Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N(CC)CC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.7 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 5 mmol), 2-chloro-N,N-diethylacetamide (1 mL, 7.5 mmol) and cesium carbonate (5 g, 15 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (160 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.52 g of 5-diethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester as an off-white solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=C.[CH3:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>CO>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][NH:6][CH2:5][CH2:2][C:1]#[N:4]
Reactant: CNCCc1ccccn1
Reactant: C=CC#N
Solvent: CO
Product: N#CCCNCCc1ccccn1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Acrylonitrile (10.1 ml, 1.1 eq) is added slowly to a solution cooled down to approximately 4° C. of 2-[2-(methylamino)ethyl]pyridine (19.5 ml, 1 eq) in methanol (200 ml). The reaction medium is then stirred for 3 hours at approximately 20° C. then concentrated under reduced pressure at 40° C. in order to produce 3-[(2-pyridin-2-ylethyl)amino]propanenitrile in the form of a yellow oil (25.6 g, 96% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (1.37 g, 9 mmol) and (bromomethyl)benzene (1.71 g, 10 mmol) in acetonitrile (100 mL) was added potassium carbonate (2.76 g, 18.8 mmol). The reaction mixture was stirred at 60° C. for 2 hours. After the reaction, the solvent was removed under reduced pressure to give the crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=100:1) to give the pure product (2.18 g, 99%). LRMS (M+H+) m/z: calcd 243.09. found 243.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([OH:21])=[C:6]([CH:8](O)[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=2[OH:19])[CH:7]=1.S(Cl)([Cl:27])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([OH:21])=[C:6]([CH:8]([Cl:27])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=2[OH:19])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(O)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cc(C(Cl)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O

Procedure:
A mixture of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl alcohol (4.5 g) and thionyl chloride (50 ml) was heated under reflux for 3 hr. Dimethylformamide (0.1 g) was added to the reaction mixture and the mixture was heated under reflux for a further hour. Excess thionyl chloride was then removed by distillation under reduced pressure and the remaining red oil was crystallised from ethanol to give 4 g of bis(5-chloro-2-hydroxy-3-nitrophenyl)methyl chloride, m.p. 180° C.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[Cl:13][C:14]1[S:41][C:17]2[NH:18][C:19]([C:21]([NH:23][CH:24]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[C:25]3=[O:40])=[O:22])=[CH:20][C:16]=2[CH:15]=1>CN(C1C=CN=CC=1)C>[Cl:13][C:14]1[S:41][C:17]2[NH:18][C:19]([C:21]([NH:23][CH:24]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:34][CH:35]4[CH2:38][O:39][C:1](=[O:2])[O:37][CH2:36]4)[C:25]3=[O:40])=[O:22])=[CH:20][C:16]=2[CH:15]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(NC1Cc2ccccc2N(CC(CO)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Agent: CN(C)c1ccncc1
Product: O=C1OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)CO1
Temperature: 50 °C
Yield: 69 %

Procedure:
Carbonyl diimidazole (143 mg, 0.88 mmol) was added to 2-chloro-N-{1-[3-hydroxy-2-(hydroxymethyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 22; 250 mg, 0.58 mmol) followed by DMAP (2 mg) and the reaction was heated at 50° C. for 4 hours. The reaction was quenched by addition of EtOAc (50 mL) and H2O (10 mL) and the organic layer was separated and washed further with saturated aqueous NaHCO3, 1M HCl (aq.) and brine. The organic layer was then dried (MgSO4), filtered and evaporated. Trituration with hot Et2O (15 mL), cooling and filtration afforded the title compound (182 mg, 0.40 mmol, 68%) as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[C:16]=3[CH:15]=[CH:14]2)=[CH:10][CH:9]=1.[OH-].[Na+].CN([CH:33]=[O:34])C>>[CH:33]([C:15]1[C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]([CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:27][CH:26]=2)[CH:14]=1)=[O:34]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2c1ccn2Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c1c(C=O)cn2Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Phosphorus oxychloride (7.74 ml, 84.6 mmol) was added slowly to ice-cold DMF (200 mL) and the resulting mixture was stirred at 0° C. for 1 h. To this mixture was added a solution of methyl 1-(4-methoxybenzyl)-1H-indole-4-carboxylate (16.6 g, 56.4 mmol) from Step A above in DMF (100 mL) and the mixture was stirred for 2 h. The reaction mixture was poured into an ice/water mixture and the pH was adjusted to 7 by adding 1 N NaOH. The compound was extracted with ethyl acetate (3×500 mL) and the combined organic layers were washed with water (4×250 mL) and brine (4×250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (ethyl acetate/hexanes: 20-40%) to afford methyl 3-formyl-1-(4-methoxybenzyl)-1H-indole-4-carboxylate (16.7 g, 93%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.48 (s, 1H), 7.99 (s, 1H), 7.85 (dd, J=10.0, 5.0 Hz, 1H), 7.55 (dd, J=10.0, 5.0 Hz, 1H), 7.30 (t, J=10.0 Hz, 1H), 7.12 (d, J=10.0 Hz, 2H), 6.86 (d, J=10.0 Hz, 2H), 5.31 (s, 2H), 3.99 (s, 3H), 3.71 (s, 3H); MS (ESI+) m/z 324 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>CN(C=O)C>[CH2:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:20][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[CH3:12]
Reactant: Oc1ccc(O)cc1
Reactant: CCN(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
A mixture of compound 3a (500 mg, 2.7 mmol), K2CO3 (750 mg, 5.4 mmol), and KI (90 mg, 0.54 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (600 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. The reaction was quenched and the solvent evaporated and purified by silica gel column chromatography to provide compound 3 (400 mg, 1.55 mmol, 57% yield) as a brown oil. 1H NMR (DMSO-d6, 400 MHz) δ 8.92 (s, 1H), 7.14 (m, 2H), 6.75-6.64 (m, 6H), 6.57 (m, 1H), 3.98 (t, J=5.8 Hz, 2H), 3.62 (t, J=5.8 Hz, 2H), 3.41 (q, J=7 Hz, 2H), 1.09 (t, J=7 Hz, 3H). HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.1494, found: 258.1436.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:11]([C:9]3[S:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=4[CH:8]=3)=[O:13])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: N#Cc1ccc2sc(C(=O)O)cc2c1
Agent: Cl
Product: N#Cc1ccc2sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2c1

Procedure:
In the same manner as in Referential Example 319, a reaction was effected using 5-cyanobenzothiophene-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([N:8]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([N:8]([CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23])=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1ccc(N)cc1
Reaction time: 6 h
Yield: 95.3 %

Procedure:
4-Nitro-bis[2′-(tert-butyldimethylsilyloxy)ethyl]-aniline (X-4a) (5.50 g, 12.1 mmol) was dissolved in 90 mL THF, 1.5 g Pd/C 10% was added, and the suspension was stirred under H2 atmosphere for 6 h. The catalyst was then filtered off, the solvent evaporated and the residue purified by column chromatography (cyclohexane:AcOEt 3:1) to yield the title compound (4.90 g, 95%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:33][C:34]#[N:35]>CN(C)C=O>[C:34]([CH2:33][N:14]1[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:18][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:13]1=[O:29])#[N:35]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
1,3-Dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-5-phenyl-2H-1,4-benzodiazepin-2-one (1.5 g) was dissolved in 25 ml of dry N,N-dimethylformamide at 0° C. To this solution was added 218 mg of (60%) sodium hydride and the resulting reaction mixture was stirred for 15 minutes. Chloroacetonitrile in 1 ml of dry N,N-dimethylformamide was then added and the reaction mixture was allowed to warm to room temperature. After 1 hour the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and 10% citric acid solution. The organic phase was washed with brine, then dried (sodium sulfate), and concentrated to give a solid. The title compound (1.53 g, 93%) was obtained in pure form after flash silica gel chromatography employing ethyl acetate-hexane (1:2 v/v) as eluant.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]1=2.C([Mg]Cl)(C)C.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.ClCCCl>[C:34]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([OH:32])([C:8]3[C:7]([OH:10])=[CH:6][C:3]4[CH:4]=[CH:5][S:1][C:2]=4[CH:9]=3)[C:24]2=[O:33])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2sccc2c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2sccc2cc1O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
To a solution of benzo[b]thiophen-5-ol (1.39 g, 9.25 mmol) in tetrahydrofuran (50 mL) at 5° C. was added a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (5.0 mL, 10 mmol). The reaction mixture was stirred at 5° C. for 15 min and concentrated in vacuo. To the residue were added 1,2-dichloroethane (100 mL) and 1-(diphenylmethyl)-1H-indole-2,3-dione (2.5 g, 8.0 mmol). The reaction mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and stirred for 48 h. Saturated aqueous ammonium chloride (10 mL) was added and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 20% gradient of ethyl acetate in dichloromethane to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one (2.2 g, 59%) as an off-white solid: MS (ES+) m/z 486.0 (M+23).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C>[Br:24][C:14]1[S:13][C:12]([C:10]2[S:11][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CCCCCCc1ccc(-c2cccs2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2ccc(Br)s2)s1

Procedure:
Under a light shielded condition, a 5-hexyl-2,2′-bithiophene (0.66 g, 2.63 mmol)/DMF (10 mL) solution was added to NBS (0.56 g, 3.16 mmol) and reacted for one hour. The reaction mixture was then washed with water and was extracted with diethyl ether. The organic layer was dried with MgSO4, and then the solvent was removed.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]4[N:20]=[C:21]([NH2:23])[N:22]=[C:18]4[CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:23][C:21]2[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:9][CH:10]=4)[N:19]3[N:20]=2)=[CH:26][CH:27]=1
Reactant: Nc1nc2cccc(-c3ccc(CN4CCOCC4)cc3)n2n1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ccc(Nc2nc3cccc(-c4ccc(CN5CCOCC5)cc4)n3n2)cc1
Yield: 44.7 %

Procedure:
A suspension of 5-(4-(morpholinomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.50 g, 1.6 mmol), 1-bromo-4-chlorobenzene (340 mg, 1.8 mmol), tris(dibenzylideneacetone)dipalladium (0) (147 mg, 0.16 mmol), cesium carbonate (782 mg, 2.4 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (94 mg, 0.16 mmol) in 1,4-dioxane (50 mL) was heated to reflux for 2 days. The reaction mixture was diluted with ethyl acetate (300 mL), and the resulting suspension was filtered though celite. Concentration of the filtrate in vacuo provided crude product, which was purified by flash column chromatography (petroleum ether→ethyl acetate) to give product (300 mg, 44% yield). LCMS (ESI) m/z: 421.
Reaction SMILES: [O:1]1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=3[CH3:27])[N:17]=2)[CH:9]=[CH:10][CH:11]=1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].NCCC(O)=O.O>CC(O)=O>[C:2]([OH:3])(=[O:1])[CH3:6].[O:34]=[C:29]1[NH:30][C:31](=[O:33])/[C:32](=[CH:2]/[C:6]2[CH:7]=[C:8]([NH:12][C:13]3[S:14][CH:15]=[C:16]([C:18]4[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=4[CH3:27])[N:17]=3)[CH:9]=[CH:10][CH:11]=2)/[S:28]1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccc(C4OCCO4)c3)n2)s1
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccc(/C=C4\SC(=O)NC4=O)c3)n2)s1
Temperature: 100 °C
Yield: 9 %

Procedure:
A solution of N-(2-{[3-(1,3-dioxolan-2-yl)phenyl]amino}-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl)acetamide obtained in Step 1 as described above (290.00 mg; 0.72 mmol; 1.00 eq.), 2,4-thiazolidinedione (151.90 mg; 1.30 mmol; 1.80 eq.) and beta-alanine (115.55 mg; 1.30 mmol; 1.80 eq.) in AcOH (6.00 ml) are heated at 100° C. for 1 h30. Water is added and the precipitate is filtered and washed with Et2O, affording (62) as a yellow solid (35 mg; 9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[CH:32]=[CH:31][N:30]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.917 min, m/z=444.4; 1H NMR (CDCl3) 1.51 (d, 3H), 1.92 (m, 1H), 2.13-2.32 (m, 5H), 2.44 (m, 1H), 2.82 (s, 3H), 2.93 (m, 1H), 5.50-5.68 (m, 3H), 7.06 (d, 2H), 7.19-7.35 (m, 5H), 7.39 (d, 2H), 7.58 (s, 1H), 7.65 (d, 1H), 8.74 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH:7]([C:11](=[O:13])[CH3:12])[C:8](=[O:10])[CH3:9])[CH3:2].[C:15]([O:19][CH2:20][C:21]([CH3:29])([CH2:23][O:24][C:25](=[O:28])[CH:26]=[CH2:27])[CH3:22])(=[O:18])[CH:16]=[CH2:17]>N12CCCN=C1CCCCC2>[C:8]([C:7]([C:11](=[O:13])[CH3:12])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:17][CH2:16][C:15]([O:19][CH2:20][C:21]([CH3:29])([CH3:22])[CH2:23][O:24][C:25](=[O:28])[CH2:26][CH2:27][C:7]([C:8](=[O:10])[CH3:9])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:11](=[O:13])[CH3:12])=[O:18])(=[O:10])[CH3:9]
Reactant: C=CC(=O)OCC(C)(C)COC(=O)C=C
Reactant: CCOC(=O)CCC(C(C)=O)C(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(CCC(=O)OCC(C)(C)COC(=O)CCC(CCC(=O)OCC)(C(C)=O)C(C)=O)(C(C)=O)C(C)=O
Reaction time: 3 h

Procedure:
5.0 g of 4-acetyl-5-oxohexanoic acid ethyl ester and five drops 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed and 2.6 g of neopentyl glycol diacrylate was added dropwise. The mixture was stirred for three hours to yield a highly viscous colorless oil. Gel permeation chromatography showed a main peak at 690 g/mol, nuclear magnetic resonance spectra and infrared spectrum are according to the expected structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:38]([BH3-])#N.[Na+].CCOC(C)=O>CC(O)=O>[C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)[CH3:38])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(C(=O)Nc2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)Nc1ccc(I)cc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 105.5 %

Procedure:
4-{[(4-tert-Butyl-phenyl)-(4-iodo-phenylcarbamoyl)-methyl]-amino}-benzoic acid tert-butyl ester (110 mg, 0.19 mmol) was dissolved in 2 mL of HOAc. paraformaldehyde (51 mg, 0.57 mmol) and sodium cyano-borohydride (36 mg, 0.57 mmol) were then added and heated to 40 C for 1 h. Cooled to RT, EtOAc (20 mL) was added and extracted water (20 mL). The organic layer was washed again with water (20 mL), dried over sodium sulfate, filtered and the organic layer was removed under reduced pressure to give a white solid (120 mg, 100%). 1H NMR showed the compound to be very clean and sufficient for the following step. LCMS (M+1=599.4)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20]C1C=CC=C2C=1NC=C2>>[CH3:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Cc1cccc2cc[nH]c12
Product: Cc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-methyl-1H-indole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH2:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][C:17]#[CH:18]>>[N:19]1([CH2:15][CH2:16][C:17]#[C:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C#CCCN1CCCCC1
Reactant: Brc1cccc(CN2CCCCC2)n1
Product: C(#Cc1cccc(CN2CCCCC2)n1)CCN1CCCCC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step D, using 2-bromo-6-piperidin-1-ylmethyl-pyridine and 1-but-3-ynyl-piperidine (56%). MS (ESI): exact mass calcd. for C20H29N3, 311.46; m/z found, 312.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.54 (t, J=7.7, 1H), 7.38 (d, J=7.7, 1H), 7.20 (d, J=7.4, 1H), 3.58 (s, 2H), 2.67-2.57 (m, 4H), 2.46-2.34 (m, 8H), 1.60-1.50 (m, 8H), 1.44-1.36 (m, 4H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:12](=O)[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O.O.Cl>C(O)(=O)C>[ClH:8].[CH:1]([NH:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[CH:13]=[C:12]1[C:11]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:9]([Cl:8])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=C(CC1CCCCC1=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)NCCN
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)NCCn1c(-c2ccc(Cl)c(Cl)c2)cc2c1CCCC2

Procedure:
2.9 g (0.028 mole) of isopropylaminoethylamine are added dropwise to a stirred solution of 8.0 g (0.028 mole) of 2-(3,4-dichlorophenacyl)cyclohexanone in glacial acetic acid under nitrogen. After refluxing for 5 hours, ice and water are added and the pH of the aqueous solution is adjusted to 1 with dilute hydrochloric acid. The aqueous solution is washed with ether. The aqueous phase is made basic with sodium carbonate and extracted with ether. The ether solution is dried over sodium sulfate and concentrated to off-white solid, which is recrystallized twice from a methanol-ether mixture to give 1-(2-isopropylaminoethyl)-2-(3,4-dichlorophenyl)-4,5,6,7-tetrahydroindole hydrochloride as crystals, m.p. 207°-210° C.