Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc(N)cc3)ccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{5-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (297 mg, 648 μmol) in a mixture of ethanol and water (4:1, 10 mL), was added palladium on carbon (60 mg, 10% w/w Pd) and ammonium formate (245 mg, 3.89 mmol). The resulting suspension was heated to reflux for 2 hours, and was then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated to dryness, to afford the crude title compound, which was used directly without further purification, [LCMS (Method A, Mobile Phase I) RT=4.04 min, MH+ 430].
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:25]5[CH2:28][CH:27]([C:29]([O:31]CC)=[O:30])[CH2:26]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+].C(O)(=O)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:25]5[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CN(C2CCCc3sc(-c4noc(-c5ccc(CC(C)C)cc5)n4)cc32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cc1ccc(-c2nc(-c3cc4c(s3)CCCC4N3CC(C(=O)O)C3)no2)cc1
Yield: 63.2 %

Procedure:
The title compound (26 mg) was synthesized in a yield of 64% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using ethyl 1-{2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzothien-4-yl}-azetidine-3-carboxylate (44 mg, 0.094 mmol) that was obtained in Example 8 (8g), lithium hydroxide monohydrate (8.7 mg, 0.20 mmol), and acetic acid (11 μl, 0.20 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(Cc2nccs2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)N1CC[C@H](N(Cc2nccs2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
A solution of tert-butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](1,3-thiazol-2-ylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.03 g) in DCM (1 ml) was treated with trifluoroacetic acid (1 ml) and stirred at room temperature for 1 h. The solution was then concentrated under reduced pressure to give the title compound (0.019 g) as a colourless solid.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Cl:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].C(N(CC)CC)C.ClCCl.[C:39](OC(=O)C)(=[O:41])[CH3:40]>CN(C)C1C=CN=CC=1.CO>[C:39]([O:28][C:5]1[C:6]([CH2:25][CH2:26][CH3:27])=[C:7]([CH:23]=[CH:24][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Cl:22])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Cl)ccc(C(C)=O)c1O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Cl)ccc(C(C)=O)c1OC(C)=O
Reaction time: 1.33 h

Procedure:
To a solution of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-chlorobenzoic acid (1.0 g), which was prepared by the manner described in European Patent Application Publication No. 80,371, triethylamine (4.6 ml), 4-dimethylaminopyridine (8 mg) and dichloromethane (6 ml) was added acetic anhydride (3.1 ml) at 5° to 7° C., and the mixture was stirred well for 80 minutes. To the reaction mixture was added dropwise methanol (5 ml) to decompose the excess amount of acetic anhydride. The mixture was subjected to concentration, the residual oily product was poured into ice-water, and the precipitate was collected by filtration. Recrystallization from ethanol-water gave white crystals of 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-chlorobenzoic acid 975 mg). M.p. 146°-148° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[C:18]2[S:22][C:21](=[S:23])[NH:20][C:19]2=[O:24])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].IC.[CH:27](N(C(C)C)CC)(C)C.O>C(O)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([C:16](=[C:18]2[S:22][C:21]([S:23][CH3:27])=[N:20][C:19]2=[O:24])[CH3:17])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(=C1SC(=S)NC1=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O
Solvent: CI
Product: CSC1=NC(=O)C(=C(C)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
A mixture of 5-[1-[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]ethylidene]-2-thioxo-4-thiazolone (1.6 g, 4 mmoles), iodomethane (0.45 mL, 7 mmoles), and diisopropylethylamine (1.1 mL, 6 mmoles) in 20 mL of ethanol is stirred under N2 at room temperature for 16 hours, then stirred into 200 mL of water. The precipitate is filtered off, rinsed with water, and dried to afford the product (1.4 g) of 5-[1-[3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl]-ethylidene]-2-(methylthio)-4(5H)-thiazolone, mp 206°-209° C. A sample recrystallized from acetonitrile was analytically pure, mp 224°-226° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH2:10][NH:11][C:12]#[N:13])(=[O:5])[CH3:4].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C1C=CC=CC=1>[C:3]([O:6][CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH2:10][N:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:12]#[N:13])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(C)CCCCCBr
Reactant: CCCCCC(CCCNC#N)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(CCCN(C#N)CCCCCC(C)C(=O)OCC)OC(C)=O
Reaction time: 1 h

Procedure:
A stirred suspension of sodium hydride (57% in mineral oil) (5.0 g., excess) in a solvent mixture of benzene (75 ml.) and dimethylformide (75 ml.) is treated, over 30 minutes, with 4-acetoxynonylcyanamide (22.6 g., 0.1 mole) (Example O, Step 5) dissolved in benzene (20 ml.). Stirring is continued for one hour. Then, ethyl 7-bromo-2-methylheptanoate (Example L, Step 4) (25.3 g., 0.1 mole) is added dropwise, and the reaction is heated on the steam bath for 3.5 hours. The cooled reaction is poured into water (400 ml.) and extracted with ethyl acetate (2 × 200 ml.). The organic fractions are combined, washed with brine, then dried over sodium sulfate. The solvent is removed in vacuo to give ethyl 7-[N-(4-acetoxynonyl)cyanamido]-2-methylheptanoate as a pale yellow liquid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[C:15](=[O:16])[N:14]2[CH:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][CH2:19][CH2:20][N:13]2[C:12](=[O:28])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.C(Cl)Cl>CCOC(C)=O>[C:1]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]2[C@H:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:18][CH2:19][CH2:20][N:13]2[C:12](=[O:28])[CH2:11][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)C1CCCN2C(=O)CCC(N)C(=O)N12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)OC(C)(C)C)N2C1=O
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Acetic anhydride (307 mg, 3.01 mmol) was added to a stirred mixture of t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 813.7 mg, 2.74 mmol), diisopropylethylamine (884 mg, 6.84 mmol) and CH2Cl2 (20 ml). The mixture was kept for 1 h then diluted with EtOAc, washed with NaHCO3 solution then brine, dried (MgSO4) and concentrated to yield a colourless oil. The product was purified by flash chromatography (0.5-8% MeOH/CH2Cl2) to afford 211c (804 mg, 71%) of colourless powder: mp 162-3° C.; [α]D23−109 (c 1.03, CH2Cl2); IR (KBr) 3358, 2974, 1733, 1693, 1668, 1528, 1462, 1431, 1406, 1371, 1278, 1271, 1250, 1233, 1217, 1154, 1124; 6H NMR (CDCl3) δ 6.32 (1H, d), 5.29-5.25 (1H, m), 4.98-4.85 (1H, m), 4.68-4.58 (1H, m), 3.55-3.39 (1H, m), 2.91-2.66 (2H, m), 2.39-2.18 (2H, m), 2.03 (3H, s), 1.88-1.64 (4H, m), 1.47 (9H, s); Anal. Calcd for C16H25N3O5: C, 56.62; H, 7.43; N, 12.38. Found: C, 56.62; H, 7.43; N, 12.36. MS (+FAB) 340 (M++1, 40%), 284 (100).
Reaction SMILES: [C:1]([CH2:3][CH2:4][OH:5])#[N:2].[CH3:6][O:7][P:8](O)[OH:9].[Cl-].[CH:12]([N-:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:12]([N-:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].[C:1]([CH2:3][CH2:4][O:5][P:8]([OH:9])[O:7][CH3:6])#[N:2]
Reactant: N#CCCO
Reactant: COP(O)O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COP(O)OCCC#N

Procedure:
0.68 ml (10 mmol) of 2-cyanoethanol are reacted analogously to Example 2 with 2 ml (11 mmol) of phosphorous acid methyl ester-diisopropylamide-chloride in the presence of 8 ml of diisopropylethylamine in 20 ml of freshly distilled methylene chloride. Drying at 30° C. in a high vacuum gives 2.5 g of an oil which, according to 31P-NMR, contains 94% of the compound VIII. ##STR15##
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[CH3:20])[O:21][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1C
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Oc2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
Ethyl 4-bromobenzoate (2.5 mmol), 3,4-dimethylphenol (3.5 or 5.0 mmol), molecular sieves (625 mg), Cs2CO3 (3.5 or 5.0 mmol), (CuOTf)2.PhH (0.0625 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), and toluene (2.0 mL) were added to an oven-dried test tube which was then sealed with a septum, purged with argon, and heated to 110 C under argon until the aryl halide was consumed as determined by GC analysis. The reaction mixture was then allowed to cool to room temperature, diluted with Et2O and washed sequentially with 5% aqueous NaOH, water and brine. The organic layer was dried over Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (1% Et2O/pentane) gave the analytically pure product as a clear oil (425 mg, 63% yield). 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=8.6 Hz, 2H), 7.12 (d, J 8.0 Hz, 1H), 6.95 (d, J=8.6 Hz, 2H), 6.85 (d, J=2.4 Hz, 1H), 6.79 (dd, J=8.0 Hz, 2.3 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 2.25 (s, 6H), 1.37 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1, 162.2, 153.3, 138.5, 132.8, 131.5, 130.8, 124.4, 121.3, 117.4, 116.8, 60.7, 19.9, 19.1, 14.3; IR (neat): 2978, 2931, 1713, 1595, 1495, 1367, 1261, 1226, 1161, 1102 cm−1. Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.77; H, 6.67.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:23](O)=[O:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3]1.[CH2:26]([NH2:29])[CH:27]=[CH2:28].C(N(CC)CC)C.C(Cl)CCl.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:26]([NH:29][C:23]([C:15]1[S:14][C:6]2[N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2](=[O:1])[CH:3]=[CH:4][C:5]=2[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:24])[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C=CCNC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a stirred solution of the compound of Example 59 (174 mg, 0.5 mmol) in dry DCM (5 mL) was added allyl amine (29 mg, 0.5 mmol), triethylamine (101 mg, 1 mmol), and a catalytic amount of 4-dimethylaminopyridine followed by EDC (96 mg, 0.5 mmol). The reaction mixture was stirred at r.t. for 4 h and then poured into 2M HCl(aq) (20 mL). The product was extracted with DCM (2×20 mL) and the combined organic fractions dried (MgSO4), filtered and the solvent removed in vacuo. Purification by radial chromatography (silica, EtOAc) gave the title compound as a solid (70 mg). δH (CDCl3) 7.7–7.1 (11H, m), 4.48 (1H, d, J 10 Hz), 5.6–5.4 (1H, m), 5.28 (1H, bs), 4.84 (1H, dd, J 10, 1 Hz), 4.69 (1H, dd, J 10, 1 Hz), 3.8–3.6 (2H, m). LCMS (ES+) 387 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18](C)(C)C)=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[CH3:22][O-:23].[Na+].Cl>O1CCCC1.CO>[CH3:22][O:23][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(C)(C)c1ccc(-c2ccc(-c3ccc(Br)s3)s2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(-c3ccc(C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
A solution of 1.5 grams (0.004 mole) of 5'-bromo-5-(4-methylphenyl) [2,2'-bithienyl] (prepared as in Example 64) in 25 ml of dry tetrahydrofuran was stirred, and 0.24 gram (0.0044 mole) of sodium methoxide in methanol was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for three hours, then was heated under reflux for 16 hours. The reaction mixture was cooled and 50 ml of aqueous 10% hydrochloric acid was added. The mixture was extracted with methylene chloride and the extract dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with 25% methylene chloride in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.6 gram of 5'-methoxy-5-(4-methylphenyl)[2,2'-bithienyl], m.p. 108°-111° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]([CH2:33][N:31]([CH3:32])[CH3:30])=[CH:35][CH:36]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(B(O)O)cc1
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: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 29 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (4-((dimethylamino) methyl)phenyl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.065 g, 29% yield). LCMS: 515.40 (M+1)+; HPLC % 96.73 (@ 254 nm) (Rt; 4.362; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.16 (t, 1H), 7.64 (d, 2H, J=6.8 Hz), 7.45 (d, 2H), 7.30 (s, 1H), 7.16 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 2.75 (t, 1H), 2.65 (s, 3H), 2.32-2.42 (m, 6H), 2.20 (s, 6H), 2.10 (s, 3H), 1.69 (m, 4H), 1.53-1.56 (m, 1H), 1.42-1.45 (m, 2H), 1.10-1.23 (m, 4H). [1H merged in solvent peak].
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH:16](=O)[CH3:17].[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:20].[Na+]>CO.C(Cl)Cl>[CH2:19]([N:1]([CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:16][CH3:17])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1CN
Reactant: CC=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)C[C@H]1COCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (S)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (1.0 g, 4.62 mmol) in MeOH (15 ml) was treated with acetaldehyde (0.204 g, 4.62 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and sodium triacetoxyborohydride (2.450 g, 11.56 mmol) was added all at once. The resulting mixture was stirred for 24 h and the mixture was diluted with DCM (15 ml) and washed with saturated aq. sodium bicarbonate (15 ml). The organic phase dried over sodium sulfate, filtered, and concentrated under pressure to give a residue which was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→20% MeOH in DCM) to give (S)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (INTERMEDIATE 86, STEP 1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.O[C:16]1[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.ClC1C=C(O)C=NC=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][O:1][C:16]2[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: Oc1cncc(Cl)c1
Product: CCOC(=O)c1ncccc1OCC1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 29 using tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate and ethyl 3-hydroxypicolinate instead of (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate and 5-chloropyridin-3-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:39][C:35]([CH3:38])([CH3:34])[CH2:36][CH3:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: CCC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.09 g of the compound obtained in EXAMPLE 13, 1 ml of 1,1-dimethylpropylamine, 1.2 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 2 hours at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl, with a 1N solution of NaOH and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (99/1; v/v) as the eluent to give 0.88 g of the expected product in the form of white crystals. M.p.=219° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=1[O:16][CH3:17].[CH3:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1>CN(C=O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:8]=1[N:22]1[CH:23]=[C:19]([CH3:18])[N:20]=[CH:21]1)[CH:12]=[O:13].[CH3:17][O:16][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:8]=1[N:20]1[C:19]([CH3:18])=[CH:23][N:22]=[CH:21]1)[CH:12]=[O:13]
Reactant: Cc1c[nH]cn1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-n1cnc(C)c1
Product: COc1cc(C=O)ccc1-n1cncc1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (4.05 g) was added to a DMF (50 mL) solution of 4-fluoro-3-methoxybenzaldehyde (3.00 g) and 4-methylimidazole (3.307 g), and the reaction liquid was stirred overnight at 100° C. The resultant reaction mixture was concentrated under reduced pressure, followed by adding water and ethyl acetate to the residue to separate an organic layer. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (elution solvent: a hexane-ethyl acetate system) to provide 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (856 mg) and 3-methoxy-4-(5-methyl-1H-imidazol-1-yl)benzaldehyde (44 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[C:33]=1[Cl:34])[C:29]#[N:30]>>[Cl:34][C:33]1[C:32]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[NH:25][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Reactant: CN1CCN(CCCc2cc(C#N)cc(N)c2Cl)CC1
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(CCCN3CCN(C)CC3)c2Cl)nn2c(C#N)cnc12

Procedure:
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was prepared from 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile and 3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile using the procedure described in Example 577D.