Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1>O1CCCC1>[Br:33][C:29]1[CH:28]=[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:10](=[O:11])[CH2:9][Cl:8])[CH:15]=3)[N:20]=[CH:19][C:18]=2[C:24]#[N:25])[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cnc2ccc(NC(=O)CCl)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and chloroacetyl chloride (0.402 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and collected. Recrystallization from methanol gave 0.540 g of tan solid: mass spectrum (electrospray, m/e): M+H 415,417.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.O>C1C=CC=CC=1>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2ccccc2sc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1S2
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
A solution of thioxanthone (10 g) in 60 mL of benzene was treated with 5.0 g of LAH by stirring for 15 min. The mixture was heated and 100 mL of ether was added carefully. Reflux was continued for 90 min. The cooled mixture was neutralized with water. The solids were filtered off and the filtrate evaporated to dryness. Pure thioxanthene (9.1 g, 98%) was isolated by chromatography using 20% ethyl acetate/hexane; 1H NMR (CDCl3) δ 3.82 (s, 3H), 7.21 (m, 4H), 7.33 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl(O)(=O)(=O)=[O:23]>C(OC(=O)C)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:16]([O-:23])(=[O:17])[CH3:18]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
250 g of florfenicol was suspended in 330 ml of acetic anhydride in one liter round bottom flask equipped with a over-head stirrer and a drying tube. To this suspension was added one ml of perchloric acid, while stirring vigorously with a pipette. A clear yellow solution was obtained in a few minutes. Stirring was continued for another 3 hours. After 3 hrs, the reaction mixture was poured into 1000 g of ice and stirring continued to arrive at a suspension of product. Solid present was filtered and resuspended in 500 ml of water, and then stirred for 10 min to remove residual acetic acid. The solid product was filtered using a Buckner funnel under vacuum and then recrystallized in ethanol. The recrystallized product was washed with hexane and dried to obtain around 260 g of solid florfenicol acetate.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O>>[Br:12][C:8]1[S:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:10]([CH3:11])[CH:9]=1
Reactant: CCNC(=O)c1sccc1C
Reactant: O=C1CCC(=O)N1Br
Product: CCNC(=O)c1sc(Br)cc1C
Yield: 92 %

Procedure:
Following the procedure as described in Preparation 19, making variations only as required to use N-ethyl-3-methylthiophene-2-carboxamide in place of N-benzyl-3-methylfuran-2-carboxamide to react with N-bromosuccinimide, 5-bromo-N-ethyl-3-methylthiophene-2-carboxamide was obtained as a colorless oil in 92% yield: 1H NMR (300 MHz, CDCl3) δ 6.85 (s, 1H), 5.65 (br s, 1H), 3.48-3.38 (m, 2H), 2.45 (s, 3H), 1.22 (t, J=7.3 Hz, 3H); MS (ES+) m/z 248.1 (M+1), 250.1 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)#[N:8].O>C1COCC1>[NH2:8][CH2:7][C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: N#Cc1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.4 %

Procedure:
LAH (42 mL, 1M solution in THF) was added dropwise through a syringe to a solution of 2-cyanoindole (2.0 g, 14.1 mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was stirred at RT under argon for 5 h. H2O was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3) and concentrated to afford the title compound (2.11 g, quantitative) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, 1H), 7.29 (d, 1H), 6.97 (t, 1H), 6.91 (t, 1H), 6.20 (s, 1H), 3.82 (s, 2H), 2. 18 (br, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([NH:19][CH:20]=[O:21])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)=[O:6].[CH3:22]N(C=O)C.CI>C1COCC1>[CH3:3][O:4][C:5]([C:7]1([N:19]([CH:20]=[O:21])[CH3:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8]1)=[O:6]
Reactant: COC(=O)C1(NC=O)CCN(C(=O)OC(C)(C)C)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(N(C)C=O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
Sodium hydride (60% in oil) (10 mg, 0.25 mmol) was added to a solution of 3-Formylamino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2T) (50 mg, 0.183 mmol) in THF (3 ml). DMF (1 ml) was added and stirred for 1 hour. Methyl iodide (0.1 ml, 1.60 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and the residue extracted with EtOAc (50 ml), washed with H2O (20 ml), dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 3% MeOH/MeCl2 yielding 3T (50 mg, 94%). LCMS (MH 287) Retention time=2.77 minutes.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16].[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][C:17](=[O:20])[CH2:18][CH3:19])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: COc1cc2c(cc1Br)CC=C2CCN
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)NCCC1=CCc2cc(Br)c(OC)cc21

Procedure:
Starting with 2-(6-bromo-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and propionyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 95%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
(6-Chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (3.67 g, 10.3 mmol) was dissolved in DCM (32 mL) and TFA (8 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h and then evaporated in vacuo. The resultant residue was treated with 5N aqueous sodium hydroxide solution (25 mL), diluted with water (100 mL) and extracted into ethyl acetate (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as yellow solid (2.37 g, 90%). 1H NMR (CD3OD, 300 MHz): 7.80 (s, 1H), 7.60 (s, 1H), 4.14 (s, 2H). LCMS (Method B): RT=3.00 min, M+H+=255.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[N:50][CH:51]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:43])([CH3:44])[CH3:42])=[CH:37][CH:36]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)=[N:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:30][CH:29]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccncc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccncc5)nc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.2 mmol of butyl lithium was slowly added to 50 ml of tetrahydrofuran cooled to −78° C. in which 1.50 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.83 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 30 ml portion of tetrahydrofuran prepared by dissolving 0.74 g of 5-bromo-2,4′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 13 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=1:1) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-tert-butylphenyl)-1,3,5-triazin-2-yl]phenyl}-2,4′-bipyridyl (0.97 g, yield 56%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=O)C.CCCCCC.CC(=O)OCC>CCO>[F:18][C:9]([F:17])([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:8][CH2:7][OH:6]
Reactant: CC(=O)OCCC(F)(F)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A 35% aq. NaOH sol. (6 ml) was added to a solution of 1.9 g (8.2 mmol) of 3,3-difluoro-3-(4-fluorophenyl)propyl acetate in EtOH (25 ml), and the mixture was stirred for 2 h at RT. Concentration in vacuo was then carried out and the residue was taken up in water (80 ml). The solution was extracted with EA (3×80 ml) and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 9:1) of the residue yielded 1.1 g (5.8 mmol, 71%) of 3,3-difluoro-3-(4-fluorophenyl)propan-1-ol.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])=[CH:14][N:13]=1>N1C=CC=CC=1>[CH3:27][C:19]1[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=1[C:15]1[CH:16]=[N:17][C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[N:13][CH:14]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(N)nc2)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2cnc(NS(=O)(=O)c3ccccc3)nc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzenesulfonyl chloride (0.192 mL) was added to a stirred mixture of N-[5-(2-aminopyrimidin-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (195 mg) and pyridine (10 mL) and the reaction mixture was heated to reflux for 18 hours. Additional benzenesulfonyl chloride (0.384 mL) was added and the mixture was heated to reflux for 2 hours. The reaction mixture was evaporated. A 7M methanolic ammonia solution (10 mL) was added to the residue and the mixture was stirred at room temperature for 1 hour. The resultant mixture was evaporated and the residue was purified by preparative HPLC. There was thus obtained the title compound (55 mg); 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.27 (s, 3H), 7.61 (m, 3H), 8.02 (m, 2H), 8.60 (s, 2H), 12.00 (br s, 1H), 12.20 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-])=O.[CH2:10]([N:12](CC)CC)[CH3:11].[C:17](=O)=[O:18]>>[NH:12]1[CH2:10][CH2:11][O:18][CH2:17][CH:3]1[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C=O
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC(=O)[O-]
Product: CCOC(=O)CC1COCCN1
Reaction time: 5 h

Procedure:
To a solution of monoethyl malonate (0.12 mol) and triethylamine (0.12 mol) acetonitrile (40 mL) and Step-1 intermediate was added (0.02 mol). The mixture was heated to a sufficient temperature to cause considerable evolution of CO2 gas. After 5 h, the solution was concentrated under reduced pressure. The residue was treated with 30% aqueous K2CO3 solution and extracted with diethyl ether, dried over Na2SO4 and concentrated to get the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: COC(=O)c1ccccc1CBr
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and methyl 2-(bromomethyl)benzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (79%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.04 (dd, J=7.7, 1.3 Hz, 1H), 7.43 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.38-7.29 (m, 1H), 7.22-7.11 (m, 3H), 7.07-6.99 (m, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.55 (s, 1H), 6.43 (s, 1H), 5.52-5.34 (m, 2H), 5.00 (d, J=8.9 Hz, 1H), 4.74 (d, J=8.9 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.95 (s, 3H), 3.08-2.94 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.2, 167.5, 161.8, 161.4, 142.3, 137.5, 132.8, 132.7, 131.4, 129.1, 128.8, 128.6, 128.0, 127.4, 126.5, 123.9, 123.5, 120.2, 120.0, 119.0, 109.4, 93.3, 80.8, 72.4, 65.9, 57.9, 52.3, 42.4, 29.1, 15.3; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][CH2:9][C:10](OC)=[O:11])=[CH:5][CH:4]=1.[CH:16](OCC)=O.[Na].[CH3:22][S:23][C:24](=[NH:26])[NH2:25].S([O-])([O-])(=O)=O.N>C(O)C.C(Cl)Cl.CO>[CH3:22][S:23][C:24]1[N:25]=[C:10]([OH:11])[C:9]([S:8][CH2:7][C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:16][N:26]=1
Reactant: CCOC=O
Reactant: CSC(=N)N
Reactant: COC(=O)CSCc1ccc(OC)cc1
Agent: N
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CSc2cnc(SC)nc2O)cc1

Procedure:
Prepared from methyl 4-methoxybenzylsulphenyl-acetate and ethyl formate in the presence of sodium and subsequent reaction with S-methylisothiourea-sulphate in ethanol, Rf value: 0.4 (silica gel; methylene chloride/methanol/conc. aqueous ammonia=20:1:0.1)
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].Cl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1.C(O)(=O)C>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:3])[CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1
Reactant: CNC1C=Cc2cc(Cl)ccc2CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)C1C=Cc2cc(Cl)ccc2CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
7.7 ml of an aqueous solution of 40% formaldehyde and then 4.5 g of sodium cyanoborohydride were added to a mixture of 4.7 g of 2-chloro-7-methylamino-6,7-dihydro [5H] benzocycloheptene hydrochloride in 47 ml of acetonitrile and the mixture was stirred for 15 minutes at room temperature. Acetic acid was added to the reaction mixture until the pH was 7 and the mixture was stirred at room temperature for 45 minutes. The mixture was evaporated to dryness under reduced pressure to obtain 2.6 g of 2-chloro-7-dimethylamino-6,7-dihydro [5H] benzocycloheptene in the form of an oil. Addition of a solution of fumaric acid in methanol yielded 3.3 g of the fumarate of the said product melting at 160° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C>[F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([O:8][CH2:20][O:21][CH3:22])=[N:6][CH:7]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: COCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1ncc(F)c(N=CN(C)C)n1
Yield: 18.5 %

Procedure:
N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and bromomethyl methyl ether (75 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was placed directly onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-80% gradient) to isolate 23 mg, 0.1 mmol (19%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 5.46 (s, 2H), 3.53 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H); HPLC-MS (ESI) m/z 229 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](Cl)=[O:11].[CH3:13][CH:14]([CH3:37])[CH:15]([NH:20][C:21]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:22])[C:16]([O:18][CH3:19])=[O:17]>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[S:24][C:23]([C:21]([NH:20][CH:15]([CH:14]([CH3:37])[CH3:13])[C:16]([O:18][CH3:19])=[O:17])=[O:22])=[N:27][CH:26]=2)=[CH:29][CH:30]=1)=[O:11]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C(Cl)C1Cc2ccccc2C1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)C3Cc4ccccc4C3)cc2)s1)C(C)C
Yield: 18 %

Procedure:
The title compound was synthesized analogous to Example 27, using 2,3-dihydro-1H-indene-2-carbonyl chloride and intermediate 2. Yield: 18%; 1H NMR (DMSO-d6, 300 MHz): δ 10.28 (s, 1H), 8.75 (d, 1H), 8.37 (s, 1H), 7.75 (s, 4H), 7.25 (m, 2H), 7.16 (m, 2H), 4.35 (t, 1H), 3.68 (s, 3H), 3.43 (m, 1H), 3.19 (d, 4H), 2.28 (m, 1H), 0.96 (t, 6H); MS (ESI) m/z 487.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]([N:46]1[CH2:51][CH2:50][CH:49]([C:52](O)=[O:53])[CH2:48][CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C=O)C>[CH3:2][N:3]([O:4][CH3:5])[C:52]([CH:49]1[CH2:50][CH2:51][N:46]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:47][CH2:48]1)=[O:53]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 176.5 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (4.26 g, 43.7 mmols), di-isopropylethylamine (33.88 g, 45.66 mL, 262.2 mmols) and HATU (19.94 g, 52.4 mmols) were added to a solution of N-Boc-piperidine-4-carboxylic acid (11.03 g, 48.1 mmols) in dry DMF (250 mL). The reaction mixture was stirred at room temperature for 72 hrs. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), and dried over MgSO4. Evaporation of the solvent afforded a dark oil (21.0 g) that was purified by flash chromatography (Silica, gradient elution with pentane/ethyl acetate 9:1 v/v to 3:2 v/v) to give the title compound 12.5 g (95%) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CS[C:16]1[N:21]=[C:20](O)[CH:19]=[CH:18][N:17]=1.O=P(Cl)(Cl)[Cl:25].Cl.O1CCOCC1>>[Cl:25][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([NH:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1
Reactant: CSc1nccc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(Nc2nccc(Cl)n2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
3,4,5-Trimethoxy-phenylamine (10 g, 54.6 mmol) and 2-methylsulfanyl-pyrimidin-4-ol (7.76 g, 54.6 mmol) are mixed and heated to 150° C. for 2 h whereupon the mixture melts. The evolving gas is absorbed in sodium hypochlorite solution. The remaining residue is suspended in acetonitrile (300 ml). POCl3 (10.8 ml, 117 mmol) and 4 N HCl in dioxane (35.2 ml, 140 mmol) are added and the mixture is heated to 90° C. until the reaction is complete. The mixture is extracted with ethyl acetate, washed with sat. sodium bicarbonate and brine. The organic layer is dried with sodium sulfate and evaporated. The residue is crystallized from methanol to give (4-chloro-pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.N[CH:12]([OH:14])[CH3:13].C([N:17](CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:17][CH2:13][CH2:12][OH:14])[CH:7]=1
Reactant: CC(N)O
Reactant: CCN(CC)CC
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: CO
Product: CSc1nc(Cl)cc(NCCO)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the solution of 4,6-dichloro-2-methylsulfanylpyrimidine (9.75 g) in methanol (150 ml) was added aminoethanol (3.1 g) and triethylamine (7.5 ml). The mixture was stirred at room temperature for 20 hrs. After removal of solvent under vacuo, the residue was dissolved in isopropanol (15 ml) and ether (30 ml) was then added. The product was collected by filtration.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=O)[C:11](=O)[CH:10]([CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[CH2:1]([N:8]1[CH2:9][CH:10]([CH3:25])[C:11]2[N:31]([C:30]3[CH:32]=[CH:33][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:14][C:12]=2[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1CN(Cc2ccccc2)CC(CC(=O)c2ccc(Cl)cc2)C1=O
Product: CC1CN(Cc2ccccc2)Cc2cc(-c3ccc(Cl)cc3)n(-c3ccc(Cl)cc3)c21

Procedure:
Using a procedure analogous to Example 3, 1-benzyl-3-methyl-5-(p-chlorophenacyl)-4-piperidone may be reacted with p-chloroaniline to give the title compound.