Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[NH:4])[NH2:3].[CH3:15][C:16](=O)[C:17](=[O:19])C.[CH3:21]C(O)C>>[OH:19][CH2:17][C:16]1[NH:3][C:2]([C:5]2[CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=2)=[N:4][C:15]=1[CH3:21]
Reactant: CC(=O)C(C)=O
Reactant: CC(C)O
Reactant: CC(=O)Nc1cccc(C(=N)N)c1
Agent: Cl
Product: CC(=O)Nc1cccc(-c2nc(C)c(CO)[nH]2)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of N-(3-carbamimidoyl-phenyl)-acetamide hydrochloride (9.75 g, 45.6 mmol, 1.0 equiv; [CAS RN 521269-31-8], prepared according to WO 03/037 327 A1 (Hoffmann-La Roche A G)) in 2-propanol (180 mL) was added butane-2,3-dione (4.91 g, 57.0 mmol, 1.25 equiv). After heating to reflux for 20 h, the solvent was removed by evaporation under reduced pressure, water (20 mL) and 4 M HCl (40 mL) were added and the reaction mixture heated to reflux for an additional time period of 16 h. The reaction mixture was cooled down to rt, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with dichloromethane/methanol (95:5) to give 2.6 g (23%) of the title compound. MS (ISP): 246.2 [M+H]+.
Reaction SMILES: [Li+].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[Si:11]([O:18][CH2:19][C:20]1[S:24][C:23]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].Br[C:31]1[C:32](C)=[C:33]2[C:38](=[O:39])[NH:37][C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1>C1COCC1>[Si:11]([O:18][CH2:19][C:20]1[S:24][C:23]([CH:25]([CH2:2][N:37]2[C:38](=[O:39])[C:33]3[C:34](=[CH:40][CH:41]=[CH:31][CH:32]=3)[C:35]2=[O:36])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)s1
Reactant: Cc1c(Br)ccc2c1C(=O)NC2=O
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF cooled to −78° C. was added a cooled solution (approx −78° C.) of methyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)acetate (E232) in THF via syringe. The solution was stirred at −78° C. for 30 min. Bromo-methylphthalimide was added directly to the anion, and the solution was immediately removed from the −78° C. bath and placed in an ice bath and stirred for 2 h. The reaction was then poured into NH4Cl(sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 15-20% EtOAc/Hexanes) gave pure methyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(1,3-dioxoisoindolin-2-yl)propanoate (E233).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC1(C)C(C)(C)[O:12][B:11]([C:16]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:17]=2[O:18][C@@H:19]([CH3:27])[C:20]([O:22]C(C)(C)C)=[O:21])[O:10]1>C(Cl)Cl>[B:11]([C:16]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:17]=1[O:18][C@@H:19]([CH3:27])[C:20]([OH:22])=[O:21])([OH:12])[OH:10]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
TFA (10 ml) was added to a solution of the product from step (iii) (4.0 g) in DCM (100 ml) and stirred for 30 min. The TPA was evaporated and the residue dissolved in a mixture of 1M hydrochloric acid (30 ml) and acetonitrile (30 ml) After 1 h the mixture was evaporated to dryness, dissolved in 1M sodium hydroxide, washed with ether and adjusted to pH 2 with concentrated hydrochloric acid. The aqueous was then extracted with ether, washed with brine, dried (MgSO4) and evaporated. Yield 2.0 g. The crude material was carried forward to step (v).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.CS[C:16](S(C)=O)=[CH:17][N+:18]([O-:20])=[O:19].[CH3:24][NH2:25]>>[N+:18]([CH:17]=[C:16]([NH:25][CH3:24])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:20])=[O:19]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: COc1cccnc1CCCCN
Product: CNC(=C[N+](=O)[O-])NCCCCc1ncccc1OC

Procedure:
Reaction of 2-(4-aminobutyl)-3-methoxypyridine with 1-methylthio-1-methylsulphinyl-2-nitroethylene and treatment of the product with methylamine according to the general procedure of Example 2 gives 1-nitro-2-methylamino-2-[4-(3-methoxy-2-pyridyl)butylamino]ethylene.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: O=C(Cl)OCCl
Reactant: COCCOCCOCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chloromethyl chloroformate (2.94 ml) was added to an ice-cold solution of triethyleneglycol monomethylether (4.70 ml) in dichloromethane (30 ml) followed by pyridine (2.93 ml) at such a rate that the temperature was kept below 10° C. After stirring overnight at room temperature the reaction mixture was washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate, filtration, evaporation in vacuo followed by distillation in vacuo, b.p.: 102-108° C. at 0.03 mbar, afforded the title compound as a colourless oil.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCCl>[ClH:1].[CH2:26]([O:25][CH:23]1[CH2:24][NH:21][CH2:22]1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)COC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCCl
Solvent: CO
Product: CC(C)COC1CNC1
Product: Cl
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1-Chloroethyl chloroformate (83 μL, 0.77 mmol) was added to a solution of 1-benzhydryl-3-isobutoxyazetidine (175 mg, 0.60 mmol) in 1,2-dichloroethane (3 mL) at room temperature. The reaction mixture was then heated up to 70° C. and stirred for 1.5 hours. After cooling down to room temperature, methanol (3 mL) was added and the reaction mixture was heated again to 70° C. and stirred for an additional 1.5 hours. After concentration to dryness, the crude mixture was triturated in pentane (2×5 mL) to give a yellow oil (98 mg, quantitative) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:23])[F:22])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]([F:24])([F:22])[F:23])[CH2:7]1
Reactant: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2R)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.70 g, 3.83 mmol, 1.00 equiv), dichloromethane (15 mL). Trifluoroacetic acid (3.80 g, 33.3 mmol, 8.70 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 1.00 g (crude) of 4-(4-[[(3R)-3-methylpiperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl)morpholine as yellow oil. LCMS (ESI, m/z): 344 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1.Cl.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][C:25]=1[O:33][CH3:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:12]([C:9]2([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:11][CH2:10]2)=[O:13])=[CH:26][C:25]=1[O:33][CH3:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: COc1ccccc1C1(C(=O)Cl)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(CCNC(=O)C2(c3ccccc3OC)CC2)ccc1OCc1ccccc1
Reaction time: 72 h

Procedure:
A solution of 1-(2-methoxyphenyl)cyclopropane carbonyl chloride (16 g) in ethyl acetate (50 ml) was added to a stirred solution of 4-benzyloxy-3-methoxyphenylethylamine hydrochloride (22.3 g) in ethyl acetate (250 ml) and triethylamine (30 ml). The mixture was stirred for 3 days then water was added. The organic layer was washed with 5M-HCl, then water, then 2M aqueous sodium hydroxide solution, and dried over sodium sulphate. Evaporation yielded N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)cyclopropane carboxamide.
Reaction SMILES: I.[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](SC)=[NH:16])=[CH:10][C:9]=2[O:19][CH3:20])[CH:7]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:27](O)=O.[NH2:37][NH2:38]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:38][N:37]=[C:15]([NH:14][C:11]2[CH:12]=[N:13][C:8]([N:6]3[CH:7]=[C:3]([Cl:2])[N:4]=[CH:5]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:16]=1)[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1
Reactant: COc1cc(NC(=N)SC)cnc1-n1cnc(Cl)c1
Reactant: O=C(O)C(CCCCCl)c1ccc(F)cc1
Reactant: NN
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)cnc1-n1cnc(Cl)c1
Yield: 47.8 %

Procedure:
Methyl 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-ylcarbamimidothioate, hydroiodide (1.00 g, 2.349 mmol, from preparation O) and 6-chloro-2-(4-fluorophenyl)hexanoic acid (0.632 g, 2.58 mmol, from preparation AH) were coupled and then reacted with hydrazine (0.295 mL, 9.40 mmol) using a procedure analogous to Step A of Example 13. The crude product was purified using silica gel column chromatography (10-50, EtOAc/chloroform, linear gradient) to afford N-(5-(5-chloro-1-(4-fluorophenyl)pentyl)-1H-1,2,4-triazol-3-yl)-6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (550 mg, 1.122 mmol, 47.7% yield). LC-MS (M+H)+ 490.2. After purification the product was still contaminated with a significant portion of HOBt. The impure product was used for subsequent chemistry without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([C:34](=[O:36])[CH3:35])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.080 g, 0.20 mmol) and triethylamine (0.059 ml, 0.42 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.016 ml, 0.22 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.062 g, 77%) as white solid. MS m/e: 403 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[CH2:11][SiH:12]([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15].BrC1C=CC(Br)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:12]([CH3:11])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccc(Br)cc1
Reactant: CC(C)O[SiH](CCl)OC(C)C
Solvent: C1CCOC1
Solvent: Brc1ccc(Br)cc1
Product: CC(C)O[Si](C)(OC(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
A solution of 4-bromophenyl magnesium bromide (7.82 g, 50 mmol) in THF (100 ml) was added at 0° C. to a solution of chloromethyldiisopropyloxysilane (10 g, 48 mmol). The mixture was stirred at room temperature for 24 hours. After evaporation of the solvent, the yellow solid was extracted by 200 ml of dry pentane and filtered. The solvent was then pumped off to afford a yellow oil. Residual 1,4-dibromobenzene was sublimated under vacuum at 80° C. to give 4-bromo-1-(methyldiisopropyloxysilyl)benzene as a colourless oil in 33% yield (5.1 g, 16 mmol). 1H NMR (CDCl3, δ, ppm) 7.52 (4H, m); 4.22 (2H, heptuplet); 1.24 (12H, d); 0.39 (3H, s). 13C NMR (CDCl3, δ, ppm) 136.1, 134.5, 131.3, 125.1, 65.8, 26.1, −2.8. 29Si NMR (CDCl3, δ, ppm) −21.8.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-].Cl>O1CCOCC1.O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2ccc(C#N)nc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
Methyl 4-(6-cyano-3-pyridinyl)benzoate (D8) (0.5 g) in dioxane (30 ml) was treated with 1.1 eq aqueous LiOH solution (2.3 ml, 1N) and stirred at rt for 2 days. Solvent was removed by evaporation to give a white solid which was dissolved in water (10 ml) and acidified with 2N HCl to give a white solid which was filtered and dried to give the title compound (D9) (0.35 g). LCMS electrospray (+ve) 224 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[CH:3]=[N:2]1)=[CH:10][C:9]([CH:13]=[O:14])=[CH:8][CH:7]=3.[I:15]N1C(=O)CCC1=O>CN(C)C=O>[I:15][C:3]1[C:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=3)[C:5]=2[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1ccc2c(c1)Cc1cn[nH]c1-2
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)Cc1c(I)n[nH]c1-2
Temperature: 25 °C

Procedure:
A solution of Example 316 (2.13 g, 11.6 mmol) and N-iodosuccinimide (3.13 g, 13.9 mmol) in N,N-dimethylformamide (45 mL) was heated to about 80° C. for about 5 hours. The reaction mixture was cooled to room temperature and was concentrated in high vacuum. The residue was partitioned between water and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to provide the desired product. MS (ESI): m/z 309 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[Cl:10]N1C(=O)CCC1=O.ClNC1C=CC(C#N)=CN=1>C(#N)C>[NH2:1][C:2]1[C:7]([Cl:10])=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc(N)nc1
Agent: N#Cc1ccc(NCl)nc1
Solvent: CC#N
Product: N#Cc1cnc(N)c(Cl)c1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 6.0 g (0.05 mol) of 2-amino-5-cyanopyridine, 8.3 g (0.0625 mol) of N-chlorosuccinimide and 200 g of acetonitrile were added, and the reaction was conducted at 50° C. for one hour with stirring. During the reaction, the reaction product was analyzed by liquid chromatography, whereby formation of 2-chloroamino-5-cyanopyridine was confirmed. After completion of the reaction, acetonitrile was distilled off. To separate succinimide and the desired product, 50 g of water was added to the remaining product, and the mixture was stirred. Precipitated crystals were collected by filtration, washed with 50 g of toluene and dried to obtain 6.9 g of 2-amino-3-chloro-5-cyanopyridine as slightly brown crystals (purity as measured by liquid chromatography: 98%, yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:23]C)=[CH:4][C:5]2[CH:11]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10][N:9]([CH3:21])[CH2:8][CH2:7][C:6]=2[CH:22]=1.[Br:25]Br>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[CH:11]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[C:14]([Br:25])[CH:13]=3)[CH2:10][N:9]([CH3:21])[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: COc1cc2c(cc1Cl)CCN(C)CC2c1cccc2c1OCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: CN1CCc2cc(Cl)c(O)cc2C(c2cc(Br)cc3c2OCC3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+) 8-Chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.0 g, 2.9 mmol) was dissolved in acetic acid (10 ml). To the stirred solution was added bromine (0.20 ml, 4.0 mmol) in acetic acid (5 ml) over a period of 2 h. The mixture was stirred overnight at room temperature. A precipitate was formed. The white solid was filtered and washed with diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.S([Cl:39])(C)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][Cl:39])[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1
Reactant: OCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-(2-chlorophenothiazin-10-yl)propyl]-1-piperazineethanol (22.5 g) was added to 186 ml of dry dichloromethane containing triethylamine (7.8 ml). The stirred solution was cooled to -10° and maintained at that temperature during the dropwise addition of a solution of 5.1 ml of mesyl chloride in 50 ml of dry dichloromethane. The ice bath was then removed and the reaction was stirred overnight at room temperature. The solution was washed with 25 ml of a 5% sodium bicarbonate solution and then dried over anhydrous potassium carbonate. The solvent was removed in vacuo (bath temperature, 25°) to yield 24.2 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4(2-chloroethyl)piperazine 2a as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[C:11]([CH3:14])[N:10]=1.[Cu][C:16]#[N:17]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[N:10]=2)[CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1n[nH]c(-c2cc(F)ccc2Br)n1
Product: Cc1n[nH]c(-c2cc(F)ccc2C#N)n1
Yield: 26 %

Procedure:
5-(2-Bromo-5-fluorophenyl)-3-methyl-1H-1,2,4-triazole (4.00 g, 15.6 mmol) was treated with copper (I) cyanide as described in the procedure for intermediate 150 to give 0.83 g (26% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.66 (3H, s, CH3), 7.21-7.25 (1H, m, aromatic), 7.84 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.10 (1H, dd, J=2.8 Hz and J=9.3 Hz, aromatic). HRMS (ESI+) calculated for C10H8FN4 [M+H+]: 203.0733; found: 203.0743.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][N:13]=[N:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][N:13]=[N:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(-c2cnns2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(-c2cnns2)ccc1OCC1CO1

Procedure:
To a solution of 0.92 g. of sodium hydroxide in 425 ml. of water is added 4.1 g. of 5-(4-hydroxyphenyl)-1,2,3-thiadiazole and 5.4 ml. of epibromohydrin, stirring the reaction mixture for 20 hours at room temperature. It is then extracted with ethyl acetate, and the organic extract washed with water to neutrality, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel plates using a mixture of chloroform-acetone (95:5) as eluant to yield 5-[4(2,3-epoxypropoxy)phenyl]-1,2,3-thiadiazole. This product can be further purified by crystallization from methylene chloridehexane.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH:21]([CH3:23])[CH3:22])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:27])(=O)=O>ClCCl>[Cl:27][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:21]([CH3:23])[CH3:22])[S:10]1(=[O:12])=[O:11]
Reactant: CC(C)c1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cccc2c1C(=O)N(CCl)S2(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-Phenylthiomethyl-4-isopropylsaccharin (53.5 g), sulfuryl chloride (40 mL, 67.2 g) and dichloromethane (250 mL) were mixed with stirring at room temperature. The mixture underwent a slightly exothermic reaction and was allowed to stand for 17 hours at room temperature, then stripped of volatiles. The residue crystallized with hexane in three crops (33.65 g, m.r. 101°-102° C.; 3.45 g, m.r. 100°-101° C.; 0.45 g, m.r. 99°-100° C.; total 38.55 g, 91% yield). The three crops were combined and recrystallized from isopropyl alcohol (30 mL)-cyclohexane (270 mL) affording 2-chloromethyl-4-isopropylsaccharin in two crops (33.5 g, m.r. 101°-102.5° C.; 2.65 g, m.r. 100°-101° C.).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[O-2:10].[Zn+2:11].[O-2:12].[Ca+2:13]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Zn+2:11].[OH:10][Ca:13][OH:12].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: [Ca+2]
Reactant: [O-2]
Agent: O=C(O)CC(O)C(=O)O
Agent: [Zn+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)[O-]
Product: O[Ca]O

Procedure:
An aqueous solution of malic acid was prepared by mixing 134.09 g of malic acid with 50 mL of water. An aqueous solution of zinc oxide was also prepared in a separate container by thoroughly mixing 81.38 g of zinc oxide in 25 mL of water. An aqueous solution of calcium oxide was also prepared in a separate container by thoroughly mixing 56.08 g of calcium oxide in 25 mL of water. The zinc oxide solution and the calcium oxide solution were then slowly added to the malic acid solution. The resulting solution was then spray dried to produce a powdered dihydroxycalcium zinc malate (or calciumhydroxy zinchydroxy malate).
Reaction SMILES: NC(N)=[S:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH2:10]Cl.[OH-].[Na+].Cl[CH2:20][C:21]([O-:23])=O.[Na+]>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH2:10][CH2:20][C:21]([OH:23])=[S:3]
Reactant: O=C([O-])CCl
Reactant: COc1ccc(CCl)cc1OC
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CCC(O)=S)cc1OC
Reaction time: 0.5 h
Yield: 69 %

Procedure:
13.07 g (0.172 mol) of thiourea and 86 ml of water are introduced into a 1 liter 3-necked flask equipped with a magnetic stirrer and a condenser. The mixture is heated to 50°-60° C. and 32 g (0.172 mol) of 3,4-dimethoxybenzylchloride are added in a single operation. -- The reactants are heated to reflux and boiling is maintained for 15 mins; the solution becomes limpid. Thereafter the mixture is cooled and a solution of 27.52 g (0.688 mol) of NaOH in 43 ml of water is introduced dropwise at about 60° C. Heating under reflux is again carried out for 30 minutes, the mixture is cooled and a solution of sodium chloroacetate (obtained by neutralising 22.76 g of chloroacetic acid in 172 ml of water with 20.23 g of NaHCO3) is added dropwise at 60°-70° C. The whole is then heated under reflux for 30 minutes, cooled, filtered and then acidified with 3N HCl. After recrystallisation from toluene, 28.7 g of 3,4-dimethoxybenzylthio-acetic acid are obtained. Yield: 69%. Instantaneous melting point: 94° C.