Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([CH:21]=O)[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:26]O>C(O)=O>[C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([C:21]#[N:26])[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C=O)c2C)CC1=O
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C#N)c2C)CC1=O
Temperature: 0 °C
Yield: 45.1 %

Procedure:
A solution of 2-butyryl-3-hydroxy-5-(3-formyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.50 g) and hydroxylamine hydrochloride (0.35 g) in 98% formic acid (7 ml) was refluxed for an hour and then allowed to cool. The mixture was diluted with ice water and the precipitate collected. Purification by column chromatography over silica gel (eluant dichloromethane) gave 2-butyryl-3-hydroxy-5-(3-cyano-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.67 g; 44%) as a pale yellow oil. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 100 (3H, t); 1.68 (2H, m); 2.45 (6H, s); 2.60 (3H, s); 2.65-4.20 (7H, m); 7.42 (1H, s); 18.35 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]>C(O)C>[Br-:6].[CH3:11][O:10][C:8](=[O:9])[CH2:7][N+:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: c1cscn1
Reactant: COC(=O)CBr
Solvent: CCO
Product: COC(=O)C[n+]1ccsc1
Product: [Br-]
Yield: 66.8 %

Procedure:
Thiazole, (850 mg, 10 mmol), methyl bromoacetate (1.52, 10 mmol) and absolute ethanol (50 ml) were refluxed for 2 hours. On cooling, the salt separated and was recrystallized from absolute ethanol to give the title compound (1.59 g), m.p. 189°-190° C. (dec).
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:43])[C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1.CO.[OH-].[Li+]>O1CCCC1>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:41])([F:40])[F:42])[CH:32]=1)[C:28]([NH:27][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:44])=[O:2])=[O:43]
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)ccc1C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 25.2 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.22 g, 0.35 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.26 mL). The crude material was triturated with hot hexanes and filtered. The product was then crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid (0.055 g, 26%) as a white solid. mp=218-219° C. (dec). 1H NMR (500 MHz, DMSO-d6); δ 13.50 (bs, 1H), 12.72 (s, 1H), 8.49 (s, 2H), 8.44 (s, 1H), 8.38 (s, 1H), 8.31 (d, 1H), 7.99 (d, 1H), 7.80-7.71 (AA′BB′, 4H), 6.82 (dd, 1H), 4.34 (t, 2H), 4.22 (t, 2H), 2.18 (m, 2H). Mass spec (MW 622.44); (ES+) m/z 623.05, (ES−) m/z 621.50. Elemental analysis; Calculated for C27H19F9N2O5: C, 52.10; H, 3.08; N, 4.50. Found: C, 51.78; H, 3.03; N, 4.26.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)=[O:6].CC1C=CC=CC=1C(N)=O.NC1C=CC(C)=C(C=1)C(NC1C=NC(N)=NC=1)=O.[F:47][C:48]([F:59])([F:58])[C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=1)[C:52](Cl)=[O:53].CCN(CC)CC>C(Cl)Cl.N1C=CC=CC=1>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([NH:1][C:52]([C:51]3[CH:55]=[CH:56][CH:57]=[C:49]([C:48]([F:47])([F:58])[F:59])[CH:50]=3)=[O:53])[C:3]=2[CH3:18])=[CH:13][N:12]=1
Reactant: Cc1c(N)cccc1C(=O)Nc1cnc(N)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Agent: Cc1ccccc1C(N)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1c(NC(=O)c2cccc(C(F)(F)F)c2)cccc1C(=O)Nc1cnc(N)nc1

Procedure:
3-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 42 (113 mg, 0.464 mmol) [prepared according to the procedure described for methylbenzamide-5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide in Example 1] was taken up in CH2Cl2 (4 mL) and pyridine (3 mL) and 3-(trifluoromethyl)benzoyl chloride (0.31 mL, 2.09 mmol) was added followed by NEt3 (0.13 mL, 0.928 mmol). Complete consumption of the amine starting material was indicated by LCMS. The crude reaction mixture was concentrated and the product purified using automated medium pressure chromatography (Isco—40 g column; eluting with a linear gradient from 97% CH2Cl2 (A line) to 100% 90/10/1 CH2Cl2/MeOH/NH3 (B line) on silica gel) to afford N-(2-amino-5-pyrimidinyl)-2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)benzamide 43 as an off-white solid. MS m/z found 416 [MH+]; calc. for C20H16F3N5O2=415.13; and 2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-N-(2-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-5-pyrimidinyl)benzamide 44 as an off-white solid. MS m/z found 588 [MH+]; calc. for C28H19F6N5O3=587.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:44]1([CH3:53])[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])[C:50](=[O:51])[C:47]1[CH:48]=[CH:49][C:44]([CH3:53])=[CH:45][CH:46]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1nsc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3snc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 60 °C

Procedure:
To a solution of {3-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester obtained from method 31 alternative procedure above in chloroform (300 ml), diisopropylethylamine (6 g, 46.5 mmol) was added and the reaction mixture was heated to 60° C. To the hot solution a solution of the p-toluoyl chloride (3.78 g, 24.4 mmol) in chloroform (150 ml) was added dropwise and the resulting solution was refluxed overnight. The TLC showed the disappearance of most of the SM. The reaction mixture was washed with water (2×100 ml), satd, NaHCO3 (200 ml) brine (100 ml) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 10-30% EtOAc in hexanes as eluent. Yield=6.14 g (62%) of {3-[[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester. White foam, mp. 70-71° C. m/z 604 (MH+), 1H NMR (DMSO-d6, 300 MHz, 95° C.) δ: 0.48 (d, 3H), 0.90 (d, 3H), 1.26 m, 1H), 1.28 (s, 9H), 2.33 (s, 3H), 2.47 (d, 2H), 2.72-2.64 (m, 1H), 2.72 (s, 3H), 3.24 (t, 2H), 5.08 (d, 1H), 5.60 (d, 1H), 5.90 (d, 1H), 7.20-7.40 (m, 9H).
Reaction SMILES: [Br:1][CH:2]([CH3:15])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:7]=2[CH:6]=1)=O.[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(O)(=O)C>C(O)C>[BrH:1].[CH3:15][C:2]1[S:21][C:17]2=[N:16][CH2:20][CH2:19][N:18]2[C:3]=1[C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:7]=2[CH:6]=1
Reactant: S=C1NCCN1
Reactant: Cc1cccc2sc(C(=O)C(C)Br)cc12
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: CC1=C(c2cc3c(C)cccc3s2)N2CCN=C2S1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixture of 2-bromo-1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.27 g), 2-imidazolidinethione (0.1 g), acetic acid (2 ml) and ethanol (4 ml) was heated under reflux for 3 hours, then cooled to ambient temperature. The solvents were removed in vacuo and the residue was triturated with ether (2×1 ml). The resulting solid was collected by filtration, washed with ethanol (2 ml) and dried in vacuo at 60° C. for 2 hours to give 2-methyl-3-(4-methylbenzo[b]thiophen-2-yl)-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.3 g) as a cream solid, m.p. 201-204° C.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].C(O[CH:9](OCC)[CH2:10][CH2:11][CH2:12][NH2:13])C.Cl>C(OCC)C>[CH2:11]1[CH:12]2[N:13]([CH2:5][CH2:4][C:2](=[O:3])[CH2:1]2)[CH2:9][CH2:10]1
Reactant: C=CC(C)=O
Reactant: CCOC(CCCN)OCC
Agent: Cl
Solvent: CCOCC
Product: O=C1CCN2CCCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
The methylvinyl ketone (18.0 g, 256 mmol) was added dropwise to a solution of the 4,4-diethoxybutylamine (24.8 g, 154 mmol) in diethyl ether at 0° C. and stirred for one hour. The reaction was allowed to warm to room temperature and stir for 2 hours. The reaction was poured into 350 ml of 2N hydrochloric acid and the layers were separated. The aqueous layer was heated on a steam bath for 1 hour and then allowed to stir at 40° C. for 18 hours. The reaction was made basic with a sodium hydroxide solution and then extracted with methylene chloride. The extracts were dried over sodium sulfate and concentrated to give 20 g of an orange oil. This oil was distilled in vacuo at 74°-84° C./5 mmHg to give 6.68 g of racemic product. (31%). MS(FD)(m/e): 139.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:21])C(=O)C1>C(O)(=O)C>[Br:21][C:10]1[C:11]([OH:13])=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1
Reactant: Oc1ccnc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Oc1nc(-c2ccccc2)ncc1Br
Temperature: 60 °C
Yield: 75.5 %

Procedure:
To a solution of 2-phenylpyrimidin-4-ol (1.0 g, 5.8 mmol, 1 eq) in acetic acid (20 mL) was added NBS (1.0 g, 5.8 mmol, 1 eq) and heated at 60° C. for 1 h. The reaction solution was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2/MeOH=97/3 as eluant) to obtain 5-bromo-2-phenylpyrimidin-4-ol (1.1 g, 75.8%) as a white solid. LC-MS (m/z): 251.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 7.35-7.51 (m, 3H), 8.10-8.18 (m, 2H), 8.46 (s, 1H), 13.32 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.C(=O)(O)O.[NH2:15][C:16]([NH2:18])=[NH:17].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:17]=[C:16]([NH2:18])[N:15]=[CH:7]2
Reactant: N=C(N)N
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1ncc2cc(Cl)ccc2n1
Yield: 50 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzaldehyde (109) (5 g, 31.6 mmol) and guanidine carbonate (7.5 g, 41.1 mmol) was heated at 140° C. in DMA (50 mL) for 3 h. 100 ml water was added and after refrigeration, a solid was isolated by filtration, and dried under vacuum to give the product (110) (2.8 g, 15.8 mmol, 50% yield). ESI-MS (M+1): 180 calc. for C8H6ClN3 179.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:9][CH2:8][CH:7]([OH:10])[CH2:6][O:5][C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[O:2][CH3:1])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1ccccc1OCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1ccccc1OCC(O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A solution of 3-(2-methoxy-phenoxy)-propane-1,2-diol (4.7 g) in pyridine, cooled at 5°-10° C., is treated under stirring with a solution of p-toluensulphonylchloride (4.5 g) in benzene (70 ml). The reaction mixture is stirred overnight at room temperature, then it is washed with 2N HCl (3×100 ml) and with water, dried on Na2SO4 and evaporated to dryness in vacuum. The oily residue is purified by column chromatography (silica gel 230-400 mesh hexane/AcOEt=3/1) to yield 5 g of 3-(2-methoxy-phenoxy)-2-hydroxy-1-propyl p-toluensulphonate (oil, NMR (--CDCl3):δ=2,4 3H (s) CH3SO2 ; δ=3,75-4,4 5H (m) OCH3 +OCH2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].[CH2:14]([C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][C:21]=2[C:20](=[O:27])[O:19]1)[CH:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:14]([C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH2:23][N:24]([C:11](=[O:13])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:25][CH2:26][C:21]=2[C:20](=[O:27])[O:19]1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)Cc1ccccc1[N+](=O)[O-])CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 2-(2-nitrophenyl)acetic acid (79 mg, 0.435 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The crude reaction mixture was concentrated to dryness and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-5-(2-(2-nitrophenyl)acetyl)-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (57 mg, 60%) as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-1.01 (m, 6H), 1.54-1.73 (m, 1H), 1.74-1.87 (m, 1H), 2.20-2.36 (m, 1H), 2.37-2.63 (m, 2H), 3.42-3.58 (m, 1H), 3.76-3.92 (m, 1H), 3.93-4.14 (m, 2H), 4.40 (m, 1H), 4.75 (d, J=19.59 Hz, 1H), 7.19-7.42 (m, 6H), 7.42-7.53 (m, 1H), 7.53-7.64 (m, 1H), 8.04-8.16 (m, 1H); MS m/z 435 (M+H)+, 457 (M+23)+, 433 (M−H)−.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([F:15])[CH:6]=1>CO>[F:15][C:7]1[CH:6]=[C:5]([CH2:4][NH:2][CH3:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: CN
Solvent: CO
Product: CNCc1cc(F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
Methylamine 33% in MeOH (1.5 mL, 46.5 mmol) was dissolved in MeOH (15 mL). The mixture was heated at 50° C. under stirring and 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1 g, 3.88 mmol) was added. The reaction mixture was stirred at this temperature for 3 h. The solvent was removed under vacuo, then NaOH 1M (50 mL) was added and the aqueous layer was extracted with DCM (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated under vacuo to give the title compound as a yellow oil (0.5 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (s, 1H), 7.30 (m, 2H), 7.25 (m, 1H), 3.88 (s, 2H), 2.54, (s, 3H). UPLC-MS: Rt=0.51; m/z (ES+): 208.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[S:9])[NH2:8].N1C=CC=CC=1.Br[CH:17]([CH:20]=O)[CH:18]=[O:19]>O1CCCC1.CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:9][C:17]([CH:18]=[O:19])=[CH:20][N:8]=1
Reactant: O=CC(Br)C=O
Reactant: NC(=S)c1ccccn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=Cc1cnc(-c2ccccn2)s1
Yield: 38.7 %

Procedure:
Pyridine-2-carbothioamide (4.5 g) was dissolved in tetrahydrofuran (40 mL). Pyridine (7.9 mL) was added and the reaction was heated to reflux. 2-Bromomalonaldehyde (7.2 g) was added in dimethylsulfoxide (15 mL) dropwise over 10 minutes and the reaction was heated for 3 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and sodium hydrogen carbonate aqueous solution. The aqueous layer was back extracted and the combined organic phase was washed with brine and concentrated. The crude reaction was purified by silica gel column chromatography using an eluant of 2% to 4% acetone/dichloromethane to obtain the title compound (2.4 g) with the following physical data.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:14])([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH:15](=[N:1][CH2:2][P:3](=[O:14])([O:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCOP(=O)(CN)OCCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CCCCOP(=O)(CN=Cc1ccccc1)OCCCC

Procedure:
A mixture of dibutyl aminomethylphosphonate (69.7 g) and benzaldehyde (33.0 g) in benzene (600 ml) is stirred with magnesium sulfate (150 g) for 3 hours. The mixture is filtered and the salts washed with benzene. Concentration of the filtrate in vacuo leaves dibutyl N-benzylideneaminomethylphosphonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](OC2C(F)=C(F)C=C(F)C=2F)=[O:29])([C:16]2[CH:21]=CC=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:41]1[C:45]2=[C:46]3[C:50](=[CH:51][CH:52]=[C:44]2[NH:43][CH:42]=1)[NH:49][CH:48]([C:53]([O:55][CH3:56])=[O:54])[CH2:47]3.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([N:43]2[C:44]3[C:45](=[C:46]4[C:50](=[CH:51][CH:52]=3)[NH:49][CH:48]([C:53]([O:55][CH3:56])=[O:54])[CH2:47]4)[CH:41]=[CH:42]2)=[O:29])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[CH2:21])[CH:17]=[CH2:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C1Cc2c(ccc3[nH]ccc23)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)OC)C3)(c1ccccc1)c1ccc(OC)cc1
Reaction time: 15 h
Yield: 80.3 %

Procedure:
A solution of 7 (0.6 g, 1.1 mmol) was combined with 0.24 g (1.2 mmol) methyl pyrrolo[4,5-e]indoline-7-carboxylate (Boger et al, supra) and 0.1 ml triethylamine in 5 ml of anhydrous CH2Cl2. The mixture was kept at room temperature for 15 h and concentrated under vacuum. The resultant solid, which was the desired product, was washed with 50% ethyl acetate/50%hexane to remove unreacted starting materials and 2,3,5,6-tetrafluorophenol. Drying under vacuum afforded 0.51 g (77%) of the title compound as a pale-yellow, crystalline solid.
Reaction SMILES: C[C:2]([CH2:4][C:5]([O:7]CC)=O)=[S:3].[NH2:10][C:11]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[NH:13][N:12]=1.[CH3:20]N(C)C=O>>[OH:7][C:5]1[CH:4]=[C:2]([S:3][CH3:20])[N:12]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:11]2[N:10]=1
Reactant: COC(=O)c1nc(N)n[nH]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(C)=S
Product: COC(=O)c1nc2nc(O)cc(SC)n2n1

Procedure:
A suspension of ethyl 2-methylthiocarbonylacetate (37.6 g) and 3-amino-5-methoxycarbonyl-s-triazole (20 g) in dimethylformamide (200 ml) was refluxed for one hour. After removing the solvent by distillation under reduced pressure, ether was added to the residue, and the formed crystals were purified by silica gel chromatography, giving 11.7 g of the objective compound.
Reaction SMILES: [CH3:1]C1C=CC2C(=O)C3C=CC=CC=3C=CC=2C=1.BrN1C(=O)CCC1=O.[Br:26][CH2:27][C:28]1[CH:43]=[CH:42][C:31]2[C:32](=[O:41])[C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[CH:35]=[CH:36][C:30]=2[CH:29]=1.C(C1C=CC2C(=O)C3C=CC=CC=3C=CC=2C=1)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH:27]([C:28]1[CH:43]=[CH:42][C:31]2[C:32](=[O:41])[C:33]3[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=3[CH:35]=[CH:36][C:30]=2[CH:29]=1)[CH3:1]
Reactant: O=c1c2ccccc2ccc2cc(CBr)ccc12
Reactant: Cc1ccc2c(=O)c3ccccc3ccc2c1
Agent: CCc1ccc2c(=O)c3ccccc3ccc2c1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 80 %

Procedure:
39.7 Gm. of 2-methyl-5H-dibenzo[a,d]cyclohepten-5-one is refluxed in 1200 ml. of carbon tetrachloride with 35.2 gm. of N-bromosuccinimide for 14 hours, irradiating with a 100 watt incandescent lamp. The solution is cooled, filtered and evaporated. The residue is recrystallized from methylene chloride/hexane to afford 27.3 gm., 51%, of 2-bromomethyl-5H-dibenzo[a,d]cyclohepten-5-one, m.p. 128°-132° C. Use of 2-ethyl-5H-dibenzo[a,d]cyclohepten-5-one gives 80% of 2-(α-bromoethyl)-5H-dibenzo[a,d]cyclohepten-5-one, m.p. 93°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.BrCBr.[C:20](=[S:22])=[S:21].[C:23]([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:16])[C:9](=[C:20]2[S:22][CH2:23][S:21]2)[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=S
Reactant: O=C([O-])[O-]
Reactant: O=C(Cc1ccncc1)c1cccc(Br)c1
Agent: [K+]
Solvent: BrCBr
Solvent: CS(C)=O
Product: O=C(C(=C1SCS1)c1ccncc1)c1cccc(Br)c1
Yield: 74 %

Procedure:
1-(3-Bromo-phenyl)-2-pyridin-4-yl-ethanone (150 mg, 0.54 mmol), dibromomethane (114 ul, 1.62 mmol) and carbon disulfide (77 ul, 1.62 mmol) were reacted at room temperature in dry DMSO in the presence of K2CO3 (225 mg, 1.62 mmol) for three hours. The reaction, evaporated to dryness, was worked up with water and ethyl acetate. The pooled organic extracts were washed with brine, dried over sodium sulphate and evaporated down. The crude material was purified by a quick elution with ethyl acetate through a pad of silica to give the clean product in 74% yield.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.CN(CC1OC(CSCCN)=CC=1)C.[CH3:26][N:27]([CH2:29][C:30]1[O:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44](OC)=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)=[CH:32][CH:31]=1)[CH3:28].[S:49]1[CH:53]=[CH:52][C:51]([CH2:54][S:55][CH2:56][CH2:57][NH2:58])=[N:50]1>CO>[CH3:26][N:27]([CH2:29][C:30]1[O:34][C:33]([CH2:35][S:36][CH2:37][CH2:38][NH:39][C:40]2[C:44]([NH:58][CH2:57][CH2:56][S:55][CH2:54][C:51]3[CH:52]=[CH:53][S:49][N:50]=3)=[N:43][S:42](=[O:48])(=[O:47])[N:41]=2)=[CH:32][CH:31]=1)[CH3:28]
Reactant: NCCSCc1ccsn1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Agent: CN(C)Cc1ccc(CSCCN)o1
Agent: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)N=C2NCCSCc2ccsn2)o1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine according to the procedure described in Example 17, Step A, and the resultant 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with one equivalent of 2-[3-isothiazolylmethylthio]ethylamine, the title compound is produced.