Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]([CH2:24][N:25]2[N:53]=[C:29]3[CH2:30][C:31](=O)[C:32]4[CH2:33][S:34][N:35]=[C:36]([N:37](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:27]([C:28]=43)=[N:26]2)[C:18]=1[CH3:54].ClC(Cl)C.[CH:59]1([NH2:63])[CH2:62][CH2:61][CH2:60]1.[OH-].[Na+]>CO.C(O)(=O)C>[CH:59]1([NH:63][CH:31]2[C:32]3[CH2:33][S:34][N:35]=[C:36]([NH2:37])[C:27]4=[N:26][N:25]([CH2:24][C:19]5[C:18]([CH3:54])=[C:17]([O:16][CH3:15])[C:22]([CH3:23])=[CH:21][N:20]=5)[N:53]=[C:29]([C:28]=34)[CH2:30]2)[CH2:62][CH2:61][CH2:60]1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: COc1c(C)cnc(CN2N=C3CC(NC4CCC4)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Sodium triacetoxyborohydride (16 mg) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (34 mg), dichloroethane (0.7 ml), cyclobutylamine (15 μl) and acetic acid (10 μl), and the mixture was stirred at room temperature overnight. Methanol (three drops) was added dropwise to the reaction mixture, and then a 1 N sodium hydroxide solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography. The resulting oil was dissolved in dioxane, followed by lyophilization to obtain the title compound (6.3 mg, 25%) as a colorless amorphous.
Reaction SMILES: [OH:1][CH:2]([C:9]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[S:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O.O.C(OCC)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:2]([C:9]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)[S:11][N:10]=1)(=[O:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC(c1ccccc1)c1nsc(N2CCN(c3ccccn3)CC2)n1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1nsc(N2CCN(c3ccccn3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To an ice-cooled suspension of 3-(1-hydroxy- 1-phenylmethyl)-5-[1-(2-pyridyl)piperazin-4-yl]-1,2,4-thiadiazole (0.625 g, 1.77 mmol) in acetone was added dropwise over a period of ca. 10 min a solution of chromium trioxide (0.15 g, 1.5 mmol) dissolved in water (12 mL) and conc. sulfuric acid (0.33 mL). The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), then made basic (pH ca. 10) by the addition of 3N sodium hydroxide solution. The organic layer was collected, washed with water, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent gradient of a mixture of hexane and ethyl acetate (6/4 and 4/6) afforded the title compound (390 mg, 75.3%) as a light yellow solid. The starting material (101 mg, 16.2%) was also recovered. M.p. 109.5-111.0° C.; 1H-NMR (CDCl3) δ8.23-8.26 (m, 3H), 7.50-7.63 (m, 4H), 6.73-6.74 (m, 2H), 3.79 (m, 8H, 4CH2); MS m/z 352 (M+ +1), 309, 258, 232, 204,147, 121,104, 77.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:34][O:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=1)=[O:37].[NH4+].[Cl-]>C1COCC1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:18]([CH:19]([CH2:20][CH2:21][CH3:22])[CH2:44][C:41]1[CH:42]=[CH:43][C:38]([C:36]([O:35][CH3:34])=[O:37])=[CH:39][CH:40]=1)=[O:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCC(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a cooled (−78° C.) solution of the title compound of Example 3 Step B (1.50 g, 4.61 mmol) in THF (20 mL) was added KHMDS (13.8 mL, 0.5 M in toluene, 6.90 mmol). After 25 min, a solution of methyl 4-bromomethyl benzoate (1.27 g, 5.54 mmol) in THF (5 mL) was added, and the resultant mixture was allowed to warm slowly to room temperature over 4 h. The reaction mixture was then poured into sat. aq. NH4Cl, and the aqueous phase was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo: LCMS A, tr=4.52 min, m/z 474.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J=8.0 Hz, 2 h), 7.64-7.63 (m, 1H), 7.27-7.25 (m, 3H), 7.22-7.19 (m, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.14 (s, 1H), 5.80 (ABq, J=16.0 Hz, Δν=61.8 Hz, 2H), 3.87 (s, 3H), 3.63-3.59 (m, 1H), 3.07 (dd, J=13.5, 8.5 Hz, 1H), 2.77 (dd, J=13.5, 6.0 Hz, 1H), 1.74-1.69 (m, 1H), 1.53-1.45 (m, 1H), 1.23-1.18 (m, 2H), 0.82 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.O1CCCC1>[C:1]([C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:2]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CC#N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(C#N)(CC(=O)OC)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of tert-butyl cyanoacetate (10.0 g) in toluene (100 mL), sodium hydride (60% dispersion in mineral oil, 2.83 g) was added under cooling with ice. After being stirred at 80° C. for an hour, the mixture was cooled to 50° C. and methyl bromoacetate (6.51 mL) was added slowly. After adding tetrahydrofuran (15 mL), the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled with ice and then sodium hydride (60% dispersion in mineral oil, 2.83 g) was added. After being stirred at 80° C. for an hour, the mixture was cooled to 50° C. and then methyl bromoacetate (6.51 mL) was added slowly. Subsequently, tetrahydrofuran (15 mL) was added and the mixture was stirred at 80° C. for two hours. After the reaction mixture to room temperature, a saturated aqueous solution of ammonium chloride and water were added and extraction was conducted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated brine successively and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-40:60) to give 2-tert-butyl 1,3-dimethyl 2-cyanopropane-1,2,3-tricarboxylate as a pale yellow oil (17.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:9]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[N:9]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2F)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2F)nc1-c1ccc(C)cc1
Yield: 9 %

Procedure:
This compound was prepared according to general method D from methyl 2-(2-(2-fluorophenyl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.069 g; 0.176 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.006 g (9%) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH2:3]1>CO>[O:1]=[S:2]1(=[O:22])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(C2=CCS(=O)(=O)c3ccccc32)cc1
Solvent: CO
Product: COC(=O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Reaction time: 6 h
Yield: 73 %

Procedure:
Methyl 4-(1,1-dioxido-2H-1-benzothiopyran-4-yl)benzoate from reaction 33c (0.64 g, 2.13 mmol) was dissolved in methanol (30 mL), degassed with nitrogen, 5% Pd/C was added and the reaction was charged to 55 PSI hydrogen. The reaction was shaken for 6 h. The catalyst was removed over Celite and the filtrate was concentrated to give methyl 4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoate (0.49 g, 73%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: Oc1ccccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Clc1ccccc1OCCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a sol. of 3-(4-bromophenyl)propan-1-ol (Glover S. A., et al.; Tetrahearon, 1990, 46, 7247; 24.5 g, 0.114 mol) in toluene (600 mL) under nitrogen were added 2-chlorophenol (17.4 mL, 0.171 mmol), diisopropyl azodicarboxylate (33.1 mL, 0.171 mol) and tri-n-butylphosphine (42.2 mL, 0.171 mol). The sol. was heated to reflux and stirred under reflux overnight. The sol. was allowed to cool to rt and the solvents were removed under reduced pressure. The residue was diluted in EtOAc and washed with aq. 1M HCl (1×) and aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (petroleum ether→Et2O/petroleum ether 1:99→1:19) led to the tide compound (15.1 g, 41%). Rf=0.70 (EtOAc/heptane 1:3).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([NH:19][N:20]1[C:29]([OH:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:37])[CH:27]=2)[N:22]=[CH:21]1)=O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>C(O)(=O)C>[Cl:37][C:26]1[CH:25]=[CH:24][C:23]([N:22]2[CH:21]=[N:20][N:19]=[C:17]2[CH2:16][NH:15][C:13](=[O:14])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[C:28]([CH:27]=1)[C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:36]
Reactant: O=C(CNC(=O)OCc1ccccc1)NCC(=O)NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(CNC(=O)OCc1ccccc1)NCc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 35.6 %

Procedure:
A solution of 3-(Nα -carbobenzoxyglycyl-glycylamino)-4-hydroxy-4-phenyl-6-chloro-3,4-dihydroquinazoline (1.5 g) in acetic acid (20 ml) is refluxed with heating for 2 hours. The reaction mixture is evaporated under reduced pressure, and the residue is dissolved in ethyl acetate (30 ml). The ethyl acetate layer is washed with aqueous sodium bicarbonate and water in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate/methanol to give 5-chloro-2-[3-(N-carbobenzoxyglycyl)aminomethyl-4H-1,2,4-triazol-4-yl]-benzophenone as a colorless oil (0.515 g).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(NC(C)=O)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (from Combi-Blocks). LCMS calculated for C23H24N5O3(M+H)+: m/z=418.2. Found 418.1.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH3:1][C:2]1[N:6]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)n[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C=O)nn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 5-methyl-1H-pyrazole-3-carbaldehyde (Werner A. et al., Tetrahedron, 51, 4779 (1995): 1.1 g) in acetonitrile (20 mL), triethylamine (1.5 mL) and chlorotriphenylmethane (3.1 g) were added and mixed for 12 hours. The reaction solution was concentrated, and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (1.9 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:17])[CH:11]=2)[CH:6]=1.F[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1.COC(=O)C(=CC1C=CC(F)=CC=1)CC(O)=O>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:17])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(O)c1C
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(Oc2ccc(S(C)(=O)=O)cc2)c1C
Yield: 33.4 %

Procedure:
Starting with (6-chloro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (132 mg, 0.5 mmol) and 1-fluoro-4-methanesulfonyl-benzene (174 mg, 1.0 mmol), using a method analogous to the one described for the methyl ester of example 1-1, [6-chloro-4-(4-methanesulfonyl-phenoxy)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (70 mg, 33%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[C:28]([C:33]#[N:34])[CH:27]=4)[CH2:21][OH:22])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH2:21][OH:22])[CH2:23][C:24]3[N:25]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[C:28]([C:33]#[N:34])[CH:27]=4)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(CO)Cc3cc4ccc(C#N)cc4[nH]3)cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC(CO)c2ccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)cc2)cc2ccc(C#N)cc21
Reaction time: 0.33 h

Procedure:
2.0 g of 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propanol was dissolved in 30 ml of N,N-dimethylformamide. 280 mg of 60% sodium hydride was added to the above solution while stirring under ice cooling, and the stirring was continued for 20 minutes at the same temperature. The resulting reaction solution was mixed with 0.5 ml of ethyl bromoacetate, and the mixture was stirred for 1 hour. The thus treated reaction solution was mixed with an aqueous solution of ammonium chloride, extracted with a toluene/ethyl acetate mixture, washed with water, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a dichloromethane/acetone mixture as an elution solvent. In this way, 1.5 g of the title compound was obtained in a viscous and oily form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45].CO>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][C:40]3=[O:45])=[O:21])[C:10]([C:23]3[C:24]([O:29][CH2:30][CH3:31])=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCOc1ncccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (100 mg, 0.211 mmol) in methylene chloride (3 mL) at room temperature were added triethylamine (88 uL) and 2-piperazinone (31.7 mg, 0.317 mmol, Tyger Scientific), respectively. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by thin layer chromatography (silica gel, 15% methanol in ethyl acetate). The reaction mixture was concentrated to dryness, and the crude residue was purified by high performance liquid chromatography (C18-silica gel, eluting with a gradient of 5-95% acetonitrile in water) to give cis-4-[(4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one as white solid (98 mg, 86%). HR-MS (ES, m/z) calculated for C27H26N5O3Cl2[(M+H)+] 538.1407, observed 538.1408.
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:30]1[C:31](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:32][C:33]([CH3:37])([CH3:36])[C:34]=1[CH3:35])#[N:29].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:35][C:34]3[C:33]([CH3:36])([CH3:37])[O:32][C:31](=[C:38]([C:39]#[N:40])[C:41]#[N:42])[C:30]=3[C:28]#[N:29])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 92.5 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 500 mg (1.37 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]benzaldehyde and 300 mg (1.51 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 106 mg of ammonium acetate, and the mixture was stirred at room temperature for 23 hours. The solvent was evaporated off in a reduced pressure. The residue was washed with ethanol and then purified by silica gel column chromatography. The crystal was washed with ethanol to give 693 mg of a black powder (yield: 92.6%; mp: 258-260° C.)
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]#[N:18])=[CH:10][C:9]=2[N+:19]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Sn]Cl.[CH2:25](O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)=O>[NH2:14][C:13]1[C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:25]=[N:19][C:9]=2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(Nc2ccccc2)c([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1cc(N)c2c(c1)ncn2-c1ccccc1
Yield: 64 %

Procedure:
To a stirred suspension of N-phenyl- 4-cyano-2,6-dinitroaniline (16.4 g, 57.8 mmol) and SnCl2, 2H2O (130.5 g, 0.58 mol) in abs. ethanol (300 ml) was added formic acid (90 ml) dropwise at ambient temperature. The reaction is exothermic. The reaction was allowed to proceed at ambient conditions overnight. The resultant mixture was rendered alkaline by addition of saturated, aqueous sodium carbonate and was filtered through Celite. The filtrate was extracted with dichloromethane. The organic extract was dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in cold ethyl acetate to leave the title product (8.65 g, 64%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[NH3:17]>CO>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:17])[CH:3]=1
Reactant: N
Reactant: CN(C)CCc1ccc([N+](=O)[O-])c(F)c1
Agent: [OH-]
Solvent: CO
Product: CN(C)CCc1ccc([N+](=O)[O-])c(N)c1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of [2-(3-fluoro-4-nitro-phenyl)-ethyl]-dimethyl-amine (800 g, 3.76 mmol) in MeOH (20 mL) was added ammonia hydroxide (5 mL). The reaction mixture was heated at 100° C. under microwave heating for 1.5 hours. The resulting yellow solid was collected and washed with water, dried under vacuum and combined with a previous batch to give the pure title compound (560 mg, yield: 55%). MS (ESI): 210 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2I.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a 500 ml round bottom flask equipped with a magnetic stir bar was added tert-butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate (6.00 g, 14.2 mmol), followed by the additions of 4-pyridineboronic acid (1.92 g, 15.6 mmol), PdCl2(dppf) (1.16 g, 1.4 mmol) and K3PO4 (9.03 g, 42.5 mmol). The mixture was dissolved in a mixture of 160 ml of dioxane and 40 ml of H2O and stirred overnight at 80° C. Upon completion, the reaction mixture was filtered through celite and washed with water (3×100 ml). The organic phase was then dried over anhydrous MgSO4, filtered and concentrated to dryness to give a crude product. The crude product was column purified to give 5-bromo-3-(pyridin-4-yl)-1H-indazole (2.74 g) as a de-BOc product.