Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(Br)(Br)(Br)[Br:40]>ClCCl>[Br:40][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCCBr
Temperature: 25 °C
Yield: 87.8 %

Procedure:
This example is a method of synthesis for inventive compound no. 3508. Triphenylphosphine (5.24 g, 20 mmol) was added incrementally to a solution of oleyl alcohol (5.37 g, 20 mmol) and carbontetrabromide (6.63 g, 20 mmol) in 400 ml of dichloromethane, the resulting reaction mixture being stirred for an hour at room temperature. Removing the solvent under reduced pressure, left a residue, which was extracted with three 200 ml aliquots of hexane. Further purification by flash chromatography over silica gel using a hexane eluant produced 5.82 g of 1-bromo-9-octadecene (88% yield).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccnc4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.6 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 65% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Br:9]Br.O>C(O)(=O)C>[Br:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: BrBr
Reactant: O=C(O)c1ccsc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1csc(Br)c1
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0 mmol) in acetic acid (140 mL), was added dropwise, a solution of bromine (6.60 g, 40.0 mmol) in acetic acid (40 mL). The reaction mixture was stirred for 30 minutes and then poured into water. The resultant solid was collected by filtration to afford the title compound as a grey solid (2.07 g, 26%). LCMS (Method B): RT=2.9 min, M+H+=208.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])[CH3:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:28](=[O:30])[CH3:29])[CH:36]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C(C)=O)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208. mg, 0.5 mmol), 3-acetylphenylboronic acid (90 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3-acetyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][NH:24][CH2:25][CH2:26][NH:27][CH3:28]>C(#N)C>[ClH:1].[ClH:1].[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:24]([CH3:23])[CH2:25][CH2:26][NH:27][CH3:28])[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CNCCNC
Solvent: CC#N
Product: CNCCN(C)c1ccc2c(C(=O)NCC3CCCCC3)c(Cl)ccc2n1
Product: Cl
Temperature: 100 °C

Procedure:
A stirred suspension of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43 (a)) (200 mg) and N,N′-dimethyl-1,2-ethanediamine (0.30 mL) in acetonitrile (2 mL) was heated at 100° C. in a microwave for 90 minutes after which it was cooled to room temperature and concentrated. Purification (SiO2, dichloromethane:methanol:ammonia in methanol (7 M) 95:5:0.5), conversion to the dihydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane) and recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (160 mg).
Reaction SMILES: [Cl-].[Ca+2:2].[Cl-].[P:4]([OH:8])([O-:7])([O-:6])=[O:5].[Na+].[Na+]>>[OH-:5].[O-:6][P:4]([O-:8])([O-:7])=[O:5].[O-:6][P:4]([O-:8])([O-:7])=[O:5].[O-:6][P:4]([O-:8])([O-:7])=[O:5].[Ca+2:2].[Ca+2:2].[Ca+2:2].[Ca+2:2].[Ca+2:2]
Reactant: O=P([O-])([O-])O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: O=P([O-])([O-])[O-]
Product: [OH-]

Procedure:
Brushite was prepared in the same manner as in Example 1 except that 1 l of an aqueous calcium chloride solution of 0.5 mol/l in concentration and 1 l of an aqueous disodium phosphate solution of 0.5 mol/l in concentration were used and reaction temperature was room temperature. Then, at 95° C., 300 ml of an aqueous sodium hydroxide solution of 1 mol/l in concentration was added to the resulting brushite over a period of 1 hour to obtain hydroxylapatite in the form of platy crystal [hereinafter referred to as "hydroxylapatite (H)"].
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([OH:13])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1[CH:18]=CC2N(O)N=[N:23][C:21]=2[CH:22]=1.CN1CCOCC1.N1CCCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:2]1([CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([N:23]2[CH2:18][CH2:17][CH2:22][CH2:21]2)=[O:13])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CN1CCOCC1
Product: O=C([C@@H]1CCCN1Cc1ccccc1)N1CCCC1
Reaction time: 8 h
Yield: 76 %

Procedure:
1-(Phenylmethyl)-L-proline hydrochloride (2.0 g, 8.247 mmol) and HOBt (1.34 g, 9.928 mmol) were dissolved in CH2Cl2 (50 mL), and 4-methylmorpholine (3.63 mL, 33.09 mmol), pyrrolidine (0.760 mL, 9.101 mmol), and EDCI (1.906 g, 9.928 mmol) were added. The solution was stirred overnight, and was then washed with water (50 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL), and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes, 1% triethylamine) to provide (2S)-1-(phenylmethyl)-2-(1-pyrrolidinylcarbonyl)pyrrolidine (1.619 g, 76%). LCMS: (M+H)+: 259.2
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:3][CH:2]=1.N.Cl[CH2:18]Cl>>[NH:14]1[CH2:13][CH:12]([CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[N:15]=[CH:18]1
Reactant: ClCCl
Reactant: NCC(N)Cc1ccnc2ccccc12
Agent: N
Product: C1=NC(Cc2ccnc3ccccc23)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 3-Quinolin-4-yl-propane-1,2-diamine (0.080 g, 3.98 mmol) in 5 ml of dry dichloromethane, formidic acid ethyl ester hydrochloride (0.174 g, 7.96 mmol) (Ohme, R. et al. Angew. Chem. Int. Engl. Ed. 1967, 6, 90) was added. The reaction mixture was stirred overnight at room temperature. Aqueous ammonia (2 ml) was added to the reaction mixture and was partitioned between EtOAc (2×5 ml) and water. The organic layer was dried, filtered and concentrated to give 0.084 g (100%) of the product as a syrup.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:35][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ncccn4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ncccn3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield the desired product. 1H NMR (400 MHz, CDCl3) δ8.76 (d, 1H), 8.45 (d, 2H), 8.06 (d, 2H), 7.15 (t, 2H), 6.76 (d, 2H), 6.71 (d, 2H), 4.14 (t, 2H), 2.93 (t, 2H), 2.33 (s, 3H), 1.45 (s, 6H); MS (EI) 460.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2C(=O)C3=CC=CC=[C:17]3[C:16]2=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[C:16]([NH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)(=[O:25])[CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
A mixture of N-[(4-benzyl-2-morpholinyl)methyl]phthalimide (162 g), 85% hydrazine hydrate (43.3 g), and ethanol (100 ml) is refluxed with stirring for 20 minutes. The reaction mixture is filtered, and the filtrate is diluted with water and extracted with chloroform. The organic layer is separated, washed with a small amount of water and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. To the filtrate is added slowly acetic anhydride (98.3 g), and the resulting mixture is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from toluene to give the title compound (101 g), mp 110°-111° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH2:13]([NH2:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([NH:15][CH2:13][CH3:14])[N:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: CC(C)Nc1nc(Cl)nc(Cl)n1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCNc1nc(Cl)nc(NC(C)C)n1

Procedure:
To the solution of 2,4-dichloro-6-isopropylamino-s-triazine in toluene remaining in the reactor are added, under strong agitation, about 915 g of an aqueous solution containing 50% by weight of ethylamine (10.15 moles) and about 1353 g of an aqueous solution containing 30% by weight of sodium hydroxide (10.15 moles). The said solutions are added in the same manner as in the first reaction step. During the second addition the temperature rises from 25° to 50° C. and the final pH is equal to 11-12. The dense suspension thus obtained is divided into two parts as quickly as possible. One part (A) is submitted to distillation to remove the toluene in the form of an azeotropic toluene-water mixture, by operating at 85°-100° C. To the distillation residue are added 3,700 ml of water and the suspension thus obtained is filtered at 60° C. The filtered solid is washed until the sodium chloride has been removed completely. After drying for ten hours in an oven at 100° C., 2-chloro-4-ethylamino-6-isopropylamino-s-triazine is obtained with a yield of the order of 96%.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=O.C[O-].[Na+]>C(#N)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2([CH3:11])[CH2:10][O:9]2)=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CSC
Solvent: CC#N
Product: CC1(c2ccc(I)cc2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 30 g of dimethyl sulfide in 30 ml of acetonitrile was added dropwise over a period of 30 minutes 30 g of dimethyl sulfate, while maintaining the temperature at 40° to 50° C., and the mixture was stirred for one hour at the same temperature. The reaction mixture was cooled to 25° C. and mixed with 30 g of 4-iodoacetophenone and 90 ml of acetonitrile. While stirring, 13.2 g of sodium methoxide was added to the mixture and stirring was continued for a further 30 minutes at room temperature to complete the reaction. Thereafter, the dimethyl sulfide and acetonitrile were removed by distillation, and to the residue were added 120 ml of cyclohexane and 120 ml of water, after which the mixture was thoroughly shaken. The organic layer was separated, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 31.5 g (99% yield) of oily 2-(4-iodophenyl)-2-methyloxirane having a melting point of 44°-45° C.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]([CH2:24][CH2:25]Cl)[CH:22]([CH2:27]Cl)[CH2:21][N:20]=[C:19]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[C:18]=2[CH:34]=1.ClC1CN=C(C2OC=CC=2)C2C=CC(Cl)=CC=2N(CCCl)C1.C(Cl)(Cl)Cl>O.O1CCOCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH2:24][CH2:25][S:10][CH2:27][CH:22]3[CH2:21][N:20]=[C:19]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[C:18]=2[CH:34]=1
Reactant: [S-2]
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Agent: ClCCN1CC(Cl)CN=C(c2ccco2)c2ccc(Cl)cc21
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)C(c1ccco1)=NCC1CSCCN21
Yield: 86 %

Procedure:
8.5 g of disodium sulphide nonahydrate in 75 ml of water are added to a solution of 12.7 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine (or a mixture of this compound and the isomeric 3,9-dichloro-1-(β-chloroethyl)-6-(2-furyl)-1,2,3,4-tetrahydro-1,5-benzodiazocine (for the preparation see Example 5B) in 150 ml of dioxane, and the reaction mixture is heated under reflux for 5 hours. After the solvent has been stripped off in vacuo, the crude reaction product is isolated from chloroform and is then purified by chromatography on aluminium oxide of activity level II, using methylene chloride, and crystallised from ether. 9.7 g of 1,2,4,4a-tetrahydro-9-chloro-7-(2-furyl)-5H-[1,4]-thiazino[4,3-a][1,4]benzodiazepine are obtained. Melting point: 138° to 140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[N:7][CH:6]=1.[Se](=O)=[O:33].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19](=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[N:7][CH:6]=1
Reactant: CCC(C)Oc1cccc(Cc2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(C)Oc1cccc(C(=O)c2ncc(CC(=O)OC)c3cc(OC)c(OC)cc23)c1
Temperature: 85 °C
Yield: 82.7 %

Procedure:
To a stirred solution of [1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester (200 mg, 0.47 mmol) in ethyl acetate (4 mL) was added selenium dioxide (65 mg, 0.59 mmol). The reaction mixture was heated at 85° C. for 1 hr. The solvent was evaporated and afford a crude product. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded [1-(3-sec-butoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid methyl ester as a light brown oil (170 mg, 83% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH2:20])[CH3:2].N1C=CC=CC=1.S(=[N:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])=O>ClCCl>[NH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:20][C:4]1[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:34]
Reactant: O=S=Nc1cccc(C(=O)Cl)c1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (2.09 g, 6.9 mmol) (prepared according to EP 1,006,102) in dichloromethane (30 ml) under stirring at 25° C., was added sequentially pyridine (0.8 ml, 9.9 mmol) and a solution of 3-sulfinylamino-benzoyl chloride (1.39 g, 6.9 mmol) (Example 1.1) in dichloromethane (7 ml). The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was quenched by addition of aqueous hydrochloric acid (2N) (4 ml) and stirred vigorously for 20 minutes. The mixture was diluted with water (20 ml) and the phases separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed successively with aqueous sodium hydrogen carbonate (saturated) and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:4 to 3:2). After evaporation of the solvents, the yellow oil was triturated with hexane, where it crystallized. The desired compound was isolated as white crystals. M.p. 143-145° C. 1H-NMR as described for Example 3.1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[K+]>CO.O.C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:27])[CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([OH:19])=[O:18])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccccc2)cc1
Yield: 74 %

Procedure:
A solution of 1.50 g of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-phenylacetate and 1.50 g of KOH in a methanol/water/THF mixture was stirred at room temperature for 18 hours. The solution was then evaporated, the residue was dissolved in water and then acidified with 2N hydrochloric acid, and the precipitate was collected and dried to give 1.07 g of 2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}(methyl)amino]-2-phenylacetic acid as colorless crystals, Calc'd for C19H19NO5S: C, 61.11, H, 5.13, N, 3.75. Found: C, 60.66, H, 5.16, N, 3.53.
Reaction SMILES: [OH:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([NH:5][C:6]1[S:10][N:9]=[N:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>O1CCCC1>[C:11]1([N:2]([O:1][C:24](=[O:27])[CH2:25][CH3:26])[C:3]([NH:5][C:6]2[S:10][N:9]=[N:8][CH:7]=2)=[O:4])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)Cl
Reactant: O=C(Nc1cnns1)N(O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)ON(C(=O)Nc1cnns1)c1ccccc1
Temperature: 20 °C

Procedure:
9.43 g (0.04 mole) 1-hydroxy-1-phenyl-3-(1,2,3-thiadiazole-5-yl)-urea were under addition of 6.15 ml (0.044 mole) triethylamine dissolved in 100 ml tetrahydrofuran. There were added to this solution under cooling to 20° C., a solution of 3.46 ml (0.04 mole) propionylchloride in 10 ml tetrahydrofuran within about 5 minutes in dropwise fashion and thereafter the resulting mixture was stirred for an hour. After separating off the precipitate which had formed the filtrate was concentrated and the residue taken up in 150 ml of ether. The ether phase was washed with water, dried over magnesium sulfate, again concentrated and the residue digested with diisopropylether.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:13][CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])(=[O:12])[CH3:11].C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.O1CCOCC1>[C:10]([O:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17][C:6]([C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:7])(=[O:12])[CH3:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC(=O)COC(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a round bottom flask containing 4-bromobenzaldehyde (1.4 g, 7.80 mmol), 2-oxobut-3-enyl acetate (1 g, 7.80 mmol) and 3-benzyl-5-(2-hydroxyethyl)-4-methyl-thiazolium chloride (0.21 g, 0.78 mmol) was added dioxane (20 ml). The mixture was stirred at room temperature and triethylamine (0.65 ml, 0.60 mmol) was added. The reaction mixture was heated to 80 C for overnight. Afterward, the reaction was cooled down to room temperature, quenched with a solution of saturated ammonium chloride and concentrated. The residue was taken up in MTBE and washed with saturated ammonium chloride solution twice, then once with brine. The organic portion was dried over sodium sulfate, filtered and concentrated. The resulting crude material was purified by column chromatography to afford the title compound as a light orange solid after drying (1.63 g, 67% yield). MS (ESI) m/z 315.0 (M+1). Retention time 1.14 min. (Condition X).