Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:21][CH2:22][O:23][CH3:24])[N:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:5])[CH3:2]
Reactant: COCCBr
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c([N+](=O)[O-])cnn1CCOC
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.54 mmol) in DMSO (1 mL) was added potassium carbonate (164 mg, 1.19 mmol) and the reaction mixture was stirred for 5 min. 1-Bromo-2-methoxyethane (110 μl, 1.19 mml) was added and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The product was obtained as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 72 mg (55%) of the desired regioisomer and 33 mg (25%) of 2-(2-methoxyethyl)-4-nitro-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrCCCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOCCCO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCCCCBr
Temperature: 80 °C
Reaction time: 7 h
Yield: 32.6 %

Procedure:
3-(Octadecyloxy)propanol (5.0 g), 1,6-dibromohexane (11.1 g) and cetyltrimethylammonium chloride (0.97 g) are added to toluene (60 ml). To the mixture is added a 50% aqueous solution of sodium hydroxide (12.2 g), and the resulting mixture is stirred at 80° C. for 7 hours. After the reaction, the organic layer is separated, and the aqueous layer is subjected to extraction with n-hexane. The organic layers are combined, washed with dilute hydrochloric acid, dried and concentrated. The residue is subjected to purification by means of silica gel chromatography to obtain the above-titled compound as colorless solid (2.44 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[C:9]2=[N:10][C:11]([CH3:26])=[C:12]([C:21]([O:23]CC)=[O:22])[C:13]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]2[CH:7]=[N:6]1)[CH3:4]>C(O)C>[CH2:3]([N:5]1[C:9]2=[N:10][C:11]([CH3:26])=[C:12]([C:21]([OH:23])=[O:22])[C:13]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]2[CH:7]=[N:6]1)[CH3:4]
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1NC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)c(C)nc21
Yield: 73.6 %

Procedure:
2M-Sodium hydroxide solution (0.75 ml, 1.5 mmol) was added to Intermediate 59 (0.248 g, 0.75 mmol) in ethanol (2 ml), and the mixture was heated at reflux for 16 hours. The reaction mixture was concentrated, diluted with water (1 ml) and acidified with 2M-hydrochloric acid (0.75 ml) to precipitate a solid which was collected by filtration to afford Intermediate 60 (0.168 g). LCMS showed MH+=305; TRET=1.86 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH2:8])[O:3]1.[N+:9]([C:12]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:6][O:5][CH:4]([CH2:7][NH:8][C:16](=[O:17])[CH:15]([O:14][C:13]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[CH:22]=[CH:23][C:12]=2[N+:9]([O-:11])=[O:10])[CH3:19])[O:3]1
Reactant: CC(Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: CC1COC(CN)O1
Solvent: ClCCl
Product: CC1COC(CNC(=O)C(C)Oc2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])O1
Temperature: -15 °C

Procedure:
N-(4-Methyl-1,3-dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2,4-dichlorophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(4-methyl-1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2,4-dichlorophenoxy)phenoxy]propionamide.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S+:12]=2)=[CH:7][CH:6]=1)[CH3:3].C(O)C.[CH3:35][N:36]([C:38]1[CH:39]=[CH:40][C:41]([N:44]=[N:45][C:46]2[CH:47]=[CH:48][C:49]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][CH:51]=2)=[CH:42][CH:43]=1)[CH3:37]>O>[CH3:35][N:36]([CH3:37])[C:38]1[CH:39]=[CH:40][C:41]([N:44]=[N:45][C:46]2[CH:51]=[CH:50][C:49]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:48][CH:47]=2)=[CH:42][CH:43]=1.[CH2:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S+:12]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: CCOc1ccc(-c2cc(-c3ccc(N(C)C)cc3)cc(-c3ccccc3)[s+]2)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)[O-])cc2)cc1

Procedure:
To a solution of 2-(4'-ethoxyphenyl)-4-(4' -dimethylaminophenyl)- 6-phenylthiapyrylium chloride, 8.95 g, in a hot mixture of water, 400 mls, and ethanol, 100 mls, is added briskly a solution of Methyl Orange, E.K. 432, 7.0 g, in hot water, 200 mls, containing approximately 25 mls ethanol. Some precipitate comes out of solution immediately and quickly solidifies, and more crystallizes out as the mixture cools. The solid is readily filtered from the cool mixture, and is taken up in hot ethanol, filtered, evaporated down and allowed to cool slowly overnight. The solid that comes down is filtered off and dried at room temperature at 60 mm pressure overnight. Yield 11.1 g having structural formula III noted above and exhibiting light absorption maxima (when dissolved in ethanol) at 578 and 425 nm.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:36]=[CH:35][N:34](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[OH-].[K+]>CO>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:36]=[CH:35][NH:34][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:26][CH2:27][N:28]([C:31](=[O:33])[CH3:32])[CH2:29][CH2:30]5)=[CH:21][CH:20]=4)[N:17]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5c(C)n[nH]c5c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5c(C)n[nH]c5c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 60 °C
Yield: 44.2 %

Procedure:
To a solution of 1-(4-(4-(4-(3-methyl-1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg, 0.047 mmol) in methanol (MeOH) (3 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. The mixture was heated at 60° C. for 5 h. and then concentrated in vacuo. The residue was acidified with HOAc (1 mL) before being purified by HPLC to give 1-(4-(4-(4-(3-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (10 mg), MS 482.2 (M+H) (Compound 2-1); and N4-(3-methyl-1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (3 mg), MS 440.1 (M+H) (Compound 2-2).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([O:9][CH3:10])=[O:8].C=C.[CH2:21](N(CC)CC)[CH3:22].Cl>[Cl].C(Cl)(Cl)Cl.CCOCC.O>[O:1]1[CH2:22][CH2:21][C:3]([C:4]2[C:5]([CH3:18])=[C:6]([CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:15])=[O:16])[C:7]([O:9][CH3:10])=[O:8])=[N:2]1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1C
Agent: C=C
Agent: Cl
Agent: [Cl]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1C
Reaction time: 0.58 h

Procedure:
6.00 g of crude methyl 3-hydroxyiminomethyl-4-methylsulfonyl-2-methylbenzoate was dissolved in 100 ml of chloroform Chlorine was blown into the resulting solution, with stirring, for 35 minutes at -3~3° C. The solution was further stirred for 30 minutes at 0° C. Nitrogen gas was blown into the reaction solution to remove excessive chlorine. Further chloroform was distilled out under reduced pressure to give viscous oil. The obtained oil was dissolved in 90 ml of ether, and ethylene was blown in, with stirring, for 5 minutes at -10° C. Then 7 ml of triethylamine and 7 ml of ether were added dropwise at -10° C. Further ethylene was blown in for 20 minutes. The resulting reaction mixture was transferred to a 200 ml, stainless-steel autoclave, which was cooled beforehand, and stirred for 3.5 hours at 60~70° C. The reaction solution was cooled down, poured into water, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. The obtained crude product was purified by column chromatography on silica gel with n-hexane/ethyl acetate=2/1 to give 3.20 g of the title compound as white crystals. m.p. 104~106.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[N:24]=1>>[CH3:29][N:25]1[C:26]([CH3:28])=[CH:27][C:23]([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[N:24]1
Reactant: Cc1cc(CBr)nn1C
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cc(C)n(C)n3)C2=O)cn1
Yield: 22 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole. Yield: 22%. MS M+H calculated 384.1; found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.3 uM
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=[C:8]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:7]3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:19]=O.Cl>C(O)=O>[CH3:19][CH:17]1[CH2:16][CH2:15][C:8]2=[CH:9][CH:10]=[N:11][CH:12]=[CH:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][CH:7]2[CH2:18]1
Reactant: C1=Cc2ccccc2OC2CCCCC2=CC=N1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CC1CCC2=CC=NC=Cc3ccccc3OC2C1
Temperature: 100 °C

Procedure:
1 gram of 6,7,8,9-tetrahydro-5H-dibenz(b,i)(1,6)oxazecine was mixed with 4 ml formic acid and 3.8 ml of 37% formalin. This mixture was heated for 1 hour at 100° C. After cooling 0.5 ml of concentrated hydrochloric acid was added and the reaction mixture was evaporated. The residue was then dissolved in dilute NaOH, and the mixture extracted with ether. The ether extract was washed, dried and evaporated to dryness.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([C:9]#[C:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].C(=O)([O-])[O-].[H][H]>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:19][Si:2]([CH3:1])([CH2:9][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:6])([F:7])[F:8]
Reactant: [H][H]
Reactant: C[Si](C)(C#CCOC1CCCCO1)CCC(F)(F)F
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(CCCOC1CCCCO1)CCC(F)(F)F
Temperature: 25 °C

Procedure:
A suspension of compound 3 (5.00 g, 20.00 mmol) palladium hydroxide on charcoal (0.68 g, 0.21 mmol) in ethyl acetate and ethanol (100 ml, 9:1) and sodiumhydrohen carbonate (0.165 g, 1.96 mmol) were stirred at room temperature and a pressure of 100 pounds inch-2 under hydrogen for 24. The reaction mixture was filtered and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.58] to yield a colorless oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C[OH:17]>C(OC(C)COC)(=O)C>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:17])=[O:5].[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C1C=CC(=O)O1
Reactant: CO
Solvent: COCC(C)OC(C)=O
Solvent: C=CCCCCCC
Product: O=C(O)/C=C\C(=O)O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A solution of 9.8 g of maleic anhydride (0.1 mole) and 11.2 g of 1-octene (0.1 mole) in 30 g of propylene glycol methyl ether acetate was heated under agitation and nitrogen to 95° C. A solution of 2 g of t-butyl peroxy-2-ethylhexanoate in 6 g of propylene glycol methyl ether acetate was then injected into the reaction vessel within half hour via a syringe pump. The reactants were agitated for another 2 hours at 95° C. before being cooled to room temperature. The product was then poured into methanol which caused precipitation of a white solid which was filtered and air-dried to give 12.7 g of a maleic acid/1-octene copolymer having a number 2 0 average molecular weight by vapor phase osmometry (VPO) of 2800. The approximate composition of the copolymer by 13CNMR:
Reaction SMILES: Cl.C([S:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:17][C:12]=2[S:11][C:10]1=[NH:23])(C)(C)C.[BrH:24]>>[BrH:24].[BrH:24].[NH:23]=[C:10]1[N:9]([CH2:8][CH2:7][S:6][S:6][CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:17][C:12]=3[S:11][C:10]2=[NH:23])[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:17][C:12]=2[S:11]1
Reactant: CC(C)(C)SCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Agent: Br
Agent: Cl
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSSCCn1c(=N)sc2cc(OC(F)(F)F)ccc21

Procedure:
3-(2-tert-Butylthioethyl)-2-imino-6-trifluoromethoxybenzothiazoline hydrochloride (16.8 g) and 48% strength hydrobromic acid (500 cc) are heated to 120° C. for 18 hours. The precipitate formed is filtered off and washed with distilled water (2×50 cc) and then with ethyl ether (2×50 cc). Bis[2-(2-imino-6-tri-fluoromethoxy-3-benzothiazolinyl)ethyl]disulphide dihydrobromide (10.0 g), m.p. above 260° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:13])[N:4]([CH2:11][CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[OH:8].[CH:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:13])[N:4]([CH2:11][CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[O:8][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:21][CH:22]=1
Reactant: ClCc1ccc(C2CCCCC2)cc1
Reactant: CCn1c(SC)nc(O)c(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(SC)nc(OCc2ccc(C3CCCCC3)cc2)c(Br)c1=O
Yield: 100 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1 g of 5-bromo-3-ethyl-6-hydroxy-2-methylthio-4(3H)-pyrimidinone and 0.8 g of 4-cyclohexylbenzyl chloride, and then 1 g of anhydrous potassium carbonate was added thereto. The mixture was subjected to a reaction at 80° C. for 3 hours. After allowing to cool in air, the resulting solution was poured into 50 ml of water and extracted twice with 30 ml of ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to give 1.65 g of a crude product.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:5][N:6]=1.[CH2:18]([C:20]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:4]2[S:3][C:2]([C:27]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:24]=[CH:25][CH:26]=3)[CH:22]=[O:23])=[N:6][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1Cl
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 130 °C
Yield: 28.3 %

Procedure:
To a suspension of 2-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazole (D10) (0.5 g), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (0.468 g) and tripotassium phosphate (0.795 g) in N,N-dimethylformamide (DMF) (10 mL) and Pd(Ph3P)4 (0.173 g). The reaction mixture was degassed and then the reaction vial was sealed and heated under microwave at 130° C. for 10 min. Water was then added to the reaction mixture. The mixture was extracted with EA. The combined organic solution was dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to give 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (D11) (164 mg). MS (ES): C20H19ClN2O2S requires 386. found 387.1 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][NH:10][C:9]2=O.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[Cl:21]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OCCCCl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OCCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (400 gm), thionyl chloride (3.2 lt) and DMF (100 ml) were refluxed for 7-8 hours. Thionyl chloride was distilled off completely under reduced pressure below 45° C. Methylene chloride (2.5 lt) and water (1.5 lt) were charged, stirred for 30 minutes at room temperature and the layers separated. The aqueous layer was extracted twice with methylene chloride (500 ml), the combined methylene chloride layer was washed with 1% sodium bicarbonate solution (1 lt), dried over sodium sulphate (20 gm) and concentrated under reduced pressure at 35-40° C. The residue was stirred with isopropyl alcohol (400 ml) at 40-45° C. for 1 hour, cooled to 0-5° C., the solids filtered, washed with chilled isopropyl alcohol (200 ml) and dried under vacuum at 45° C. to yield the title compound (406 gm, 95% yield).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:23][C:22](=[O:24])[NH:21][S:20]3(=[O:26])=[O:25])=[C:13]([OH:18])[CH:14]=2)[CH2:9]1.[OH-].[Na+]>C1COCC1.CO.O>[OH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:19]1[CH2:23][C:22](=[O:24])[NH:21][S:20]1(=[O:26])=[O:25])[CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][C:4]([CH3:28])([CH3:27])[C:3]([OH:29])=[O:2])[CH2:17][CH2:16]2
Reactant: COC(=O)C(C)(C)CCCC1CCc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(CCCC1CCc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2C1)C(=O)O
Temperature: 80 °C

Procedure:
To a solution of 5-[6-Hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-2,2-dimethylpentanoic acid methyl ester (50 mg, 0.12 mmol) in THF/MeOH/H2O (3:3:1 v/v/v, 1 mL,) is added NaOH (50 mg) and it is heated at 80° C. in microwave for 10 min. The solution is concentrated, dissolved in H2O and neutralized with 1N HCl solution. It is then purified by RP-HPLC to give the title compound as a light yellow solid: 1H NMR(CD3OD) δ1.17 (s, 6H), 1.29-1.35 (m, 5H), 1.39-1.41 (m, 2H), 1.60-1.70 (m, 1H), 1.90-1.94 (m 1H), 2.25-2.35 (m, 1H), 2.71-2.75 (m, 3H), 4.27 (s, 2H), 6.59 (s, 1H), 7.09 (s, 1H); (M−H)−=409.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=2)[C:12]([CH2:21][OH:22])([CH3:20])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:23]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=2)[C:12]([CH2:21][O:22][CH3:23])([CH3:20])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C)(CO)c2ccc(Br)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(C)CN(C(=O)OC(C)(C)C)c2cc(Br)ccc21
Yield: 80.2 %

Procedure:
NaH (60% dispersion in mineral oil, 60 mg, 1.5 mmol) was added to a solution of 6-bromo-3-hydroxymethyl-3-methyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (360 mg, 1.05 mmol) in dry DMF (5 mL). After 10 minutes MeI (66 μL, 1.1 mmol) was added and the stirring was maintained for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. Chromatography (20% EtOAc in 40-60 petroleum ether) gave the title compound (300 mg) as a colourless liquid. MS: [M−tBu]+=300.