Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[NH:7][C:6]=2[C:5]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:4]2[NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=3[C:3]=12.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:4]1[C:5]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:11]([F:15])=[CH:12][C:13]=4[C:14]3=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:3]2=1
Reactant: C1CCNC1
Reactant: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(Br)c2c1[nH]c1ccc(F)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(N2CCCC2)c2c1[nH]c1ccc(F)cc12
Temperature: 200 °C
Yield: 15.1 %

Procedure:
A mixture of 2-(12-bromo-2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (35.2 mg, 0.07681 mmol), pyrrolidine (19.1 μL, 0.2304 mmol), Pd(OAc)2 (5.2 mg, 0.02304 mmol), BINAP (14.3 mg, 0.02304 mmol) and sodium tert-butoxide (22.1 mg, 0.2304 mmol) in toluene (5 mL) was purged with high-purity Ar for five minutes and sealed with Teflon cap. The reaction tube was heated to 200° C. in a Smith Microwave Reactor for 10 minutes. The solvents were removed via vacuum pump. The residue was subjected to flash chromatography to provide the title compound (5.2 mg, 15%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 2H), 7.70 (dd, J=10.0, 2.4 Hz, 2H), 7.47 (dd, J=8.8, 4.8 Hz, 2H), 7.19 (td, J=9.2, 2.4 Hz, 2H), 4.29 (t, J=5.6 Hz, 2H), 3.52-3.45 (m, 4H), 2.72 (t, J=5.6 Hz, 2H), 2.40-2.39 (m, 10H); MS (ESI) m/z 447.2 (M−H)−; MS (ESI) m/z 449.0 (M+H)+
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:35]1[CH:36]=[CH:37][C:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:39][CH:40]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:35]2[CH:36]=[CH:37][C:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:39][CH:40]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C2CC2)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Cyclopropylboronic acid (43.2 mg), tricyclohexylphosphine (10.9 mg), palladium acetate (4.34 mg) and potassium phosphate (288 mg) were added to a mixed solution of tert-butyl 5-bromopyridine-2-carboxylate (100 mg) in toluene (2 mL) and water (100 μL), and the mixture was stirred at 100° C. for nine hours and 30 minutes. After returning to room temperature, water was added to the reaction solution. After extraction with ethyl acetate, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (11.6 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:16](=O)(O)[O-:17].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([N:7]=[C:16]=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccccc1)N=C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To an ice-cold suspension of L-phenylalanine ethyl ester hydrochloride (25.0 g, 109 mmol) in methylene chloride (800 mL) a saturated solution of sodium bicarbonate (800 mL) was added and the mixture was vigorously stirred at 0° C. for 30 minutes. Stirring was stopped to allow the separation of the two layers and a solution of phosgene in toluene (20%, 100 mL, 190 mmol) was added directly into the organic layer. Stirring was resumed while keeping the mixture at 0° C. for one hour and at room temperature for one additional hour. The organic layer was separated, and washed sequentially with water and a saturated solution of sodium chloride, dried with sodium sulphate, filtered and evaporated to yield a colorless oil that slowly solidifies (22.7 g, 95% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14](Cl)=[O:15].CCN(CC)CC>CC#N>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:15])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of indoline (2.0 mL, 17.8 mmol) in MeCN (45.0 mL) was added 3,4-dichlorobenzoyl chloride (4.11 g, 19.6 mmol) followed by Et3N (7.5 mL, 53.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was triturated with water and dried under high vacuum to give the title compound (5.2 g, 100%) as a light brown solid. 1H NMR (DMSO-d6) δ 7.89 (d, J=1.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.19 (m, 1H), 7.06 (t, J=7.2 Hz, 1H), 4.00 (t, J=8.3 Hz, 2H), 3.09 (t, J=8.3 Hz, 2H); MS(ESI+) m/z 292.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][NH:28][C:29]([C:31]1([CH2:44][CH2:45][CH2:46]Br)[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]([F:48])([F:49])[CH2:27][NH:28][C:29]([C:31]1([CH2:44][CH2:45][CH2:46][N:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:11]=[CH:12][C:2]([CH3:1])=[C:3]([CH:9]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17]2)[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30]
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1cc(N2CCNCC2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CCN(CCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)ccc1C
Temperature: 75 °C
Reaction time: 7 h
Yield: 59.4 %

Procedure:
Ethyl 2-methyl-5-piperazinylbenzoate (1.8 g, 9.1 mmol) was dissolved in 20 ml of anhydrous DMF. Potassium carbonate (1.7 g) and 3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl bromide (2.5 g, 6.1 mmol) were added to the solution, and the mixture was stirred at 75° C. for 7 hr. The temperature of the reaction solution was returned to room temperature, and the reaction solution was then diluted with ethyl acetate. The dilution was washed twice with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography (development system, n-hexane:ethyl acetate=2:1) to give 2.1 g (yield 59%) of ethyl 5-[4-[3-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]propyl]piperazinyl]-2-methylbenzoate as a pale yellow foam.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:44][CH:45]([F:47])[F:46])=[C:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:17][N:16]([CH2:31][C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([O:42]C)=[O:41])[CH2:36][CH2:35]3)=[O:33])[N:15]=2)[CH:13]=1.Cl>O.CO>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:44][CH:45]([F:46])[F:47])=[C:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:17][N:16]([CH2:31][C:32]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([OH:42])=[O:41])[CH2:38][CH2:39]3)=[O:33])[N:15]=2)[CH:13]=1
Reactant: COC(=O)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1cn(CC(=O)N2CCC(C(=O)O)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
K2CO3 (500 mg, 3.59 mmol) in H2O (5 mL) was added to methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate (500 mg, 0.85 mmol) in methanol (10 mL). The resulting solution was stirred at 50° C. overnight and acidified with 1 N HCl to pH 2. The solids were collected by filtration. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% MeCN up to 34.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 390 mg (80%) of 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperidine-4-carboxylic acid as a light yellow solid. LCMS (Method 28) [M+H]+=574.1, RT=1.11 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 12.34 (s, 1H), 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.29-5.19 (m, 2H), 4.28-4.18 (m, 1H), 3.87-3.84 (m, 1H), 3.19-3.13 (m, 1H), 2.83-2.77 (m, 1H), 1.86-1.85 (m, 2H), 1.60-1.57 (m, 1H), 1.43-1.41 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6](Cl)=[C:5]([N+:8]([O-:10])=[O:9])[C:4]([CH3:11])=[N:3]1.[C-]#N.[K+].[I-].[K+].[CH3:17][N:18](C=O)C>C(#N)C>[CH3:1][N:2]1[C:6]([C:17]#[N:18])=[C:5]([N+:8]([O-:10])=[O:9])[C:4]([CH3:11])=[N:3]1
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(C)c(C#N)c1[N+](=O)[O-]

Procedure:
Fifty-five g of 1,3-dimethyl-4-nitro-5-chloropyrazole was dissolved in 400 ml acetonitrile and 17.45 g potassium cyanide added, followed by 0.5 g potassium iodide and 5 ml DMF. The mixture was refluxed for 22 hours, then cooled, and filtered. The filtrate was concentrated under reduced pressure, then added to stirred water. The resulting percipitate was collected, dried, and recyrstallized in isopropanol. mp, 85°-87° C. A second recrystallization again in ethanol gave the product having increased purity, mp 96°-98° C.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:32][NH2:33]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:33][CH3:32])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2oc(Cl)cc2c1
Temperature: 85 °C
Yield: 48 %

Procedure:
To a stirred solution of 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)-phenyl)but-1-enyl)phenol (220 mg, 1.0 eq) in 15 mL MeOH was added 5 mL CH3NH2 (aq) and heated at 85° C. for 48 h. The organic solvent was removed in vacuo, water was added to the residue and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (105 mg, 48%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.14 & 7.08 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.87 & 6.78 (d, J=8.8 Hz, 2H), 6.73 & 6.69 (d, J=8.8 Hz, 2H), 6.49 & 6.42 (d, J=8.6 Hz, 2H), 6.45 (s, 1H), 4.10 & 3.92 (t, J=5.0 Hz, 2H), 3.00 & 2.89 (t, J=5.0 Hz, 2H), 2.53 & 2.46 (s, 3H), 2.50 (q, J=7.6 Hz, 2H), 0.91 (t, J=7.6 Hz, 3H); m/z=448[M+1]+.
Reaction SMILES: N1C=CN=C1.Cl.Cl[CH2:8][CH2:9][CH2:10][CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])[C:12](=[NH:16])OCC.Cl.Cl.[CH3:29][O:30][C:31]1[N:36]=[C:35](/[CH:37]=[CH:38]/[C:39]([NH:41][NH2:42])=O)[CH:34]=[CH:33][C:32]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1.Cl>CO>[CH3:29][O:30][C:31]1[N:36]=[C:35](/[CH:37]=[CH:38]/[C:39]2[N:16]=[C:12]3[CH:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:24])([F:25])[F:26])[CH2:10][CH2:9][CH2:8][N:42]3[N:41]=2)[CH:34]=[CH:33][C:32]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1
Reactant: CCOC(=N)C(CCCCl)c1ccccc1C(F)(F)F
Reactant: COc1nc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CO
Product: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Temperature: 30 °C
Reaction time: 40 h
Yield: 86 %

Procedure:
Imidazole (4.75 g, 69.7 mmol) and Ethyl 5-chloro-2-(2-trifluoromethylphenyl)pentanimidoate hydrochloride (2.00 g, 5.81 mmol) were added the solution of (2E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylohydrazide dihydrochloride in methanol (10 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 30° C. for 40 hours. The reaction mixture was adjusted to the pH6.5 with 5N HCl aq., and extracted with ethyl acetate (22 mL). The organic layer was washed with water (4 mL), concentrated under the reduced pressure and azeotroped with 2-propanol under the reduced pressure to obtain the title compound (2.4 g, 86% yield). Traces of seed crystal of the title compound which was obtained by the method similar to this step was added to the solution of the crude title compound in 2-propanol (10 mL), and the mixture was stirred at room temperature for 13.5 hours. The suspension was stirred for 2 hours with an ice-bath cooling. The solids were collected by filtration and washed with 2-propanol and dried under the reduced pressure to obtain the title compound (1.55 g, 56% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>CN1C(=O)CCC1.CO>[OH:21][CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:2]2[C:3]3[N:4]([CH:11]=[CH:12][CH:13]=3)[N:5]=[CH:6][C:7]=2[C:8]([NH2:10])=[O:9])[CH2:16][CH2:17]1
Reactant: NC(=O)c1cnn2cccc2c1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: NC(=O)c1cnn2cccc2c1NC1CCC(O)CC1
Temperature: 80 °C
Yield: 85 %

Procedure:
A solution of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide, Preparation 3 (15 mg, 0.077 mmol) and (trans)-4-aminocyclohexanol (22.08 mg, 0.192 mmol) in NMP (0.3 ml) was heated at 80° C. for 1.5 h. The product mixture was diluted with methanol and purified by preparative HPLC (condition A) to afford the title compound as a white solid (17.8 mg, 85% yield). 1H NMR (400 MHz, MeOD) δ ppm 1.44-1.56 (m, 4 H) 1.97-2.08 (m, 2 H) 2.17-2.28 (m, 2 H) 3.62-3.76 (m, 1 H) 4.03-4.19 (m, 1 H) 6.69 (dd, J=4.52, 2.76 Hz, 1 H) 6.91 (dd, J=4.77, 1.51 Hz, 1 H) 7.56 (dd, J=2.64, 1.63 Hz, 1 H) 8.10 (s, 1 H). HPLC (method F): ret. Time 2.105 min.; LC/MS [m/z, (M+H)] 275.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10](=[O:17])[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].Cl[CH2:19][C:20](=[O:22])[CH3:21].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:7][O:8][CH2:9][C:10](=[O:17])[C:11]([CH2:19][C:20]([CH3:21])=[O:22])([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(=O)CCl
Reactant: COCC(=O)C(C)C(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COCC(=O)C(C)(CC(C)=O)C(=O)OC
Yield: 38.4 %

Procedure:
1.66 g (12 mmol) of potassium carbonate and 0.04 g (0.2 mmol) of benzyltriethylammonium chloride are suspended in 5 ml of acetonitrile. While stirring there are added thereto 1.60 g (10 mmol) of methyl 4-methoxy-2-methylacetoacetate and there are then added dropwise thereto within 15 minutes 1.39 g (15 mmol) of chloroacetone. The mixture is stirred at 20°-25° C. for a further 21 hours. The reaction mixture is poured into 20 ml of 2N HCl (pH value=1) and extracted 3 times with 20 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate and evaporated on a rotary evaporator. The crude product distils at 95° C./0.03 mbar. There results 0.83 g (38.4%) of methyl 4-methoxy-2-acetonyl-2-methylacetoacetate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].OO.C(N(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=[O:18].[Na+].[Na+].[Na+].[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:8][C:7]1[C:6](=[O:18])[CH:5]=[C:4]([CH3:9])[C:3](=[O:10])[C:2]=1[CH3:1]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 84 %

Procedure:
A solution of 13.6 g (100 mmol) of 2,3,6-trimethylphenol in 40 ml of acetic acid and 62.3 g (550 mmol) of 30% by weight aqueous hydrogen peroxide were simultaneously added dropwise to a stirred solution of 0.68 g (2.0 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene, 2.52 g (2.0 mmol) of a 40% by weight aqueous solution of a pentasodiumdiethylenetriaminepentaacetate and 0.5 ml of concentrated sulfuric acid in 50 ml of acetic acid at 40° C. with cooling. The reaction mixture was then subjected to steam distillation. The distillate was extracted by shaking with methylene chloride. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated to a yellow oil, which slowly solidifed. 12.6 g (84%) of 2,3,5-trimethyl-p-benzoquinone were obtained in the form of yellow oily crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC/C=C/c1ccccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCc1ccccc1OC
Yield: 99.2 %

Procedure:
To a solution of ethyl (4E)-5-(2-methoxyphenyl)-4-pentenoate (3.40 g, 14.5 mmol) in a mixture of EtOAc and MeOH (40.0/10.0 mL), Pd/C (palladium on carbon 10%, 0.700 g) was added in small portions to avoid fire. The reaction mixture was then stirred for overnight at room temperature under 300 psi of hydrogen. After the pressure was released, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×50 mL). The filtrate was concentrated in vacuo to afford crude product as a light yellow oil (3.40 g 100%), which was used without further purification.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]([C:11]1[CH:16]=[CH:15][N+:14]([O-])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[C:5]([C:15]1[CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=[CH:13][N:14]=1)#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)c1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To trimethylsilylcyanide (25.0 ml, 187.5 mmol) was added a solution of 4-tert-butylpyridine-N-oxide (Description 3; 22.68 g, 150 mmol) in anhydrous dichloromethane (200 ml). To this mixture was added dropwise a solution of dimethyl carbamoyl chloride (17.26 ml, 187.5 mmol) in anhydrous dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 24 hours. A solution of 10% aqueous K2CO3 (200 ml) was added dropwise and the resulting mixture stirred for 10 minutes. The organic layer was separated and the aqueous layer extracted with 2 further portions of dichloromethane (100 ml). The combined organic layers were dried (Na2SO4) and evaporated to give the title compound (24 g, 100%).
Reaction SMILES: C(C1C(O[SiH](C)C)=CC(CBr)=CC=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]2=[N:18]1)(C)(C)C.CN1C(C)(C)CC(O)CC1(C)C.[H-].[Na+]>CN(C)C=O>[NH:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[N:17]1
Reactant: C[SiH](C)Oc1cc(CBr)cc(-n2nc3ccccc3n2)c1C(C)(C)C
Agent: CN1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]nnc2c1
Temperature: 6 °C

Procedure:
This compound was synthesized strictly under dry and inert reaction conditions. The compound 2-(2′-tert-butyl-di-metylsilyloxy-5′-bromomethylphenyl)benzotriazole (2.1 gms, 0.00501 M) was taken in one 25 mL capacity RB and dissolved in 8 mL dry dimethylformamide (DMF) under Argon atmosphere with stirring. In another two-necked RB, 1,2,2,6,6-pentamethyl-4-piperidinol (1.0356 gm, 0.00601 M) and sodium hydride (0.3 gms, 0.01252 M) were taken and dissolved in 6 mL dry DMF with stirring under Argon atmosphere. This reaction mixture was agitated for almost 60 min and then cooled to 4-8° C. To this reaction mixture the contents of the first RB was added gradually over a period of 30-60 min. This reaction mixture was further agitated for 2-4 hrs followed by refluxing the same for a period of 2-4 hrs. The contents of the RB were cooled to room temperature and further agitated for 4-6 hrs at room temperature. The solvent in the RB was evaporated under reduced pressure and the solid mass in the RB was dissolved in 15 mL water and repeatedly extracted with dichloromethane (4×10 mL). Dichloromethane was then evaporated under vacuum at 38° C. over a rotavapor to give pale yellow colored crystalline product 2-[2′-tert-butyldimetylsilyloxy -5′-methyleneoxy((1″, 2″, 2″, 6″, 6″-pentamethyl-4″-piperidinyl) phenyl )benzotriazole. The TLC showed very little amount of unreacted starting material. The crude yield was 2.22 gms (87%). The product was purified by recrystalization technique using an appropriate organic solvent to get (83%) yield of pure product.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>CN(C=O)C>[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:3]=2)(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine and 1.43 g of 5-isopropyl pyridine-2-sulfonamide potassium salt were suspended in 20 ml of dry DMF. The mixture was stirred under argon at room temperature and became clear within a few h. After 16 h at room temperature, most of the solvent was removed by evaporation under reduced pressure. The residue was taken up in 20 ml water and the pH was adjusted to 4-5 by adding about 1 ml of acetic acid. A precipitate formed. The precipitate was filtered off, washed with water and dried. The yellow powder was further purified by column chromatography on silica gel eluting first with hexane:ethyl acetate 1:1 then with DCM:MeOH 10:1. 1.43 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was obtained as a slightly yellow powder. LC-MS: tR=5.00 min, [M+1]+=512.19, [M−1]−=510.26.