Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 89 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 120, step 2 and 2-fluoro-5-methylaniline (0.043 g, 0.34 mmol), the title compound (0.108 g, 90%) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([S:28]([C:31]3[S:35][C:34]4[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:33]=4[CH:32]=3)(=[O:30])=[O:29])[CH2:24][C:23]2=[O:41])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:40][C:37]1[CH:38]=[CH:39][C:33]2[CH:32]=[C:31]([S:28]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)[C:23](=[O:41])[CH2:24]3)(=[O:30])=[O:29])[S:35][C:34]=2[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1

Procedure:
Trifluoroacetic acid (4 mL) is added to a solution of 4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.0 mmol) in CH2Cl2 (15 mL). After 1 h the reaction is concentrated and the residue is dissolved in CH2Cl2 and washed with Na2CO3, dried (MgSO4) and concentrated to provide 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one. 1H NMR (300 MHz, CDCl3) δ 7.87-7.83 (m, 3H), 7.46 (dd, 1H), 3.86 (dd, 2H), 3.45 (s, 2H), 3.23 (d, 2H), 3.07 (d, 2H), 2.54 (dt, 2H), 2.39 (s, 1H), 1.83-1.75 (m, 1H), 1.56 (d, 2H), 1.24-1.11 (m, 2H); MS (Ion spray) 428 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:14][C:13](=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>ClCCl>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(C(=O)OCc2ccccc2)C1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCN(CC)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
To a solution of 3-oxocyclobutane carboxylic benzyl ester (88.1 mg, 0.43 mmol) in dichloromethane (4.3 mL) were successively added diethylamine (0.18 mL, 1.73 mmol) and sodium triacetoxyborohydride (137.0 mg, 0.65 mmol). The mixture was stirred at room temperature for 5 hours, and then to the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol 20/1 to 5/1) to give the titled compound (66.3 mg, 59%).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]([N:24]2[CH2:28][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26](/[CH:35]=[N:36]/O)[CH2:25]2)=[O:23])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([N:24]2[CH2:28][CH:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]([C:35]#[N:36])[CH2:25]2)=[O:23])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1
Reactant: COc1cc(C=CC(=O)N2CC(/C=N/O)C(c3ccccc3)C2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(/C=C/C(=O)N2CC(C#N)C(c3ccccc3)C2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a THF (3 ml) solution of (E)-1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}-4-phenylpyrrolidine-3-carbaldehyde oxime (17.8 mg) obtained in Example 359, CDI (32.4 mg) was added at room temperature, and heat-refluxing was carried out for 3 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate methanol 10:1), and the 14.6 mg (86%) title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]1[C:13]([N:17]=[C:18]=[S:19])=[CH:14][S:15][CH:16]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[NH2:10][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:18]([NH:17][C:13]1[C:12]([CH3:11])=[CH:16][S:15][CH:14]=1)=[S:19]
Reactant: Cc1cscc1N=C=S
Reactant: COc1cccc(N)c1N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(NC(=S)Nc2cscc2C)c1N

Procedure:
is obtained analogously to the procedure described in example 25 a) from 3-methoxy-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF, followed by medium-pressure chromatography on silica gel using a mixture of 1 part of toluene and 1 part of ethyl acetate. Crystalline solid, m.p.: 148-153° C. Solidification of the melt and next m.p. at 260° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11]Cl)[CH:5]=[CH:4][C:3]=1[OH:14].C([O-])(=O)C.[K+].C(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH:10]=[CH2:11])[CH:5]=[CH:4][C:3]=1[OH:14]
Reactant: O=C(CCCl)c1ccc(O)c(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=CC(=O)c1ccc(O)c(Cl)c1Cl
Yield: 83.8 %

Procedure:
A solution of 2,3-dichloro-4-(3-chloropropionyl)phenol (8.4 g, 0.033 mole) in methanol (30 ml) and potassium acetate (3.5 g, 0.033 mole) in methanol (30 ml) were united and refluxed for 20 minutes. The mixture was treated with chloroform (200 ml), washed with water, dried over MgSO4, filtered and the solvent removed from the filtrate by evaporation in vacuo. The residue was recrystallized from carbon tetrachloride to give 6 g of 2,3-dichloro-4-acryloylphenol, m.p. 135°-137° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CCN(CC)CC>C(Cl)Cl>[S:15]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g, 24.80 mmol, 1 eq), TsCl (5.70 g, 29.80 mmol, 1.2 eq) and Et3N (10.7 mL, 74.40 mmol, 3 eq) in 100 mL of anhydrous CH2Cl2 was stirred for 8 h at room temperature. The resulted mixture was washed with brine (30 mL) and water (30 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (5:1 (v/v) PE/EtOAc) to afford the title compound as a white solid (5.50 g, 68.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 356.2 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14]O>C(O)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1Cc1ccccc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of 2-benzylpyridine (10.0 g, 0.059 moles) and hydrogen peroxide (33% w/v, 4.02 g, 12.2 ml, 0.118 moles) in glacial acetic acid (40 ml) was heated at 60° C. for 17 hours. The reaction mixture was cooled to room temperature, the acetic acid evaporated under reduced pressure and the residue dissolved in chloroform. After neutralisation with potassium carbonate (20 g) the chloroform was removed to give 2-benzylpyridine-N-oxide (10.86 g, 99%) as a viscous oil which crystallised on standing.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methylbenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-2.04 (m, 16H) 2.10-2.22 (m, 3H) 2.29 (s, 3H) 2.77 (d, J=11.1 Hz, 2H) 3.72 (dd, J=7.3, 4.0 Hz, 1H) 3.98 (t, J=14.0 Hz, 2H) 4.60 (t, J=8.2 Hz, 1H) 7.64 (d, J=8.3 Hz, 1H) 7.68-7.80 (m, 2H) 8.08 (d, J=7.8 Hz, 1H) 8.19 (s, 1H) 8.60 (s, 1H). [M+H] calc'd for C27H35F2N7O2, 528. found 528.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH:11]=O)[CH:10]=1)=[O:5])[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C([BH3-])#N.[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:18][C:17]2[CH:19]=[CH:20][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cc(CNc2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
0.5052 g (3.02 mmol) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester was dissolved in 12.0 mL (0.25 M) of 5% acetic acid in methanol. 4-chloroaniline (0.4633 g, 3.63 mmol) was added, and the reaction was stirred at room temperature under nitrogen for 30 minutes, then sodium cyanoborohydride (0.3013 g, 4.79 mmol) was added slowly and the reaction was allowed to stir at room temperature overnight. About 5 mL of saturated K2CO3 were added, and the reaction was extracted twice with ethyl acetate. The combined organics were washed with saturated NaHCO3 (˜6 mL) and brine (˜6 mL), then the combined organics were dried with Na2SO4, filtered and concentrated en vacuo. The crude product was purified by silica gel chromatography (Combiflash column, 85:15 Hexanes:Ethyl acetate) to obtain 0.5806 g (69%) of 4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187) as a light tan solid. Note: Starting material 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has an HPLC retention time=7.337 min. HPLC: 8.543 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:59][C:60]([NH2:64])([CH3:63])[CH2:61][NH2:62]>CN(C=O)C.ClCCl>[NH2:64][C:60]([CH3:63])([CH3:59])[CH2:61][NH:62][C:23]([C:22]1[N:5]2[CH:6]=[C:7]([CH3:21])[CH:8]=[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:24]
Reactant: CC(C)(N)CN
Reactant: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)NCC(C)(C)N)n2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
70 mg (0.20 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylic acid Example 265A, 84 mg (0.22 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) and 77 mg (0.60 mmol) of N,N-diisopropylethylamine were dissolved in 1.3 ml of DMF, and after 20 min at 0° C., 19.4 mg (0.22 mmol) of 2-methylpropane-1,2-diamine were added. The mixture was stirred at 0° C. for 45 min and then purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fraction obtained was taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 54 mg (64% of theory) of the title compound.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Br:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35]2[CH:39]=[C:38]([C:40]3[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=3O)[NH:37][N:36]=2)=[N:32][CH:33]=1>C1COCC1>[Br:27][C:28]1[N:29]=[CH:30][C:31]([NH:34][C:35]2[CH:39]=[C:38]([C:40]3[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=3[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[NH:37][N:36]=2)=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COc1cccc(O)c1-c1cc(Nc2cnc(Br)cn2)n[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COc1cccc(OCCCNC(=O)OC(C)(C)C)c1-c1cc(Nc2cnc(Br)cn2)n[nH]1
Reaction time: 0.75 h
Yield: 54 %

Procedure:
Diisopropyl azodicarboxylate (1.73 mL, 8.76 mmol) is added to a stirred solution of tert-butyl 3-hydroxypropylcarbamate (0.83 mL, 4.83 mmol), 2-(3-(5-bromopyrazin-2-ylamino)-1H-pyrazol-5-yl)-3-methoxyphenol) (1.59 g, 4.38 mmol) and polystyrene triphenylphosphine (5.91 g, 8.76 mmol) in THF (50 mL) at room temperature. After stirring for 45 min, the reaction is filtered, and the solvent is removed under reduced pressure. The resulting residue is chromatographed (methanol/CH2Cl2) to afford 1.27 g (54%) of a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]([CH3:55])[CH2:50][C:51](=[O:54])[NH:52][N:53]=2)=[CH:44][C:43]=1[OH:56]>O.CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]([CH3:55])[CH2:50][C:51](=[O:54])[NH:52][N:53]=3)=[CH:44][C:43]=2[OH:56])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(O)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(C#N)cc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
403 mg (2.74 mmol) 4-cyano-benzoic acid and 967 mg (3.01 mmol) TBTU are added to 40 ml DMF and the mixture is stirred for 30 min at RT, then 791 μl (5.47 mmol) diisopropylamine and 600 mg (2.74 mmol) 6-(4-amino-3-hydroxy-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one are added and the mixture is stirred overnight. The reaction mixture is mixed with water and extracted with DCM. The org. phase is again washed with water, dried on sodium sulphate and concentrated by rotary evaporation i. V. The residue is extracted with methanol, filtered off, washed with methanol and then dried in the vacuum dryer at 50° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[CH:10][C:11]([O:15]C)=[CH:12][C:13]=13)[C:8]([CH2:17][CH3:18])=[C:7]2[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[CH:10][C:11]([OH:15])=[CH:12][C:13]=13)[C:8]([CH2:17][CH3:18])=[C:7]2[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(C(C)=O)c3cc(OC)cc1n32
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(-c2ccc(O)cc2)c2cc(C(C)=O)c3cc(O)cc1n32
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A solution of 4-acetyl-1-ethyl-6-methoxy-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine (0.2 g, 0.58 mmol) in 5 ml of dry dichloromethane was cooled to -65° C. and stirred in a nitrogen atmosphere, while 1.61 ml of a 1M boron tribromide solution in dichloromethane was added. The cooling source was removed and the mixture was stirred for seventy-two hours at room temperature. The mixture was neutralized with a saturated sodium hydrogen carbonate solution. The precipitate was isolated and dried to afford 177 mg (95%) of the title compound. M.p. 274-75° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.37 (t, 3H), 2.58 (s, 3H), 3.08 (q, 2H), 7.00 (d, 2H), 7.55 (d, 1H), 7.66 (d, 2H), 7.71 (d, 1H), 8.04 (s, 1H), 9.81 (s, 1H), 10.50 (s, 1H). (Compound 8).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:32]=O)=[CH:17][CH:16]=1.[CH2:36]([P:45](=[O:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:23][C:22]=2/[CH:32]=[CH:36]/[P:45](=[O:52])([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2C=O)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a mixture of 5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]ethenylphosphonate as colorless crystals (0.41 g, yield 62%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-125° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[NH2:34][CH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCC(Nc1cccc(-c2cnc3c(NC4CCC(N)CC4)nccn23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (4-{3-[6-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (250 mg, 0.38 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative-HPLC to give N-{3-[6-(3-amino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 18 mg).
Reaction SMILES: B([C:4]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])(O)O.[NH2:19][C:20]1[C:25](Br)=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.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>[NH2:19][C:20]1[C:25]([C:4]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:5]=2[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1B(O)O
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: CO
Product: Cc1cnc(N)c(-c2cc(C(F)(F)F)ccc2OCC(=O)O)c1
Temperature: 100 °C

Procedure:
A mixture of the product from step (iv) (0.1 g), 2-amino-3-bromo-5-methylpyridine (0.071 g), tetrakis(triphenylphosphine)palladium(0) (0.046 g), sodium carbonate (0.12 g) in methanol (2 ml) was heated in a CEM microwave (variable wattage up to 150 W) at 100° C. for 10 min. The mixture was loaded onto SCX resin (sulphonic acid resin), flushed with methanol then the product eluted with methanol/ammonia. The methanol/ammonia filtrate was evaporated under reduced pressure then loaded onto bondelut-NH2 resin. The resin was flushed with methanol then the product eluted with methanol/acetic acid. The methanol/acetic acid filtrate was evaporated and the residue purified by RPHPLC. Yield 0.089 g