Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]#[N:13].[C:14](=O)([O:22]C1C=CC=CC=1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1>[C:12]([CH:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[C:14]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])#[N:13]
Reactant: COc1ccccc1CC#N
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C(C#N)C(=O)Oc1ccccc1
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a slurry of sodium hydride (3.39 g of 60% in mineral oil, 84.9 mmol) in tetrahydrofuran (200 mL) at room temperature was added 2-(2-methoxyphenyl)acetonitrile (10.0 g, 67.9 mmol) dropwise. The reaction mixture was then heated to reflux and the gray suspension turned dark red over 30 min. Diphenyl carbonate (18.2 g, 84.9 mmol) was added portionwise, and the reaction suspension was heated at reflux for an additional 18 h. The reaction mixture was cooled, poured into 1 N HCl (200 mL) and extracted with ethyl acetate (3×200 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated onto Celite® under reduced pressure. The resultant residue was purified by chromatography on silica gel using 10-90% ethyl acetate/hexane as eluant to give the title compound as a light yellow solid (14.3 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]([CH2:14][CH2:15][NH2:16])([CH3:13])[CH3:12]>C(O)C>[CH3:12][N:11]([CH3:13])[CH2:14][CH2:15][NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN(C)CCN
Solvent: CCO
Product: CN(C)CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 61 %

Procedure:
A solution of 2-chloro-3-nitropyridine (1.76 g, 20.0 mmol) in ethanol is treated with Me2NCH2CH2NH2 (3.17 g, 20.0 mmol), stirred at ambient temperature for 17 h, heated to reflux temperature for 7 h, cooled to room temperature and concentrated in vacuo. The resulting solid residue is triturated with ethanol and suction filtered. The filtercake is air-dried to give the title compound as a yellow solid, 3.20 g (61% yield), mp 202-203° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([C:23]3[N:16]4[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=5)=[N:15]4)=[C:20]([CH3:21])[N:22]=3)=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4[nH]ccc4c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc5[nH]ccc5c4)n3n2)cc(OC)c1OC
Yield: 37.5 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-5-carboxamide (Intermediate 38) (176 mg, 0.39 mmol), and 1,2,4-triazole (161 mg, 2.34 mmol) in pyridine (4 mL) and phosphorous oxychloride (0.11 mL, 1.2 mmol) gave 7-(1H-indol-5-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (63 mg, 37%) as a yellow solid. 1H NMR (CDCl3): δ8.87 (s, 1H), 8.79 (s, 1H), 8.35 (s, 1H), 8.29 (dd, J=8.61 and 1.46 Hz, 1H), 7.47 (d, J=8.61 Hz, 1H), 6.95 (s, 2H), 6.84 (s, 1H), 6.62 (s, 1H), 3.87 (s, 3H), 3.77 (s, 6H), 2.64 (s, 3H). MS m/z 430 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=O)=[C:4]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[CH:15][CH:14]=2)[CH:3]=1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>O>[Cl:26][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=2)[N:12]=[C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[CH:15][C:14]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccnn1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cc2nc3c(cnn3-c3ccccn3)c(Cl)c2cc1F
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of 4,5-difluoro-2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (7.00 g, 22.1 mmol) in phosphorous oxychloride (10.3 mL, 111 mmol) was heated under reflux for 1 hour. The solution was allowed to cool to room temperature, and poured into iced water. After neutralization by addition of a sodium hydroxide solution, the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (3.99 g, 57% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C:18]([CH3:17])([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC1(O)CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(O)CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 4-bromobenzyl bromide (0.50 g, 2.0 mmol), triethylamine (0.42 mL, 3.0 mmol) and 3-methyl-piperidin-3-ol (0.46 g, 4.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The reaction mixture was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (0.50 g, 88%). 1H NMR (CDCl3, 300 MHz): 7.49-7.43 (m, 2H), 7.23-7.15 (m, 2H), 3.78 (s, 2H), 3.69-3.59 (m, 2H), 2.63-2.51 (m, 2H), 2.14 (br s, 1H), 1.77-1.49 (m, 4H), 1.15 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]COCCOC)[CH:6]=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[C:23](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COCCOCOc1ccc(C=O)cc1OC
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1cc(/C=C(\C#N)c2ccc(OC)c(OC)c2)ccc1O
Yield: 48.2 %

Procedure:
The hydroxyl group of 4-hydroxy-3-methoxybenzaldehyde (1.4 g) was protected by use of 2-methoxyethoxymethyl chloride (1.7 g) in accordance with (production process 1), to thereby produce 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g, yield: 31%). The thus-produced 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g) and 3,4-dimethoxybenzyl cyanide (0.6 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (0.5 g, yield: 51%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[CH:1]1([CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(O)CC(=O)O
Reactant: C1=NCCc2ccccc21
Product: O=C(O)CC1NCCc2ccccc21
Temperature: 120 °C
Yield: 47.6 %

Procedure:
3,4-Dihydroisoquinoline (147) (2.2 g, 16.77 mmol) and malonic acid (1.94 g, 16.77 mmol) were mixed at room temperature and heated at 120° C. for 1 hour in an oil bath. The mixture was then allowed to cool to room temperature, and the product was recrystallised from methanol (150 ml). Drying gave a colourless solid (1.52 g, 7.99 mmol, 48%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCOC(C)=O.CCCCCC>[C:26]1([C:4]2[CH:3]=[C:2]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:25])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccccc2)cc1C1=CCCCC1
Yield: 85 %

Procedure:
The title compound was prepared by the procedure of Example 28, step (a) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the Example 11, step (f), 19 mg, 0.038 mmol), and phenylboronic acid (5.1 mg, 0.042 mmol). Silica gel chromatography (5-10% EtOAc/hexane) afforded the title compound (16 mg, 85%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.5 Hz), 7.78 (s, 1H), 7.59 (m, 2H), 7.52 (dd, 1H, J=8.5, 2.1 Hz), 7.44 (m, 2H), 7.41 (d, 1H, J=2.1 Hz), 7.33 (m, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.67 (t, 2H, J=8.3 Hz), 2.26-2.36 (m, 4H), 1.75-1.93 (m, 4H), 0.98 (t, 2H, J=8.3 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C29H34N4O2Si, 499.3 (M+H), found 498.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:28]3[CH2:27][CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCN1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCN1CCCCC1
Reaction time: 10 h
Yield: 88.8 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 250 ml of toluene, 4.05 ml (0.0305 mol) of 2-piperidinoethylamine and 0.13 g of p-toluenesulphonic acid monohydrate were added thereto and the mixture was boiled for 4 hours on a water separator. After concentration the residue was hydrogenated with 1.3 g of Raney-nickel in 500 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with CH2Cl2 /MeOH 49:1. There were obtained 4.45 g (89%) of oily rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(2-piperidinoethyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[CH3:35].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([O:27][C:18]3[C:17]4[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=4)[N:21]=[CH:20][CH:19]=3)=[C:29]([CH3:35])[CH:30]=2)=[S:12])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 64%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:28]=[C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:1]([C:3]2[N:4]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1

Procedure:
tert-Butyl 3-[(2-cyano-6-pyridyl)]methoxypropanoate (2.62 g, 10 mmol) and methyl thiosalicylate (1.85 g, 11 mmol) were dissolved in toluene (30 ml), and triethylamine (1.70 ml, 12 mmol) were added thereto. The reaction mixture was refluxed under nitrogen atmosphere for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The titled compound (2.92 g, 71%) was given from the fraction eluted with ethyl acetate-hexane (1:2, v/v) and recrystallized from ethyl acetate-isopropyl ether.
Reaction SMILES: C([BH-](CCCCC)CCCCC)CCCC.[K+].C1COCC1.[CH3:23][C:24](=[O:45])[C@@H:25]1[C@:42]2([CH3:43])[C@H:28]([C@H:29]3[C@H:39]([CH2:40][CH2:41]2)[C@:37]2([CH3:38])[C@H:32]([CH2:33][C:34](=[O:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[OH:44][C@@H:34]1[CH2:35][CH2:36][C@@:37]2([CH3:38])[C@@H:32]([CH2:31][CH2:30][C@@H:29]3[C@@H:39]2[CH2:40][CH2:41][C@@:42]2([CH3:43])[C@H:28]3[CH2:27][CH2:26][C@@H:25]2[C:24](=[O:45])[CH3:23])[CH2:33]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCCC[BH-](CCCCC)CCCCC
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
The reaction was carried out under a dry N2 atmosphere. Potassium trisamylborohydride solution (KS-Selectide) in THF (6cc, 5.83 mmol) was introduced into a three neck round bottom flask and cooled to 0° C. 5α-Pregnan-3,20-dione (1.58 g, 5 mmol) dissolved in 10 ml of anhydrous chloroform was added to the cooled reducing agent. The resulting mixture was stirred vigorously for 2 hours at 0° C. and then allowed to equilibrate to room temperature for 1 hour. The reaction was quenched with 3 ml of water and 7 ml of ethanol. The organoborane was oxidized with 5 ml of 6M NaOH and 7 ml of 30% H2O2. The reaction mixture was saturated with anhydrous potassium carbonate, and the organic layer was separated. The aqueous phase was neutralized with 0.1N HCl and extracted with 20 ml of chloroform twice. The combined organic layers were dried over anhydrous MgSO4 and the solvent removed by rotary evaporation. Acetone was added to effect crystallization to produce a yield of 33%. The product has been identified by co-migration with authentic samples using silica based TLC and capillary GC. Melting point is 174°-175°. Elemental analysis: Calc. C=79.19, H=10.76. Obs. C=78.86, H=10.70, NMR: 200 MHz ppm delta; 0.59 (s)(CH3), 0.77 (s)(CH3). 9-2.0 (m) (CH2), 2.1 (s) (CH3--C=O), 2.5 (t) (17-H), 4.02 (t) (3-H equatorial). The preparation method is a modification of the method shown in Gyermek et al., "Steroids CCCX. Structure-Activity Relationship of Some Steroidal Hypnotic Agents," J. Med. Chem., 11:117-125 (1968).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:25])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[H-].[Na+].[CH3:28]I>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:25][CH3:28])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(OC)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.1 %

Procedure:
To a solution of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (350 mg, 0.930 mmol) in N,N-dimethylformamide (3.0 mL) was added sodium hydride (60% in oil, 44.8 mg, 1.12 mmol), and the mixture was stirred at room temperature for 5 min. To the mixture was added methyl iodide (657 mg, 4.65 mmol), and the mixture was stirred at room temperature for 1 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (76.5 mg, 0.196 mmol, 21%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[NH:19][N:20]=[C:21]([CH3:23])[CH:22]=1>>[CH3:23][C:21]1[C:22]2[C:18](=[N:17][C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:8]=2[C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:19][N:20]=1
Reactant: Cc1ccc(C(=O)Cc2ccncc2)cn1
Reactant: Cc1cc(N)[nH]n1
Product: Cc1ccc(-c2nc3[nH]nc(C)c3c(-c3ccc(C)nc3)c2-c2ccncc2)cn1
Yield: 24 %

Procedure:
Following a similar procedure to that described in example 1 method A, but using 1-(6-methylpyridin-3-yl)-2-(4-pyridyl)ethanone (obtained in reference example 13) instead of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone and 3-amino-5-methyl-2H-pyrazole instead of 3-amino-2H-pyrazole, the title compound was obtained (yield: 24%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.0 g (6.51 mmol) of 3-[3-(imidazo-[1,2-a]pyridin-5-ylthio)propyl]thiazolidine-2,4-dione and 0.59 ml (6.51 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.06 ml (0.65 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/4) to yield 1.57 g (66.7%, light orange oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCc1cccs1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNCc1cccs1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-thiophenemethylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:20].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][C:14](=[O:16])[NH:20][C:10](=[O:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: [NH4+]
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CN(Cc2ccccc2)CC(=O)N1
Temperature: 160 °C
Yield: 86.6 %

Procedure:
A suspension of 2,2′-(benzylazanediyl)diacetic acid (5.0 g, 22.4 mmol) and ammonium formate (4.2 g, 67.2 mmol) in N,N-dimethylformamide (75 mL) was stirred to reflux (160° C.) for 2 days. After cooling to room temperature, the reaction mixture was diluted by successive addition of ethyl acetate (150 mL) and a saturated solution of sodium hydrogen carbonate (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL) and the combined organic phases were washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give the title product as a yellow liquid (3.96 g, 87%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([O:21]CC)=O)=[CH:17][N:18]=3)[CH:15]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C[NH:58][C:59]1[CH:64]=[C:63]([C:65]2[N:69]=[C:68]([CH:70]3[CH2:73][C:72]([F:75])([F:74])[CH2:71]3)[O:67][N:66]=2)[CH:62]=[CH:61][C:60]=1[CH3:76]>CN1C(=O)CCC1>[F:75][C:72]1([F:74])[CH2:71][CH:70]([C:68]2[O:67][N:66]=[C:65]([C:63]3[CH:62]=[CH:61][C:60]([CH3:76])=[C:59]([NH:58][C:19]([C:16]4[N:14]5[CH:15]=[C:10]([CH2:9][CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[CH:11]=[CH:12][C:13]5=[N:18][CH:17]=4)=[O:21])[CH:64]=3)[N:69]=2)[CH2:73]1
Reactant: CCOC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Reactant: CNc1cc(-c2noc(C3CC(F)(F)C3)n2)ccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of ethyl 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylate (114) (25 mg, 0.087 mmol) in anhydrous NMP (1 mL) was added HATU (26 mg, 0.104 mmol) and DIEA (23 uL, 0.130 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then, 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (23 mg, 0.087 mmol) was added and the reaction was stirred for two days. The crude product was purified by reverse phase preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (F63). MS m/z 536.3 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 90 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 12.1b) in 2.0 mL acetonitrile is added at RT 63 μL (0.75 mmol) pyrrolidine. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).