Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:14][C:15]([CH:17]=[CH2:18])=O>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5]([C:17]([CH3:18])=[CH:15][CH:14]=[N:8]2)=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2c(C)ccnc2c1
Temperature: 12 °C

Procedure:
A solution of 3-methyl-phenylamine (1 eq), in 1,4-dioxane is stirred and cooled to approximately 12° C. Sulfuric acid (2 eq.) is slowly added and heated at reflux. Methylvinyl ketone (1.5 eq) is added dropwise into the refluxing solution. The solution is heated for 1 h after addition is complete. The reaction solution is evaporated to dryness and dissolved in methylene chloride. The solution is adjusted to pH 8 with 1 M sodium carbonate and extracted with three times with water. The residue is chromatographed on SiO2 (70/30 hexane/ethylacetate) to yield the title compound.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].Br[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].O>CO>[C:20]([O:19][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To dimethyl malonate (102 mL), a solution of sodium methoxide in methanol (28%, 90.4 mL) was added at room temperature, and the mixture was stirred at 60° C. for 30 minutes. The white suspension was cooled to room temperature. Then, tert-butyl (3-bromopropyl)carbamate (106 g) was added thereto at once, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, water was added, and organic matter was extracted with diethyl ether. The organic layer was washed with a 1 N aqueous sodium hydroxide and saturated sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of dimethyl {3-[(tert-butoxycarbonyl)amino]propyl}malonate. The obtained ester (94 g) was dissolved in methanol (100 mL). To the solution, a solution of lithium hydroxide monohydrate (13.6 g) in water (300 mL) and methanol (300 mL) was added at 0° C., and the mixture was stirred at room temperature for 15 hours. Methanol was distilled off under reduced pressure, and organic matter was extracted with ethyl acetate. 2 N hydrochloric acid (160 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=10/1) to obtain the title compound (69.1 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([OH:17])=[C:7]([C:13]([O:15]C)=O)[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([OH:17])=[C:7]([C:13]([NH:20][C:21]3[S:22][C:23]([CH3:26])=[CH:24][N:25]=3)=[O:15])[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2ccc(F)cc2S(=O)(=O)N1C
Reactant: Cc1cnc(N)s1
Solvent: Cc1ccccc1C
Product: Cc1cnc(NC(=O)C2=C(O)c3ccc(F)cc3S(=O)(=O)N2C)s1
Yield: 56.9 %

Procedure:
0.29 gm (1 millimol) of methyl 7-fluoro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 0.125 gm (1.1 millimols) of 2-amino-5-methyl-thiazole were refluxed in 50 ml of xylene for 24 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was recrystallized from xylene/cyclohexane. 0.21 gm (57% of theory) of 7-fluoro-4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: C1CNCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
To a mixture of 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one (15.2 g, 38.5 mmol) and piperazine (6.78 g, 77.1 mmol) in ethanol (6 mL) was added tetraisopropyl-orthotitanate (22.8 mL, 77.1 mmol) at room temperature. After stirring at room temperature for 3 days the reaction mixture was diluted with ethanol (250 mL) and sodium cyanoborohydride (5.10 g, 77.1 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (30 mL). The inorganic precipitate was filtered off and washed with ethanol and dichloromethane. The solvent was evaporated and the residue was taken up in ethylenglycol (100 mL) and sodium hydroxide (3.08 g, 77.1 mmol) was added. The reaction mixture was stirred at 130° C. for 15 min. After cooling water (200 mL) was added and the mixture was extracted four times with 200 mL tert.-butyl methyl ether. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with methylene chloride/methanol/triethyl amine 98:1:1 gave rac-cis-1-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine (9.54 g, 67%) as a yellow oil, MS: m/e=336.3 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 3-iodophenol (2.20 g, 10.0 mmol) in dimethylformamide (20 ml) were added potassium carbonate (2.07 g, 15.0 mmol) and t-butyl bromoacetate (1.62 ml, 11.0 mmol), and the mixture was stirred for 1 hour at room temperature. Thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in the order, and dried over magnesium sulfate. The solvent was removed to give the subject compound as a colorless oil (3.28 g, 98%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After adding tetrahydrofuran (4 ml) and diethylamine (0.2 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(thiazol-2-yl) urea (200 mg), the mixture was stirred at 50° C. for 2 hours. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (60 mg) as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([C:9](=[CH:12]N(C)C)[C:10]#[N:11])=O)=[CH:5][CH:6]=1.Cl.[O:17]=[C:18]1[NH:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CO>[Br:1][C:2]1[S:3][C:4]([C:7]2[C:9]([C:10]#[N:11])=[CH:12][N:28]=[C:26]([NH:25][CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][NH:22][C:18]3=[O:17])[N:27]=2)=[CH:5][CH:6]=1
Reactant: N=C(N)NCCN1CCNC1=O
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Temperature: 100 °C

Procedure:
2-(2-Bromothiophene-5-carbonyl)-3-(dimethylamino)acrylonitrile) (3 g, 10 mmol) in N-methylpyrrolidone (15 mL) was treated with 1-(2-(2-oxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (1 M solution in N-methylpyrrolidone, 15 mL, 15 mmol) and cesium carbonate (3.4 g, 10 mmol). The mixture was heated at 100° C. overnight. The reaction was then allowed to cool to room temperature and poured onto crushed ice. The resulting solid that formed was suspended in hot methanol to give a yellow solid (2.3 g). The filtrate was concentrated and purified by flash chromatography using a gradient of 3 to 10% methanol in dichloromethane to obtain an additional 0.9 g of the desired product. Total yield=3.2 g. MS (M+H)+ 394.
Reaction SMILES: [F:1][C:2]([F:18])([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6]1.Cl[C:20]1[C:21]2[C:22](=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:28]=2)[N:23]=[CH:24][N:25]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:1][C:2]([F:18])([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH2:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([NH:10][C:20]2[C:21]3[C:22](=[N:26][N:27]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[CH:28]=3)[N:23]=[CH:24][N:25]=2)[CH2:6]1
Reactant: Clc1ncnc2nn(C3CCCCO3)cc12
Reactant: Cc1ccc(C(F)(F)CN[C@H]2CC[C@H](N)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(C(F)(F)CN[C@H]2CC[C@H](Nc3ncnc4nn(C5CCCCO5)cc34)C2)cc1
Temperature: 150 °C
Yield: 87.4 %

Procedure:
A mixture of (1S,3S)-N-[2,2-difluoro-2-(4-methylphenyl)ethyl]cyclopentane-1,3-diamine (627 mg, 2.46 mmol), 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-d]pyrimidine (588 mg, 2.46 mmol), n-butanol (1.6 mL) and diisopropylethylamine (1.6 mL) was heated in microwave for 15 min at 150° C. The reaction mixture was concentrated in vacuo to a viscous brown oil, which was purified by silica gel chromatography (CH2Cl2/MeOH gradient) to give the title compound (0.982 g) as a cream colored foam: MS=457.4 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:14])[CH3:13].[OH-].[Na+]>CC(CC)=O>[CH2:12]([NH:14][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1)[CH3:13]
Reactant: CCN
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CCNc1nc(Cl)c(SC)c(Cl)n1
Reaction time: 6 h

Procedure:
230 parts of 2,4,6-trichloro-5-methylthio-pyrimidine are dissolved in 740 parts of methylethylketone, 650 parts of ice are added, and 120 parts of an aqueous 38% solution of ethylamine are run in over 30 minutes while cooling in order that the temperature should not exceed 5° C. 129.5 parts of a 31% solution of caustic soda are added in a period of an hour at 20° C. and the mixture is stirred for 6 hours. The desired isomer is then precipitated while the 4-ethylamino-2,6-dichloro-5-methylthiopyrimidine remains in solution. After cooling for 15 hours, the product is filtered off and washed with methylethylketone. 73 parts of the desired product are obtained, which is recrystallised from ethanol. M.p. 147° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(N)CC
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CCC(CC)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (750 mg, 1.48 mmol) and 3-aminopentane (520 μl, 4.44 mmol) as starting materials.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[C:11](=[O:17])[NH:12][N:13]=[CH:14][C:15]=1[Cl:16].[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:15]1[CH:14]=[N:13][NH:12][C:11](=[O:17])[C:10]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]ncc(Cl)c1-c1ccccc1
Yield: 73.4 %

Procedure:
Phenyl magnesium bromide (prepared from bromobenzene (171 g), magnesium (38.8 g) and diethyl ether (1.6 l)) was slowly added to a stirred solution of 4,5-dichloro-3[2H]-pyridazinone (60 g) in tetrahydrofuran (1 l) cooled at water bath temperature. This mixture was stirred at room temperature for 30 minutes and hydrolysed with 20% ammonium chloride solution (800 ml) in the cold. The aqueous layer was extracted with diethyl ether and the combined organic extracts were washed with dilute hydrochloric acid, water, brine, dried (MgSO4) and evaporated under reduced pressure to give 5-chloro-4-phenyl-3[2H]-pyridazinone (55.13 g), m.p. 193°-5° C. on recrystallisation from ethyl acetate.
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]([CH:28]([CH3:30])[CH3:29])[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)([CH3:8])[CH3:7].C1C=CC=CC=1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>O>[CH3:37][N:38]([CH3:42])[C:39]([N:12]([CH2:11][CH2:10][N:9]([CH:6]([CH3:7])[CH3:8])[CH:28]([CH3:30])[CH3:29])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:40]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(OCc2ccccc2)nc(NCCN(C(C)C)C(C)C)n1
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(OCc2ccccc2)nc(N(CCN(C(C)C)C(C)C)C(=O)N(C)C)n1

Procedure:
Under a nitrogen atmosphere, n-butyl lithium solution (22.2 ml, 0.036 mole) is added dropwise with stirring to a solution of 2-(2-diisopropylaminoethylamino)-4-methyl-6-benzyloxypyrimidine (12.4 g, 0.036 mole) in 75 ml. of dry benzene at 25° to 30° C. with occasional cooling over a 20 minute period. After stirring an additional 3/4 hour, dimethylcarbamoyl chloride (4.3 g, 0.04 mole) is added dropwise over 15 minutes. The reaction is stirred at room temperature for 16 hours. After cooling, the reaction mixture is treated with water and the benzene layer is separated. The crude product is extracted into 1 N-hydrochloric acid. This aqueous solution is basified and the product is extracted into ether, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel eluting with 25% methanol, 75% chloroform yields N,N-dimethyl-N'-(2-diisopropylaminoethyl)-N'-(4-methyl-6-benzyloxy-2-pyrimidinyl)urea.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of 1-benzylpyrrolidin-3-one (9.98 g, 57.0 mmol) in THF (57.0 mL) at −20° C. was added to 1.4M MeMgBr (85.4 mL, 120 mmol). When addition was complete, the ice bath was removed and the reaction was allowed to warm to ambient temperature and then quenched with water (200 mL). The mixture was diluted with saturated NH4Cl (200 mL) and ethyl acetate (300 mL) and stirred vigorously for 5 minutes. An inseparable emulsion formed with fine particulates. The reaction mixture was filtered under vacuum and the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL) and the organic layer was washed with brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to an oil which was purified by flash chromatography (0-5% Methanol/DCM) to give (+/−)1-benzyl-3-methylpyrrolidin-3-ol (6.10 g, 31.9 mmol, 56.0% yield).
Reaction SMILES: COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:10]2)=CC=1.[CH3:23][N:24]1[C:29]2[C:30](=[O:41])[N:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:32](=O)[O:33][C:28]=2[C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[S:25]1(=[O:47])=[O:46]>C1(C)C(C)=CC=CC=1>[CH3:23][N:24]1[C:29]2[C:30](=[O:41])[N:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:32](=[S:10])[O:33][C:28]=2[C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[S:25]1(=[O:47])=[O:46]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1c2c(oc(=O)n(-c3ccccn3)c2=O)-c2ccccc2S1(=O)=O
Solvent: Cc1ccccc1C
Product: CN1c2c(oc(=S)n(-c3ccccn3)c2=O)-c2ccccc2S1(=O)=O
Temperature: 140 °C

Procedure:
8.1 g (0.02 mols) of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane and 3.6 g (0.01 mol) of 5-methyl-3-(2-pyridyl)-2H,5H-1,3-oxazino[5,6-c][1,2]benzothiazine-2,4-(3H)dione-6,6-dioxide in 80 ml of xylene are maintained under reflux at 140° C. for 36 hours. The mixture is subjected to chromatography over a column containing silica gel as the stationary phase by initially eluting with xylene and then with chloroform. 1.4 g (38%) of 5-methyl-3(2-pyridyl)-2H,5H-1,3-oxazino[5,6-c][1,2]benzothiazine2(3H)thione-4-one-6,6-dioxide corresponding to the following formula are recovered from the chloroform solution: ##STR9##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:43]([N:46]=[C:47]=[O:48])([CH3:45])[CH3:44]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][C:47](=[O:48])[NH:46][CH:43]([CH3:45])[CH3:44])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 50 °C

Procedure:
5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.27 mmol, 1.0 equiv) was dissolved in tetrahydrofuran and treated with triethylamine (1.50 equiv) and isopropyl isocyanate (0.4 mmol, 1.50 equiv). The resulting mixture was heated to 50° C. for 18 h. The reaction mixture was concentrated and crude product was purified on silica using gradient elution from ethyl acetate (100%) and ethyl acetate/methanol (5%).
Reaction SMILES: C([O-])(=O)C.[O:5]=[C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:18])=[NH2+:17])[N:10]=[C:9]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=2)[CH:8]=[CH:7]1.[CH:31]([CH:33]([CH:39]=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.O>N1C=CC=CC=1>[O:5]=[C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:16]3[N:18]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:17]=3)[CH:19]=[CH:20][CH:21]=2)[N:10]=[C:9]([C:22]2[CH:23]=[C:24]([F:30])[C:25]([F:29])=[C:26]([F:28])[CH:27]=2)[CH:8]=[CH:7]1
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NC(=[NH2+])c1cccc(Cn2nc(-c3cc(F)c(F)c(F)c3)ccc2=O)c1
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4.7 g (11.23 mmol) of 3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidinium acetate are suspended in 40 ml of pyridine, and 2.4 g (16.85 mmol) of ethyl 2-formyl-3-oxopropionate (prepared in accordance with S. H. Berz et al., Journal of Organic Chemistry 1982, 47, 2216) are added, and the mixture is stirred at 80° C. for 4 h. A further 500 mg (3.47 mmol) of ethyl 2-formyl-3-oxopropionate are subsequently added, and the mixture is stirred at 80° C. for 1 h. The reaction mixture is stirred into 400 ml of water, and the precipitate is filtered off with suction, washed a number of times with water and dried in a drying cabinet. Yield: 4.43 g of “A29” (76%), Rt=3.58 min (method B), ESI 467.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[C:8]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)(=[O:24])/[CH:9]=[CH:10]/[C:11]([O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)=[O:12]>C(O)C>[C:8]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3])[C:28]([CH3:35])([CH3:34])[CH2:27]1)(=[O:24])/[CH:9]=[CH:10]/[C:11]([O:13][CH:14]1[CH2:15][C:16]([CH3:23])([CH3:22])[N:17]([C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3])[C:18]([CH3:21])([CH3:20])[CH2:19]1)=[O:12]
Reactant: CC1(C)CC(OC(=O)/C=C/C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: C=C(C(=O)OCC)N1C(C)(C)CC(OC(=O)/C=C/C(=O)OC2CC(C)(C)N(C(=C)C(=O)OCC)C(C)(C)C2)CC1(C)C
Temperature: 25 °C

Procedure:
44 g of ethanol propiolate were added dropwise to a solution of 78.4 g of bis(2,2,6,6-tetramethyl-4-piperidinyl) fumarate in 300 ml of ethanol at 40° to 60° C. The mixture was then refluxed for 3 hours. The precipitate which resulted on cooling to room temperature was filtered off, washed with petroleum ether and dried. 107 g of the compound of the formula shown below were obtained in the form of a colorless solid of melting point 185°-186° C. ##STR24##
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](C2C=CC=CC=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2,4-Difluoro-1-((E)-2-{4-[(2-nitrophenyl)sulfonyl]phenyl}vinyl)benzene was prepared according to the method of Example 135 Step 2 using 2-iodonitrobenzene and Intermediate 2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Br[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=1>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Reactant: Fc1ccc(Br)nc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(F)cn3)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2′-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-yl]-acetic acid ethyl ester and 2-bromo-5-fluoropyridine.