCC1.C(OCC)(=O)C>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH2:13][CH2:14][CH2:15][CH2:16][Cl:17]
Reactant: ClCCCCBr
Reactant: COC(=O)CS
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CSCCCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
A solution of methyl thioglycolate (10.0 mL, 113 mmol) in tetrahydrofuran (200 mL) at −78° C. under argon atmosphere was treated dropwise with n-butyllithium (2.5 M hexanes solution, 45 mL, 113 mmol). After 1 h at −78° C., the cloudy solution was rapidly treated with 1-bromo-4-chlorobutane (13.0 mL, 113 mmol) and allowed to warm to room temperature overnight. It was poured into water and hexanes, washed with cold aqueous sodium hydroxide solution (0.1 M) followed with saturated aqueous ammonium chloride, and the organic layer was stored over anhydrous sodium sulfate. The volatiles were removed and the residue was purified by chromatography and eluted with 8:1 hexane:ethyl acetate to yield [(4-chlorobutyl)thio]acetic acid methyl ester (10.7 g, 54.5 mmol) as a colorless liquid: EIMS m/z 198 (M+ with 37Cl), 196 (M+ with 35Cl).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[CH2:5][C:4](=O)[CH2:3]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21]>CS(C)=O>[C:8]([CH:7]1[C:6](=[O:12])[C:5]2[S:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:14][C:4]=2[CH2:3][CH:2]1[CH3:1])([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1C(=O)CC(=O)CC1C
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)C2=C(CC1C)Nc1ccccc1S2

Procedure:
A mixture of methyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7a (5.52 g, 30 mmole) and 2-aminothiophenol, 6 (X=H, 3.75 g, 30 mmole), in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4a, (R=H), mp 218-221° C. occurs as light orange crystals; yield: 1.47 g (55.0%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.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.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:15]=[C:16]([F:18])[CH:17]=2)[O:9][N:8]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1cc(-c2ccncc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 6.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (30 mg, 0.093 mmol), pyridine-4-boronic acid (17.1 mg, 0.093 mmol), and Pd(PPh3)4 (10.4 mg, 0.0093 mmol) in a solution of and ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 2 mg (7%) of 3-(2-pyridyl)-5-(3-fluoro-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 8.88 (d, 1H), 8.79 (d, 2H), 8.40 (s, 1H), 8.25 (d, 1H), 8.06 (md, 1H), 7.90 (td, 1H), 7.60 (m, 3H), 7.50 (ddd, 1H).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[C:32]([OH:37])=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.Br[CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:46][C:2]([F:1])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:43])([F:42])[F:44])[CH:40]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2′-{[(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-ol (150 mg) is dissolved in N,N-dimethylformamide (3 ml) and thereto are added ethyl 4-bromobutyrate (50 μl) and potassium carbonate (47 mg), and the mixture is stirred at room temperature for 2 hours and at 80° C. for 2 hours. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyrate (163 mg). MS (m/z): 771 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:8][CH2:7]2.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.N>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]3)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Brc1cccc2c1CC1(CC2)OCCO1
Agent: CC(C)(C)[O-]
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc3c2CC2(CC3)OCCO2)CC1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
8′-Bromo-3′,4′-dihydrospiro-[1,3-dioxolane-2,2′(1H)-naphthalene] (6.0 g, 22 mmol; described in Sunkyung L.; Stewart P. F.; David E. N. Synth. Commun. 1995, 25(18), 2775-2780) was dissolved in toluene (180 mL) and flushed with argon. N-Methylpiperazine (3.0 mL, 27 mmol), R(+)-bis(diphenylphosphino)-1,1′-binaphthyl (830 mg, 1.3 mmol), tetrakis(dibenzylideneacetone)dipalladium (0) (510 mg, 0.45 mmol) and sodium t-butoxide (3.0 g, 31 mmol) were added and the reaction mixture was stirred at 85° C. for 2.5 h. After cooling to room temperature ethyl acetate (400 mL) and 2 M ammonia (60 mL) were added. The phases were separated and the organic layer was washed with 2 M ammonia (30 mL), brine (40 mL) and dried (MgSO4). Evaporation of the solvent gave 7.5 g of a crude product. Purification by column chromatography on silica using chloroform/methanol/conc. NH3 (180:5:0.5) as eluent afforded 5.5 g (84% yield) of the title compound as a yellowish solid: mp 127-128° C.; EIMS (70 eV) m/z (relative intensity) 288 (43, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:24]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1c(Cl)cncc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 0 °C
Yield: 50.4 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (2.06 g, 12.7 mmol) in dry tetrahydrofuran (30 ml) was cooled down to −78° C., then a 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (7.4 ml, 13.3 mmol) was added dropwise under stirring, keeping the temperature below −70° C. The resulting solution was stirred for 30 min., then a solution of 3,4-dimethoxy-benzoyl chloride (2.55 g, 12.7 mmol) in dry tetrahydrofuran (20 ml) was added dropwise, maintaining the temperature below −70° C. After stirring for 15 minutes, ice (20 g) was added, followed by further 500 ml of water. The mixture was extracted with ethyl acetate (2×50 ml), the combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give an oil that was purified by flash chromatography (Eluent: ethyl acetate/petroleum ether from 10/90 to 30/70 v:v). 2.1 grams (6.4 mmol, 52% yield) of the title compound were obtained as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C(O)C>[CH2:17]([O:16][C:12]([CH2:13][CH2:14][NH:1][CH:2]([CH3:11])[C:3]([CH3:9])([CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:15])[CH3:18]
Reactant: CCOC(=O)C(C)(C)C(C)N
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCNC(C)C(C)(C)C(=O)OCC

Procedure:
In order to carry out this Michael addition, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is dissolved with ethyl acrylate in a reaction medium which is inert under the reaction conditions chosen, preferably in a straight-chained or branched C1-4 -alkanol, most preferably ethanol, and heated, preferably to reflux temperature. After the reaction has taken place the solvent is eliminated in vacuo and the resulting ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate 5 is isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][N:26]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:23]3=[N:24][CH:25]=2)[CH:15]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][NH:46][CH3:47].C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:10]([C:11](=[O:12])[N:46]([CH3:47])[CH3:45])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][N:26]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[C:23]3=[N:24][CH:25]=2)[CH:15]=1)[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C(=O)OC(C)(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)N(C)C)N(C)C(=O)OC(C)(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of (tert-butoxycarbonyl-methyl-amino)-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid, (100 mg, 0.16 mmol), dimethylamine (2 N in THF, 0.12 mL, 0.24 mmol), and diisopropylethylamine (31 mg, 0.24 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 646 (M+H+).