Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[CH3:13][N:14]([CH3:32])[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(Br)C=C.Cl>O1CCCC1>[CH3:32][N:14]([CH3:13])[C:15](=[O:31])[CH:16]([CH2:3][CH:2]=[CH2:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCCCCCC(=O)N(C)C
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(CCCCCCCCCCCCCC)C(=O)N(C)C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of n-butyl lithium (hexane, 44 mmol) in 120 mL of anhydrous tetrahydrofuran at 0° C., under nitrogen atmosphere it was added 6.2 mL (44 mmol) of diisopropylamine. After 5 min., 10 g (35 mmol) of N,N-dimethylhexadecanamide was added dropwise and the solution was stirred for 1 h at the same temperature. To the solution 3.7 mL (44 mmol) of allyl bromide were added and the mixture was stirred at room temperature for 12 h. Afterwards the solution was poured on water and the resulting mixture was acidified with 12 N HCl, and extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and after evaporation of the solvent it was obtained 10.94 g of an oil that was purified by column chromatography (silica gel, hexane: ethyl acetate 15%). In that way, 10.2 g of a colorless oil was obtained (85% yield).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH:15]=2)[C:10]([C:26]([C:29]#[N:30])(C)C)=[CH:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:19]([N:17]([CH3:18])[C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:26][C:29]#[N:30])=[CH:9][NH:8]2)=[CH:12][CH:13]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1ccccc1)c1ccc2c(C(C)(C)C#N)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)c1ccc2c(CC#N)c[nH]c2c1
Yield: 88.2 %

Procedure:
A solution of 6-(benzyl-methyl-amino)-3-(cyano-dimethyl-methyl)-indole-1-carboxylic acid tert-butyl ester (26.4 g, 90%, 58.9 mmol) in DCM-TFA (2:1, 180 mL) was stirred for 20 h at 20° C. Evaporation of solvent gave a crude, which was redissolved in DCM and the solution was washed with water, aqueous sodium bicarbonate and water and dried over MgSO4. Evaporation of solvent gave a solid, which was triturated with hexane to give [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile as a solid (14.3 g). MS (ES): 304 (MH+). [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile was then treated in a manner similar to that described in Step 34D-H, but using greater than three equivalents of iodomethane, to give 6-(benzyl(methyl)amino)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33].C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>C(O)C.O.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>[NH2:12][CH:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=3)[N:14]([CH3:13])[C:15](=[O:33])[CH2:16][CH2:17]4)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: NC1CCCc2c(Br)cncc21
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: [Cl-]
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4N)ccc21
Temperature: 85 °C
Yield: 137.9 %

Procedure:
In a 100 mL round-bottomed flask, (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (745 mg, 3.28 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-1) (1.13 g, 3.94 mmol) were dissolved in ethanol (60 mL) to give a light brown solution. Na2CO3 (382 mg, 3.61 mmol), dissolved in water (10 mL) was added followed by tetrakis(triphenylphosphine)palladium (0) (114 mg, 98.4 μmol) after evacuation and replacing 5 times with Argon. The solution was then heated at 85° C. overnight. The reaction was treated with an aq. 10% NaCl solution and extracted with AcOEt (3×). The organic phases were washed again with an aq. 10% NaCl solution, dried over Na2SO4, filtered and evaporated under reduced pressure to give 1.39 g brown foam which was purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (3, 5, 7.5, 10 and 15%)) and precipitated from CH2Cl2 with n-pentane to give the title compound (690 mg, 68%) as a light brown foam. MS: 308.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][O:11][CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH:23][C:15](=[O:17])[C@H:9]([CH2:10][O:11][CH2:12][CH:13]=[CH2:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Purified N-tert-butoxycarbonyl O-allyl L-serine 3 (6.94 g, 28.3 mmol) was dissolved in 30 mL DMF and the solution cooled to 0° C. (icebath). Glycine methyl ester hydrochloride (3.55 g, 28.3 mmol) was suspended in 10 mL DMF and N,N-diisopropylethyl amine (3.66 g, 28.3 mmol) added. The suspension was then added in one portion to the solution of 3 together with an additional 5 mL DMF. HOBt hydrate (4.33 g, 28.3 mmol) was added. Finally, EDC hydrochloride (5.97 g, 31.1 mmol) was added together with an additional 10 mL DMF. The reaction mixture was stirred at 0° C. for 1 hour. In total the reaction mixture was stirred for 24 hours before the solvent was evaporated. The residue was taken up in 150 mL EtOAc and washed with 1 M aqueous H2SO4 (3×100 mL), 7.5% (w/w) aqueous K2CO3 (3×100 mL) and finally saturated brine (100 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a clear and slightly greenish/yellowish liquid (7.49 g, 84%); δH (200 MHz; d6-DMSO) 8.31 (1H, t, J 6, NH(Gly)), 6.85 (1H, d, J 8, NH(Ser(All))), 5.86 (1H, ddt, J 5, 11 and 17, CH═CH2), 5.29-5.11 (2H, m, CH═CH2), 4.22 (1H, ddd, J 8 and 12, CαH(Ser(All))), 3.94 (2H, dt, J 1 and 5, CH2CH═CH2), 3.86 (1H, d, J 6, CαHH(Gly)), 3.83 (1H, d, J 6, CαHH(Gly)), 3.62 (3H, s, OCH3), 3.56-3.44 (2H, m, CH2), 1.38 (9H, s, (CH3)3); δC (50 MHz; d6-DMSO) 170.3, 170.0, 155.1, 134.9, 116.3, 78.2, 70.9, 69.6, 54.1, 51.6, 40.5, 28.1; m/z (ESI) 339.1541 ([M+Na]+; C14H24N2O6Na requires 339.1532)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:23])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:9][CH2:10][CH:11]=1.[NH2:25][O:26][K].C(O)(=O)C>CO.C(OCC)(=O)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][CH:11]=[C:6]([CH2:5][CH2:4][C:3]([NH:25][OH:26])=[O:2])[C:7]1=[O:23]
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Reactant: NO[K]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN2CCC=C(CCC(=O)NO)C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
46 mg of compound (d) prepared by the above Step 3 was dissolved in methanol solution (0.138 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.122 ml, 0.207 mM) was added thereto at 0° C. and the resulting mixture was stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:10) solvent mixture as an eluant to give 32 mg of the title compound (e1) (yield: 73%).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1.[CH3:29][C:30]1([CH3:42])[CH2:34][C:33]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=2[O:31]1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][N:2]([CH3:1])[C:3]1[N:4]([C:36]2[CH:37]=[CH:38][C:32]3[O:31][C:30]([CH3:29])([CH3:42])[CH2:34][C:33]=3[CH:35]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1
Reactant: CCCc1nc(N(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(N(C)C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 10.6 %

Procedure:
To a suspension of 4′-{[2-(dimethylamino)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.1 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (2.1 g), triethylamine (3.8 mL), pyridine (2.2 mL) and molecular sieves 4 A (4 g) in dichloromethane (50 mL) was added copper(II) acetate (2 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.31 g, 11%).
Reaction SMILES: [O:1]([C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=[N:19][C:15]=2[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=CC=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1)C1C=CC=CC=1>C(O)(=O)C.O>[O:1]([C:8]1[CH:44]=[CH:43][CH:42]=[CH:41][C:9]=1[CH2:10][O:11][CH2:12][CH:13]1[CH2:40][CH2:39][C:16]2[NH:17][CH:18]=[N:19][C:15]=2[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Agent: c1ccc(Oc2ccccc2COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)cc1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(Oc2ccccc2COCC2CCc3[nH]cnc3C2)cc1
Temperature: 90 °C

Procedure:
A mixture of 5-((2-phenoxybenzyloxy)methyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-((2-phenoxybenzyloxy)methyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (1.20 g, 2.1 mmol) was dissolved in a mixture of acetic acid (9 ml) and water (1 ml). The mixture was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (10 ml). a 3.5 M solution of hydrogen chloride in ethyl acetate (0.60 ml) was added. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (first: 100:10:1, then 100:20:2) as eluent to give 74 mg of the title compound. For biological testing, the title compound was transferred into its hydrochloride salt by lyophilization of its solution in 0.1 N hydrochloric acid (40 ml).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)=[CH:7][C:6]=2[CH:18]=1.C([BH3-])#N.[Na+]>[I-].[Zn+2].[I-].ClCCCl>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][C:6]=2[CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(c1ccccc1)c1cc2cc(Br)ccc2o1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: Brc1ccc2oc(Cc3ccccc3)cc2c1
Reaction time: 0.5 h

Procedure:
(5-bromobenzofuran-2-yl)(phenyl)methanone (2.0 g, 6.6 mmol), sodium cyanoborohydride (3.2 g, 51 mmol), zinc iodide (2.6 g, 13.2 mmol) and 1,2-dichloroethane (50 mL) were combined and heated to reflux for overnight. The mixture was cooled, quenched with saturated ammonium chloride, acidified with concentrated HCl and stirred for 30 minutes. The layers were separated, the aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 20% dichloromethane in hexanes) to give the product as a white solid: 1H NMR (400 MHz, CDCl3) δ7.59 (s, 1H), 7.27-7.34 (m, 7H), 6.32 (s, 1H), 4.10 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:12]([CH:14]3[CH2:16][CH:15]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:8][CH2:9][C:10]=2[N:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:14]3[CH2:16][CH:15]3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCN(C(=O)C1CC1c1ccccc1)CC2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc2c(s1)CCN(CC1CC1c1ccccc1)CC2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g (6.4 mmol) of 2-amino-6-(2-phenyl-1-cyclopropyl-carbonyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine (melting point: 122°-126° C.; prepared from 2-phenyl-1-cyclopropyl-carboxylic acid chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform) in 40 ml of tetrahydrofuran is added dropwise, with stirring and under nitrogen, to 0.73 g (19.1 mmol) of lithium aluminium hydride in 40 ml of tetrahydrofuran. The mixture is stirred for 2 hours in a bath at 40° C., then cooled, ethyl acetate is added to decompose any excess lithium aluminium hydride and hydrolysis is carried out by dropwise addition of saturated ammonium chloride solution. The precipitate is filtered off and the filtrate is evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=10:1). Yield: 0.65 g (34% of theory), Melting point: 109°-113° C. (isopropanol).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:40][C:41]1[N:45]2[C:46](=[O:55])[N:47]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[CH2:48][C:44]2=[CH:43][N:42]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:52]1[CH2:51][CH2:50][CH:49]([N:47]2[CH2:48][C:44]3=[CH:43][N:42]=[C:41]([CH3:40])[N:45]3[C:46]2=[O:55])[CH2:54][CH2:53]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1)C2
Yield: 93.3 %

Procedure:
To a solution of Boc-D-tert-leucine (0.23 g) and HOBt (0.23 g) in acetonitrile (5 ml) was added WSC (0.29 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.29 g), DBU (0.30 g) and triethylamine (0.30 g) in acetonitrile (5 ml) was added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound as colorless powder (0.40 g, 92%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7](I)=[C:6]([CH3:18])[N:5]=1)[CH3:2].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].CCN(CC)CC>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:11]1([NH:10][C:8]2[C:7](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]([CH3:18])[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCNc1nc(C)c(I)c(NC2CCCCC2)n1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c(/C=C/C(=O)OCC)c(NC2CCCCC2)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
To a solution of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine (660 mg, 1.83 mmol) in DMA (7 mL) was added ethyl acrylate (458 mg, 4.58 mmol), Pd(OAc)2 (121 mg, 0.18 mmol), (o-Tol)3P (110 mg, 0.37 mmol), and Et3N (740 mg, 7.32 mmol). The mixture was then stirred at 100° C. for 12 h under N2. Standard workup and purification by column chromatography gave 411 mg (67% yield) of (E)-ethyl 3-(4-(cyclohexylamino)-2-(ethylamino)-6-methylpyrimidin-5-yl)acrylate
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.B([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([NH:39][C:40](=[O:50])[C:41]2[C:46]([CH3:47])=[CH:45][C:44]([CH3:48])=[CH:43][C:42]=2[CH3:49])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=1)(O)O.CCN(CC)CC>ClCCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([NH:39][C:40](=[O:50])[C:41]3[C:42]([CH3:49])=[CH:43][C:44]([CH3:48])=[CH:45][C:46]=3[CH3:47])[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)[CH2:21][CH2:20]1
Reactant: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Reactant: Cc1cc(C)c(C(=O)NC(Cc2ccc(B(O)O)cc2)C(=O)O)c(C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(N3CCC(CNc4nc5ccccc5[nH]4)CC3)cc2)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
95 mg (0.207 mmol, calculated as bistrifluoroacetate salt) of crude piperidine derivative (19), 113 mg (0.621 mmol) Cu(OAc)2, 147 mg (0.415 mmol) boronic acid (6) and 1.72 ml (12.42 mmol) NEt3 were mixed in 10 ml DCE and stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol and subsequently submitted to reversed phase HPLC purification using a water/acetonitrile gradient containing 0.1% TFA. The required fractions were collected and lyophilized to yield (20) as white solid.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:28])[NH2:5])=[CH:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 1,1-dimethylethyl{(1R)-1-methyl-2-[(4-{[3-(methyloxy)phenyl]oxy}phenyl)amino]-2-oxoethyl}carbamate (Intermediate 1, 435 mg) in dry dichloromethane (6 mL), TFA (2 mL, 26.0 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge to afford the title compound as a yellow gum (320 mg).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15][CH2:14]3)=[C:4]([O:28][CH3:29])[CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(Cl)Cl.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:29][O:28][C:4]1[CH:3]=[C:2]([C:32]2[CH:33]=[CH:34][S:30][CH:31]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C@H:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15][CH2:14]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(Br)cc3OC)ccc21
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4ccsc4)cc3OC)ccc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
Ethyl {(1S)-5-[3-(4-bromo-2-methoxyphenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (140 mg, 0.3 mmol) (Example 97), 3-thiopheneboronic acid (81.2 mg, 0.63 mmol), PdCl2(dppf).CH2Cl2 (90.5 mg, 0.07 mmol), and NaHCO3 (76.1 mg, 0.91 mmol) were suspended in DME (10 mL) and water (1 mL). The reaction mixture was degassed under vacuum for 3 min, and then purged with argon, after which the reaction mixture was agitated by orbital shaker at 80° C. for 24 h, and then at rt for 24 h. The reaction mixture was filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (EtOAc/hexanes (v/v)=1:9 to 1:1 gradient) to give 83 mg (59%) of the title compound as a yellow oil. 1H NMR (400 MHz, acetone-d6): δ 7.62-7.71 (m, 1H), 7.52-7.46 (m, 2H), 7.29 (d, 1H), 7.23-7.19 (m, 1H), 7.11-7.09 (m, 1H), 7.02-6.99 (m, 1H), 6.83-6.82 (m, 1H), 6.76-6.73 (m, 1H), 4.22-4.09 (m, 6H), 3.87 (s, 3H), 3.44 (m, 1H), 2.87-2.66 (m, 3H), 2.40-2.18 (m, 4H), 1.74-1.70 (m, 1H), 1.25 (t, 3H).
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([C:11]1[N:15]2[C:16]([CH2:20]Cl)=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)([O:8]CC)=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:20][C:16]3[N:15]4[C:11](=[CH:12][N:13]=[C:14]4[CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:8])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: CCOC(=O)c1cnc2cccc(CCl)n12
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCCN2Cc3cccc4ncc(n34)C2=O)CC1
Yield: 60 %

Procedure:
A solution prepared by dissolving 3.59 g (10.66 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine sulfate, 3.10 g (12.79 mM) of 3-(1-tert-butoxycarbonylpiperidin-4-yl)-1-propylamine, and 5.94 ml (42.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of chloroform. The organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=50:1) to provide 2.55 g (yield 62.1%) of the title compound as yellow oil.