Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[NH+]([O-])=O.[CH3:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27]=3[CH3:28])[N:20]=[C:19]2S)[CH:12]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[CH3:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:27]=3[CH3:28])[N:20]=[CH:19]2)[CH:12]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(-c3cnn(-c4ccccc4)c3C)nc2S)c1
Agent: O=C([O-])O
Agent: O=[NH+][O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1ccc(C)c(-n2cnc(-c3cnn(-c4ccccc4)c3C)c2)c1
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To 1 mL of 20% HNO3 was added 28 mg of HNO2. This mixture was then added to 3-[2-mercapto-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (280 mg, 0.69 mmol) suspended in 5 mL of rapidly stirring HOAc over 15 min. After stirring an additional 5 min, the solution was poured into ice-cold water. The pH was adjusted to about 7 with NaHCO3, and the mixture was extracted with EtOAc. The extract was washed once with brine, dried with Na2SO4, filtered, and concentrated. The resulting residue was chromatographed (5-60% EtOAc in hexanes) to provide 210 mg (0.56 mmol, 82%) of 4-methyl-3-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester. ESI MS m/z 373 [C22H20N4O2+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].O>ClCCl>[Cl:26][CH2:25][CH2:24][CH2:23][CH2:22][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[N:11][C:10]1=[O:13]
Reactant: O=c1ncc(-c2ccccc2)c[nH]1
Reactant: ClCCCCBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1ncc(-c2ccccc2)cn1CCCCCl
Temperature: 60 °C
Yield: 51.9 %

Procedure:
To a suspension of 5-phenyl-2(1H)-pyrimidinone (77 mg, 0.45 mmol, Aurora Screening Library or MDPI Product List or ref Helv. Chim. Acta, 10, 1927, 305//Collect. Czech. Chem. Commun., 61, 3, 1996, 458-477) in dry dichloromethane (4.0 ml), triethylamine (0.062 ml, 0.45 mmol) was added. The reaction mixture was stirred at room temperature for 30′, then 1-bromo-4-chlorobutane (0.052 ml, 0.44 mmol) was added and the reaction mixture was then heated at 40° C. for 24 hours and other 24 hours at 60° C. Water (22 ml) was added to the cold mixture and the organic layers were extracted with DCM (3×10 ml). The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM/methanol 96/4 to afford the title compound (60 mg, 51%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:6]=1)C.[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:4](=[O:3])[C:5]2[CH:6]=[C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[CH:10]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
N-(8-phenyl-octyl)-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.331 g, 74%) from 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester and phenyloctyl amine using a procedure similar to step 2 of Example 1. 1H NMR (CDCl3) δ 7.96-7.50 (m, 10H); 7.35-7.10 (m, 5H); 6.28 (m, 1H); 3.45 (m, 2H); 3.31 (m, 4H); 2.60 (m, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[CH:17]1([C:22](=[O:36])[CH2:23][CH2:24][C:25]#[C:26][C:27]2[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:28]=2[CH3:35])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[CH3:16][O:15][C:9](=[O:14])[CH2:10][C:11](=[O:12])[CH2:13][C:22]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)([OH:36])[CH2:23][CH2:24][C:25]#[C:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:28]=1[CH3:35]
Reactant: COC(=O)CC(C)=O
Reactant: Cc1cc(C#CCCC(=O)C2CCCC2)c(C)cc1O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a freshly prepared solution of LDA (1 M, 2.2 mL, 2.2 mmol) cooled to 0° C. was added methyl acetoacetate (0.12 mL, 1.1 mmol) dissolved in THF (1 mL). After stirring for 30 minutes, 1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one (0.10 g, 0.37 mmol) from Step 1 above dissolved in THF (1 mL) was added. The reaction was stirred for 1 hour, and then warmed to room temperature. After quenching with 10 mL saturated ammonium chloride, the layers were separated. The aqueous layer was extracted with 2×15 mL CH2Cl2, and the organic layers were combined. After drying over Na2SO4, and filtering to remove the solids, the mother liquor was concentrated to an oil. Flash chromatography of the oil gave the desired product (69 mg, 48% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]([N+:20]([O-])=O)=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](N)[CH2:27][CH2:28][CH3:29]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]([NH:20][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCNc1cc2c(cc1[N+](=O)[O-])C1CC2CN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (500 mg, 1.43 mmol) and 1-butylamine (1.42 mL, 14.3 mmol) were combined in THF (5 mL) and stirred 4 hours. The mixture was diluted with EtOAc (50 mL) and washed with H2O (3×30 mL) then dried (Na2SO4), filtered and concentrated to an oil. This oil was passed through a Silica gel filter column to remove baseline impurities eluting with 30% EtOAc/hexanes (510 mg, 1.41 mmol, 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH2:22])=[C:20]([O:28][CH3:29])[CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[F:17][C:18]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2cnn3c2CCCC3)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (Intermediate 128, 3.6857 g, 15.70 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 2.92 g, 15.70 mmol) and p-toluenesulfonic acid hydrate (3.29 g, 17.28 mmol) in 2-pentanol (100 mL) was stirred at 85° C. under an atmosphere of N2 for 1.5 h. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH2Cl2 (250 mL). This solution was washed with sat. NaHCO3 (2×100 mL), water (100 mL), and sat. brine (100 mL). The organic solution was concentrated in vacuo to give crude product. Purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 provided an orange solid. This material was triturated with CH3OH to give a solid which was collected by filtration and dried in vacuo to give the title compound (2.26 g, 37%) as a yellow solid; 1H NMR: 1.75-1.86 (2H, m), 1.92-2.04 (2H, m), 3.09 (2H, t), 4.02 (3H, s), 4.12 (2H, t), 7.13 (1H, d), 7.35 (1H, d), 8.14 (1H, s), 8.25 (1H, s), 8.42 (1H, d), 9.02 (1H, d); m/z: ES+ MH+ 385.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCOCC1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridin-2-yl-morpholin-4-yl-methanone by a procedure analogous to Example 1C. MS: 393 (MH+), HPLC Rf: 3.90 min.; HPLC purity 96%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9](CC3C=CC(OC)=CC=3OC)[CH:10]=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(Cn2cnc(-c3ccc(F)cc3)c2-c2ccnc(Br)c2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2nc[nH]c2-c2ccnc(Br)c2)cc1
Yield: 64.5 %

Procedure:
2-Bromo-4-[3-(2,4-dimethoxy-benzyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-pyridine (720 mg, 1.54 mmol) is dissolved in DCM (12 mL) and trifluoroacetic acid (3.0 mL) is added at room temperature. The mixture is stirred for 60 hrs before saturated NaHCO3 aqueous solution is used to adjust the pH to about 7.5. Then the mixture is extracted with EtOAc (3×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is purified by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) to give 316 mg of desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: FC(F)(F)CCBr
Reactant: COc1ccc(CC(C#N)C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 27.7 %

Procedure:
Using 0.39 g of 2-(4-methoxybenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.15 g of 2-(4-methoxybenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (89)).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([O:12]C)[CH:8]=2)[C:3]1=[O:16].Cl.N1C=CC=CC=1>>[CH3:17][C:2]1([CH3:1])[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([Cl:14])=[C:7]([OH:12])[CH:8]=2)[C:3]1=[O:16]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2C
Agent: Cl
Solvent: c1ccncc1
Product: CC1c2cc(O)c(Cl)c(Cl)c2C(=O)C1(C)C

Procedure:
By following the procedure described in Example 7, Step B, using as the reactants 2,2,3-trimethyl-5-methoxy-6,7-dichloro-1-indanone (10 g.) and pyridine hydrochloride (100 g.), there is obtained 2,2,3-trimethyl-5-hydroxy-6,7-dichloro-1-indanone.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16]I.O>O1CCCC1>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: ClCCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCCCCl
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilylacetylene (4.9 g., Aldrich) in dry tetrahydrofuran (40 ml.) was stirred at 0° under a current of nitrogen and n-butyllithium (31.25 ml. of 1.6M solution in hexane) was added dropwise. The solution was stirred for 30 minutes and a solution of 1-chloro-4-iodobutane (10.9 g.) in dry tetrahydrofuran (30 ml.) was added. The reaction mixture was allowed to warm to 20° and stirred for 18 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 6-Chloro-1-trimethylsilylhex-1-yne was obtained as a yellow liquid and was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:18]1[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[C:15]([O:28][CH3:29])=[C:14]([O:30][CH3:31])[C:13]=1[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[C:18]1[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[C:15]([O:28][CH3:29])=[C:14]([O:30][CH3:31])[C:13]=1[N:12]2[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1c(OC)c(OC)c2c(=O)c3ccc(OCc4ccccc4)c(OC)c3[nH]c2c1OC
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(OC)c(OC)c2c(c1OC)c(=O)c1ccc(OCc3ccccc3)c(OC)c1n2C
Temperature: 25 °C

Procedure:
A mixture of 6-benzyloxy-1,2,3,4,5-pentamethoxy-9-acridone (2.257 g, 5 mmol), K2CO3 (3.0 g) and methyl iodide (2.128 g, 15 mmol) in acetone (60 ml) was heated under reflux for 20 hours. After cooling to room temperature, the mixture was filtered and washed with acetone. The combined filtrate and washings are evaporated in vacuo to dryness. The residue was dissolved in chloroform (60 ml), and the solution is washed with water (30 ml×3), dried over sodium sulfate, and concentrated to dryness. The residue was crystallized from ethanol to give 6-benzyloxy-10-methyl-1,2,3,4,5-pentamethoxy-9-acridone, 2.007 g (89%), mp 127-8 ° C. 1H-NMR (CDCl3): δ3.70, 3.87, 3.91, 3.93, 3.98, and 4.10 (each 3H, s, 5×OMe, 1×NMe), 5.24 (2H, s, CH2), 6.96 (1H, d, J=9.05 Hz, H-7), 7.32- 7.48 (5H, m Ph), 8.01 (1H, d, J=9.05, H-8). Analyses: Calculated for C25H27NO7 : C, 66.21; H, 6.00; N, 3.09. Found: C, 65.99; H, 6.18; N, 3.11.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:27]([N:26]1[C:22]([C:17]2[N:18]=[C:19]3[C:20]4[CH:21]=[C:8]([CH:6]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH3:7])[CH:9]=[CH:10][C:11]=4[O:12][CH2:13][CH2:14][N:15]3[CH:16]=2)=[N:23][CH:24]=[N:25]1)([CH3:28])[CH3:29]
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: CN1CCNCC1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCN(C)CC1
Temperature: 90 °C

Procedure:
A mixture of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (246 mg, 0.590 mmol) in 1-methylpiperazine (25 mL) was heated at 90° C. for 16 h. The solvent was removed and the residue was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 146. Separation of the enantiomers and further purification by chiral HPLC (AY-H column, 5% EtOH isocratic) gave: 44.3 mg of one enantiomer and 40.0 mg of the other (34% total yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([O:32][C:33]1[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]2)=[C:35]([F:49])[C:34]=1[F:50])[CH3:31].O>C1COCC1>[CH2:30]([O:32][C:33]1[CH:48]=[CH:47][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:49])[C:34]=1[F:50])[CH3:31]
Reactant: CCOc1ccc(OCC2CCC(C=O)CC2)c(F)c1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(OCC2CCC(C=COC)CC2)c(F)c1F
Reaction time: 1 h
Yield: 90 %

Procedure:
In a reactor under nitrogen atmosphere, 30 mL of THF was added to 9.7 g of methoxymethyltriphenylphosphonium chloride, and the mixture was cooled to −20° C., to which 3.1 g of t-BuOK was added, followed by stirring for 1 hour. A solution containing 6.6 g of 4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexane carboaldehyde obtained in the seventh step dissolved in 70 mL of THF was added dropwise thereto, followed by stirring for 1 hour. The temperature of the reaction mixture was increased to room temperature, to which 100 mL of water was added, and the mixture was extracted three times with 100 mL toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to about 100 mL, and the concentrated solution was placed in 500 mL of n-hexane, followed by removing deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 6.5 g of 1-ethoxy-2,3-difluoro-4-[4-(2-methoxyvinyl)cyclohexylmethoxy]benzene.
Reaction SMILES: [N+](=C)=[N-].C1(C2C=CC=CC=2)C=CC=CC=1.[C:16](O)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[O:24]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CCCCC(=O)O
Agent: C=[N+]=[N-]
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=CCCCCC(=O)O
Yield: 18 %

Procedure:
After the reaction, the autoclave was cooled with ice, and the pressure was reduced; subsequently, the contents were treated with diazomethane, and the reaction mixture was analyzed by gas chromatography using biphenyl as an internal standard. The results confirmed that adipic acid was obtained in a yield of 38%, and 6-oxohexanoic acid was obtained in a yield of 18%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:17]=1[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccccc1C=O
Reactant: Nc1nccs1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1nc2sccn2c1NC(C)(C)C

Procedure:
Compound 32 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-methoxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:20]=[C:19]([Cl:31])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:31][C:19]1[NH:20][C:21]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCOCC2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NN=c1nc(Cl)[nH]c(NC2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate (0.602 g, 1.071 mmol) in MeOH (20 mL) was added 4M HCl in 1,4-dioxane (20 mL). After stirring at room temperature for 2 days, the solvent was evaporated and saturated NaHCO3 was added. The aqueous layer was extracted, and the organics were dried (Na2SO4) and concentrated in vacuo to provide 2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4(1H)-pyrimidinone hydrazone as a red solid (0.199 g). LCMS: (M+H)+=261.8.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH:18]([OH:20])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CN(C)CCNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCNc1c2c(nc3ccccc13)CCCC2O
Reaction time: 0.5 h

Procedure:
To a cooled solution of 4.4 g of 3,4-dihydro-9-[2-(dimethylamino)ethylamino]acridin-1(2H)-one in 80 ml of tetrahydrofuran was added 8 ml of 1 molar solution of lithium aluminium hydride in THF. This was stirred for 1/2 hour and then quenched with 6 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate. The combined organics were then dried over anhydrous magnesium sulfate and concentrated to give a solid. This was twice recrystallized from acetone/hexanes to give 1.4 g of an analytically pure powder, mp 135°-138° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[N:15]#[C:16][NH2:17].[N+:18]([O-:21])([OH:20])=[O:19]>C(O)C>[N+:18]([O-:21])([OH:20])=[O:19].[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:16]([NH2:17])=[NH:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Reactant: N#CN
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reaction time: 24 h
Yield: 36.1 %

Procedure:
A suspension of 3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamine (500 mg, 2.62 mmol), of 50% aqueous cyanamide solution (249 mg, 2.96 mmol) and of 65% aqueous nitric acid (253 mg, 2.62 mmol) in ethanol (2.6 mL) was heated for 5 days to reflux under an atmosphere of nitrogen. Twice the same amounts of cyanamide and nitric acid were added to the reaction mixture after 2 and 4 days, respectively. The mixture was cooled and let stand at 20° C. for 1 d. The precipitated solid was filtered off (Caution: the filtrate may contain the ethyl ester of nitric acid) and washed with ethanol to yield the title compound (280 mg, 36%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][NH:19]C)[C:12]=2[F:21])[CH:9]=1)[C:5]#[N:6].[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([OH:30])=O.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>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH3:31])[NH:26][C:27]=1[C:28]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]=1[F:21])=[O:30]
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 56.2 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.062 g, 0.20 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.032 g, 0.20 mmol), HATU (0.091 g, 0.24 mmol), DIPEA (0.042 mL, 0.24 mmol) and DMF (2 mL). Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.051 g, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (br. s., 1H), 8.08 (br. s., 1H), 7.80-7.84 (m, 1H), 7.44-7.53 (m, 3H), 7.36 (t, 1H), 4.49-4.56 (m, 2H), 2.26 (s, 3H). ES-LCMS: m/z 453.0, 454.0 (M+1).