Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]([OH:27])=[O:26])=[C:10]1[C:28]([O:30][CH2:31][CH3:32])=[O:29].[OH-].[CH2:34]([N+](C)(C)C)[C:35]1C=CC=CC=1.C(Br)C>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]([O:27][CH2:34][CH3:35])=[O:26])=[C:10]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CCOC(=O)C1=C(COCC#CC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [OH-]
Solvent: CCBr
Solvent: CS(C)=O
Product: CCOC(=O)C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Yield: 83.9 %

Procedure:
A solution of 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-butynoic acid (2.50 g), benzyltrimethylammonium hydroxide (0.87 g) and ethyl bromide (0.62 g) in dimethyl sulphoxide (5 ml) was stirred at room temperature for 48 hours, quenched into water and extracted twice into ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over MgSO4 and evaporated. The residue was crystallised from methanol to give the title compound (2.22 g), m.p. 123°-125°.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([CH2:6][CH:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=32)=[CH:4][N:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][CH2:33][NH2:34]>CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([CH:7]2[CH2:6][C:5]3[C:10](=[C:11]([C:12]#[N:13])[C:2]([NH:34][CH2:33][CH2:32][CH:28]4[CH2:29][CH2:30][CH2:31][N:27]4[CH3:26])=[N:3][CH:4]=3)[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]2=3)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: N#Cc1c(Cl)ncc2c1-c1ccccc1C(c1ccc(Cl)c(Cl)c1)C2
Reactant: CN1CCCC1CCN
Solvent: CN(C)C=O
Product: CN1CCCC1CCNc1ncc2c(c1C#N)-c1ccccc1C(c1ccc(Cl)c(Cl)c1)C2
Yield: 50 %

Procedure:
A solution of 2-chloro-6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[f]isoquinoline-1-carbonitrile (156 mg, 0.405 mmol) in N,N-dimethylformamide (3.5 ml) and 2-(1-methylpyrrolidin-2-yl)ethanamine (250 ul) was heated under microwave conditions at 20° C. for 40 minutes. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The aqueous layer was removed and the organic layer was washed with water (3×30 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using a gradient of dichloromethane-methanol as eluent to afford 6-(3,4-dichlorophenyl)-2-(2-(1-methylpyrrolidin-2-yl)ethylamino)-5,6-dihydrobenzo[f]isoquinoline-1-carbonitrile as a yellow solid (96 mg, 50%). M.p.=131-134° C. 400 MHz 1H NMR (DMSO-d6) δ 8.30 (m, 1H), 8.14 (s, 1H), 7.49 (m, 5H), 7.13 (m, 1H), 7.00 (dd, J=8 and 2 Hz, 1H), 4.30 (m, 1H), 3.43 (m, 2H), 3.08 (dd, J=15.2 and 7.2 Hz, 1H), 2.92 (dd, J=15.2 and 5.6 Hz, 1H), 2.37 (m, 6H), 1.97 (m, 1H), 1.89 (m, 1H), 1.68 (m, 3H), 1.55 (m, 1H). LCMS m/e 477 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16].OO.NC(N)=O>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:4]([O-:16])[CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1ncc(Br)cn1
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. cooled solution of 1-ethyl 5-bromopyrimidine-2-carboxylate (2, 1.5 g, 6.5 mmol) in dichloromethane (30 mL), trifluoroacetic anhydride (13.69 g, 65 mmol) and Urea hydrogen peroxide (6.1 g, 65 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. TLC showed consumption of starting material, the reaction mixture was diluted with water (10 mL) and neutralized with solid sodium bicarbonate. The solution was extracted with dichloromethane (2×40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-bromo-2-(ethoxycarbonyl) pyrimidine 1-oxide (3) as yellow liquid which was used without further purification. Yield: 0.64 g, crude; MS (ESI) m/z 247.13 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])#[N:28]>>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:25]=[N:24][C:23]([C:32]3[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[C:30]([F:38])[CH:31]=3)=[N:22][CH:21]=2)=[O:19])[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Product: N#Cc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1F

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 4-cyano-3-fluorophenylboronic acid following a procedure analogous to that described in Intermediate 6. LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=366 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=1>>[CH2:2]([C:10]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=1)[CH2:1][CH2:6][CH3:5]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: O=c1[nH]cnc2ccccc12
Product: CCCCc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The quinazolinone prepared as described in Example 17 was alkylated with 4-bromomethyl-2'-t-butoxycarbonyl-biphenyl. The product was purified by flash chromatography over silica gel eluting with 1% EtOAc/methylene chloride. 1H-NMR (300 MHz, CDCl3): 8.32 (m, 1H), 7.76 (m, 2H), 7.46 (m, 2H), 7.38 (m, 1H), 7.32-7.18 (m, 5H), 5.46 (bs, 2H), 2.79 (3 line m, 2H), 1.80 (m, 2H), 1.44 (m, 2H), 1.23 (s, 9H), 0.95 (t, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.[CH2:8]([CH:17]1[S:21][CH:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[NH:19][C:18]1=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].[Cl-]>CN(C)C=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][N:19]1[C:18](=[O:28])[CH:17]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:21][CH:20]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)CCCl
Reactant: CCCCCCCCCC1SC(c2cccnc2)NC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Reaction time: 10 h
Yield: 33.3 %

Procedure:
K2C03 (0 9 g, 6.52 mmol) and 2-dimethylamino-ethyl chloride hydrochloride (0.47 g, 3.26 mmol) were added to a solution of 5-(n-nonyl)-2-(3-pyridyl)-thiazolidin-4-one (1 g, 3.26 mmol) in dry dimethylform-amide (10 ml). The mixture was kept at 50° C. for 10 hours. The resulting mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel, giving 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.41 g, 33% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:24][CH:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:16])[O:15][CH:11]2[CH:10]([CH3:25])[CH2:9]1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>CCOC(C)=O>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]2[CH2:24][CH:12]3[N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:14](=[O:16])[O:15][CH:11]3[CH:10]([CH3:25])[CH2:9]2)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)CC2C1OC(=O)N2C(=O)OC(C)(C)C

Procedure:
Following Method 9, (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, (+/−)-tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate was obtained. LCMS (m/z): 549.2/551.2 (MH+), Rt=0.78 min.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([F:18])=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[C:9]([F:18])=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: COC(=O)c1cccc(N2CC[C@H](N)[C@H](OC)C2)c1F
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC)c3F)C[C@H]2OC)nc1Cl
Yield: 36.5 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-2-fluorobenzoate obtained in Example (263b) (about 0.06 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (9 mg, 0.05 mmol), WSC hydrochloride (34 mg, 0.18 mmol), HOBT (12 mg, 0.09 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 8 mg of the title compound as a colorless oily substance (33%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(F)cc1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 43) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed 437.1653, Calcd for (M+H)+: 437.1654.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:18])=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:19][C:20](O)=O>>[CH3:19][C:20]1[NH:1][C:2]2=[N:11][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]2[N:18]=1
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(N2CCOCC2)nc(N)c1N
Product: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12

Procedure:
A solution of methyl 2,3-diamino-6-morpholinoisonicotinate (4.3 g, 17 mmol) in CH3COOH (100 mL) was refluxed for 16 h. LCMS showed no methyl 2,3-diamino-6-morpholinoisonicotinate left and the desired product formed. It was cooled to room temperature and the solvent was removed in vacuo. The residue was then purified by chromatography on silica gel eluted with MeOH/DCM=1/50 to afford the desired product as a black solid (1.07 g, 23%); LC/MS: MS (ES+) m/e 277 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 2.69 (s, 3H), 3.58 (t, J=4.8 Hz, 4H), 3.86 (t, J=4.8 Hz, 4H), 4.02 (s, 3H), 7.12 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:18].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1c(N)cccc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(F)cccc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.8 %

Procedure:
Add isopropyl chloroformate (20.7 mL, 20.7 mmol, 1.0 M in toluene) dropwise to a solution of 2-Amino-6-fluor-benzoic acid methyl ester (3.5 g, 20.7 mmol) and pyridine (4.2 mL, 51.75 mmol) in dichloromethane (41 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 14 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (3.00 g, 63%). MS (ES+): 256 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH:4]([CH3:16])[CH:3]1[CH3:17].C[OH:20]>>[CH:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:13])[C:5]([CH3:15])([CH3:14])[CH:4]([CH3:16])[CH:3]([CH3:17])[C:2]2([CH3:18])[CH3:1])=[O:20]
Reactant: Cc1cc2c(cc1C)C(C)(C)C(C)C(C)C2(C)C
Reactant: CO
Product: Cc1cc2c(cc1C=O)C(C)(C)C(C)C(C)C2(C)C
Temperature: 50 °C

Procedure:
To prepare the corresponding 6-carboxaldehyde, 16 portions of Ce(NH4)2 (NO3)6 (16×16.0 g=256.0 g) in methanol (16×100 ml) is added to a solution of 1,1,2,3,4,4,6,7-octamethyl-1,2,3,4-tetrahydronaphthalene (16.0 g) in methanol (700 ml), over 8 hrs, while maintaining the temperature at 50° C. After about 1/2 of the methanol is evaporated, the resulting product is extracted with petroleum ether 30° C.-50° C./saturated NaCl. After crystallizing in ethanol, treating the mother liquors and recrystallizing, the desired 6-carboxaldehyde, 6-formyl-1,1,2,3,4,4,7-heptamethyl-1,2,3,4-tetrahydronaphthalene is obtained.
Reaction SMILES: [SH3+].[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(C)C=CC=CC=1.C(O)CC.[OH-].[Na+]>>[O:9]1[CH2:10][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: [SH3+]
Solvent: CCCO
Product: c1ccc(C2CO2)cc1
Temperature: 50 °C

Procedure:
To the sulphonium salt mixture was added benzaldehyde (13.52 g at 98%, 0.125 moles), toluene (92 g, 1 mole), and n-propanol (35.5 g, 0.59 moles) and the mixture stirred and heated to 50° C. Aqueous sodium hydroxide solution (32 g at 53%, 0.425 moles) was added and a temperature rise to 80° C. was observed (due to neutralisation of excess acid). The mixture was cooled to 70° C. and stirred at this temperature for 1 hour. The mixture was cooled, the organic layer separated, washed with water and dried over magnesium sulphate. Qualitative GC analysis showed 76% conversion to the title epoxide (by comparison with authentic sample).
Reaction SMILES: [CH2:1]([NH:3][N:4]=[CH:5][C:6](=[O:8])[CH3:7])[CH3:2].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]=[O:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(O)(=O)C>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:6](=[O:8])[CH3:7])[C:20]=2[OH:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Reactant: CCNN=CC(C)=O
Solvent: CC(=O)O
Product: CCn1nc(C(C)=O)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 15.6 %

Procedure:
2-Oxopropanal ethylhydrazone (4.736 mmol, 540.6 mg) synthesized in Reference Synthetic Example 2 and (4-tert-butylphenyl)(oxo)acetaldehyde (4.736 mmol, 901.0 mg) synthesized in Reference Synthetic Example 4 were dissolved in acetic acid (20 mL) and stirred at 100° C. for about 3.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel thin layer chromatography (n-hexane/AcOEt=1/2, 3/1 and 4/1) to give the desired product as an orange liquid (212 mg, yield 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>N1CCCCC1.C(O)C>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[C:15]2[O:14][C:13](=[O:16])[C:12]([C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:18])=[C:11]2[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1ccc(C2=C(C(=O)N3CCOCC3)C(=O)OC2)cc1OC
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C2=C(C(=O)N3CCOCC3)C(=O)OC2=Cc2ccc(Cl)cc2)cc1OC

Procedure:
4-(3,4-Dimethoxyphenyl)-2-oxo-2,5-dihydrofurane-3-carboxylic acid morpholide (1.00 g, 3 mmol) and 4-chlorobenzaldehyde (0.42 g, 3 mmol) were refluxed with ethanol (15 ml) and a small amount of piperidine (3 drops) for 3 h, then the reaction mixture was concentrated. The residue was dissolved in ethyl acetate (5 ml), petrol ether (2.5 ml) was added and the solution was applied onto a flash chromatography column (silica gel, 30 g). The column was eluted with ethyl acetate/petrol ether (2:1). The fractions containing the compound with the Rf (ethyl acetate/petrol ether, 2:1): 0.32 were collected and concentrated. 5-(4-Chlorobenzylidene)-4-(3,4-dimethoxyphenyl)-2-oxo-2,5-dihydro-furane-3-carboxylic acid morpholide was precipitated by addition of petrol ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[C:28]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)#[N:29].N1C=CC=CC=1>O1CCCC1>[C:28]([C:30]1[CH:31]=[C:32]([S:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)#[N:29]
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCOc1ccc(NS(=O)(=O)c2cccc(C#N)c2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
200 mg (0.566 mmol) of the compound from example 44A are reaccted with 342 mg (1.70 mmol) of 3-cyanobenzenesulfonyl chloride and 0.46 ml (5.66 mmol) of pyridine in 15 ml of tetrahydrofuran overnight.
Reaction SMILES: [CH:1]1[C:6]([SH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>>[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([S:7][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH:1]=1
Reactant: Cc1cccc(S)c1
Reactant: CC(C)=CCCC(C)=CCBr
Product: CC(C)=CCCC(C)=CCSc1cccc(C)c1

Procedure:
thio-m-cresol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl m-tolyl sulphide (b.p.122° C/0.07 mmHg);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH2:1][Br:17])[CH:3]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of 3,5-dimethylbromobenzene (70 g, 0.378 M), NBS (67.3 g, 0.373 M), and benzoyl peroxide (2.27 g, 0.009 M) in carbon tetrachloride (300 mL) was refluxed for 3 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a pale brown oil. The crude product was dissolved in hexane and filtered through a short silica gel pad (diameter: 9.5 cm, height: 7 cm). The silica gel pad was washed with hexane until the product eluted completely. The filtrate was evaporated in vacuo to give 94 g of 1-bromo-3-(bromomethyl)-5-methylbenzene (contaminated with starting material and 1-bromo-3,5-bis-bromomethylbenzene) as a pale brown oil, which solidified on standing at room temperature. The mixture was used directly in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])[N:10]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:24][CH2:25][CH2:26]Br>CN(C=O)C.O>[F:24][CH2:25][CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]2[N:8]=1
Reactant: FCCBr
Reactant: Nc1ccn2nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccn2nc(-c3ccccc3OCCF)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.3 %

Procedure:
To a solution of 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-phenol (250 mg, 1.10 mmol) in dry DMF (6 ml), K2CO3 (611 mg, 4.42 mmol) was added under positive nitrogen pressure and the mixture was stirred for 20 min at rt in a sealed tube. A solution of 1-fluoro-2-bromoethane (93 mg, 0.66 mmol) in DMF was added dropwise and the reaction mixture was heated for 8 h at 90° C. On completion of reaction (monitored by TLC), the mixture was cooled, diluted with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude product. Purification by silica gel column chromatography using 2% MeOH in DCM as eluent afforded the desired product (200 mg, 66%) as off-white solid. LC-MS: m/z=273.2 [M+H]+.
Reaction SMILES: O.S(=O)(=O)(O)O.[OH:7][C:8]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C#N>C(O)(=O)C>[C:12]1([CH2:9][C:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:7])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC(=C(O)C1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cc1ccccc1)C1CCN(Cc2ccccc2)CC1
Yield: 96.3 %

Procedure:
To 200 parts of water were added carefully 200 parts of acetic acid while stirring and cooling. Then there were added dropwise (slowly) 368 parts of sulfuric acid. 90 Parts of α-[hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]benzeneacetonitrile were added and the whole was stirred and refluxed overnight. The acetic acid was evaporated and the residue was poured into crushed ice. The mixture was alkalized with concentrate ammonium hydroxide and the oily product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 79 parts (96.3%) of 2-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]ethanone as a residue (intermediate 6).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](Cl)(Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18]>C1COCC1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9]2(=[O:10])[O:19][CH2:15][CH2:16][CH2:17][O:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCCO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(Cl)Cl)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude (4-Nitrobenzyl)phosphonic dichloride (Compound 230E) above was dissolved in anhydrous THF (20 mL). To this solution was added TEA (840 mg, 7.5 mmol) and 1,3-propane-diol (190 mg, 2.5 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, concentrated and the residue was purified by column chromatography to give the target product (70 mg). 1H NMR (CD3OD, 400 MHz): δ=2.85 (d, J=20.0 Hz, 2H), 3.28-3.30 (m, 2 H), 3.55-3.58 (m, 2 H), 3.75-7.78 (m, 2 H), 6.64 (d, J=8.4 Hz, 2 H), 7.07 (d, J=8.4 Hz, 2 H).