Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:12][C:13]([C:16]1[C:24]2[O:23][CH2:22][CH2:21][C:20]=2[CH:19]=[C:18]([Br:25])[CH:17]=1)([CH3:15])[CH3:14])C>C1COCC1>[Br:25][C:18]1[CH:17]=[C:16]([C:13]([CH3:15])([CH3:14])[CH2:12][C:11]([C:26]([F:29])([F:27])[F:28])([OH:30])[CH2:10][OH:9])[C:24]2[O:23][CH2:22][CH2:21][C:20]=2[CH:19]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)cc2c1OCC2)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(Br)cc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a suspension of 1.25 g (33 mmol) of lithium aluminum hydride in 50 nL of THF at 0° C. was added dropwise a solution of 11.7 g (27.5 mmol) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester in 20 mL of THF. The reaction was warmed to room temperature, stirred 2 hours, cooled to 0° C., carefully quenched with water, followed by 1N HCl, and extracted with EtOAc. The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with hexanes and the solid collected by filtration to afford 7.6 g (72%) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O)=[CH:33][CH:32]=2)=[C:28]([CH:46]([CH3:48])[CH3:47])[NH:27][N:26]=1)(=[O:3])[CH3:2].[NH2:49][C:50]([CH3:58])([CH3:57])[C:51]([NH:53][CH2:54][CH2:55][OH:56])=[O:52].[I-].[Na+]>C(#N)C.C(O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:8]([CH2:9][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:49][C:50]([C:51](=[O:52])[NH:53][CH2:54][CH2:55][OH:56])([CH3:58])[CH3:57])=[CH:33][CH:32]=2)=[C:28]([CH:46]([CH3:47])[CH3:48])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(N)C(=O)NCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNC(C)(C)C(=O)NCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 60.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.77 g) in dichloromethane (5 mL) were added triethylamine (0.26 mL) and methanesulfonyl chloride (0.12 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)-propoxy]phenyl}methyl)-1H-pyrazole (0.85 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]phenyl}-methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (1.5 mL) and ethanol (1.5 mL). To the solution were added 2-[2-amino-2-(methyl)propionylamino]ethanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethylcarbamoyl)-1-(methyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole (0.13 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (93 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][C:16]=3[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>C(Cl)Cl>[CH2:39]([N:41]([CH2:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][C:16]=3[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH2:42][CH3:43])[CH3:40]
Reactant: CCNCC
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(CCl)cc2)c1
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A solution of {4-[3-(4-chloromethyl-benzyloxy)-phenyl]-8-trifluoromethyl-quinolin-3-yl}phenyl-methanone (011 g, 0.2 mmol) and diethylamine(0.3 g, 5.7 mmol) in CH2Cl2 (5 ml) was stirred at r.t. After 24 hr, the reaction was concentrated and purified by column chromatography (eluent 25% EtOAc/Hex) to give the title compound as a foam (0.10 g); MS m/z 569.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=[N:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=3[F:25])=[CH:11][N:10]=[C:9]([S:26][CH3:27])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1([NH:6][C:7]2[C:12]([CH2:13][NH:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=3[F:25])=[CH:11][N:10]=[C:9]([S:26][CH3:27])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOc1ccc(F)c(N=Cc2cnc(SC)nc2NC2CCCC2)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(NCc2cnc(SC)nc2NC2CCCC2)c1F
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 99.8 %

Procedure:
A solution of 8.00 g (20.4 mmol) cyclopentyl-{5-[(3-ethoxy-2,6-difluoro-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl }-amine prepared above, in 200 mL dry THF, was cooled in an ice / water bath. To the cooled solution was added dropwise 1 equivalent (20.4 m, 20.4 mmol) of a 1 M LAH solution in THF. The reaction was stirred cold for 4.5 hours and then warmed to 50° C. for 3.5 hours. The reaction was cooled to room temperature, treated with another 0.5 equivalent (11.0 mL, 11.0 mmol) of 1 M LAH solution in THF, and stirred at room temperature overnight. The reaction was quenched by sequential addition of 1.3 mL water, followed by 5.2 mL of 15% NaOH solution, and finally 2.9 mL of water. The reaction was filtered through Celite and the filter pad was washed well with THF. The THF filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with a saturated solution of NaCl, and concentrated in vacuo to give 8.03 g (100%) of the title compound as a waxy solid: MS (APCI) (m+1)/z 395.1. Analysis calculated for C19H24F2N4SO: C, 57.85; H, 6.13; N, 14.20. Found: C, 57.92; H, 6.19; N, 14.01.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[C:34](Br)=[CH:33][C:32]([F:36])=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2.[OH-].[Na+]>CN(C=O)C>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[C:34]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[CH:33][C:32]([F:36])=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(-c3ccc(OC(F)(F)F)cc3)c2o1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A mixture of 40 mg (0.29 mmol) of 4-(trifluoromethoxy)phenylboronic acid, 70 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-7-bromo-1-benzofuran-2-carboxamide (Example 5A), 0.57 ml (0.57 mmol) of 1N sodium hydroxide solution, 14 mg (0.02 mmol) of 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is mixed with 1N sodium hydroxide solution and extracted three times with a total of 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane, again with methanol, with THF and finally once more with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. Silica gel 0.60 (Merck, Darmstadt; eluent: dichloromethane/triethylamine 100:1, then dichloromethane/methanol/triethylamine 100:1:1 to dichloromethane/methanol/triethylamine 100:10:1) is used for final purification. The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 52 mg (61% of theory) of the title compound are isolated.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]([OH:16])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[S:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[S:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=S)OCCCC[C@@H](O)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=S)OCCCC[C@@H](OS(C)(=O)=O)c1cccnc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of (R)-5-hydroxy-5-(3-pyridyl)pentyl thioacetate (2.8 g) in dry dichloro- methane (15 ml) under a nitrogen atmosphere is cooled to -15° C. and treated with triethylamine (1.4 g) using a syringe. It is then treated with methanesulphonyl chloride (1.5 g) by syringe during 5 minutes. The temperature rises spontaneously to -8° C. during this addition. When the addition is complete the reaction mixture is allowed to warm to room temperature. After 2 hours it is washed with water (4×15 ml) until its pH is 7. The organic phase is then dried with magnesium sulphate, filtered and evaporated under reduced pressure, to give (R)-5-methanesulphonyloxy-5-(3-pyridyl)pentyl thioacetate (3.66 g), in the form of a yellow oil. This material is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]3[CH2:21][CH2:22][O:23][CH2:24][CH:25]=3)=[C:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[C:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C3CC3)cc2C1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1Cc2cc(C3CCOCC3)c(C3CC3)cc2C1

Procedure:
Prepared in analogy to Example A49(b) from 5-cyclopropyl-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Colourless oil. MS (m/e): 288.0 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccccn2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 9.4 g of product from Example 20, 3.87 g of product from Example 12, 1.24 g of 50% sodium hydride and 130 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 31/2 hours. The residue is purified by column chromatography (silica gel: 60-100% ethyl acetate/hexane) to give 9.42 g of the desired product as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:11]([O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=O)[CH3:12].C1([SiH3])C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:17][CH2:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:26])=[O:4]
Reactant: COC(=O)c1sccc1N
Reactant: CCOC(=O)CCCC(=O)C1CCCCC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)CCCC(Nc1ccsc1C(=O)OC)C1CCCCC1
Temperature: 60 °C
Yield: 57.7 %

Procedure:
A flask was charged with 3-amino-thiophene-2-carboxylic acid methyl ester (600 mg, 3.82 mmol, 1.0 equiv), 5-cyclohexyl-5-oxo-pentanoic acid ethyl ester (864 mg, 3.82 mmol, 1.0 equiv), phenyl silane (496 mg, 4.58 mmol, 1.2 equiv), dibutyltin dichloride (116 mg, 0.38 mmol, 0.1 equiv) and dioxane (3.0 mL). The resulting solution was heated at 60° C. for 18 hours. The solution was then concentrated and the residue was purified by silica gel column chromatography, CH2Cl2/heptane 30% to 100%, to give 3-(1-Cyclohexyl-4-ethoxycarbonyl-butylamino)-thiophene-2-carboxylic acid methyl ester 810 mg (yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.O.[NH2:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:21][NH2:22])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 72 h

Procedure:
A mixture of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione and hydrazine hydrate is allowed to stand for 72 hours at about 25° C. After evaporation of the ethanol, the solid products obtained are recrystallized from methylene chloride-benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine of melting point 204°-207° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1>CC(O)C>[CH:8]([O:12][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1)([CH3:9])[CH3:7]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Solvent: CC(C)O
Product: COc1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from propan-2-ol and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-isopropoxy-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 343(MH+).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:16][C:17]([N:19]1[CH2:22][CH:21]([C:23](=[CH2:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.[Cl-].[Na+].O>[CH2:9]([O:16][C:17]([N:19]1[CH2:20][CH:21]([C:23]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:2][CH2:29]2)[CH2:22]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C(C(=O)OCC)C1CN(C(=O)OCc2ccccc2)C1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(C2CN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To 1.27 g (5.76 mmol) of trimethylsulfoxonium iodide dissolved in 10 ml of dimethyl sulfoxide was added 192 mg (4.80 mmol) of 60% sodium hydride, followed by 15 minutes of stirring at room temperature. Thereto was then added 1.39 g (4.80 mmol) of ethyl 2-(1-benzyloxycarbonyl-3-azetidinyl)acrylate which has been dissolved in 10 ml of dimethyl sulfoxide. The resulting mixture was stirred at room temperature for 4 hours and then at 100° C. for 1 hour. The reaction solution was mixed with 200 ml of saturated brine and extracted with ethyl acetate (100 ml×3), and the organic layer was washed with saturated brine (100 ml×2) and dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (100 ml, ethyl acetate:hexane=1:2) to yield 536 mg (37%) of the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=[NH:22])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]=2[O:2]1.C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([N:11]2[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=[C:10]2[C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc3c(c2)OCO3)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc3c(c2)OCO3)cc1
Yield: 46.7 %

Procedure:
To a mixture of 3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (2.32 g, 7.3 mmol) and sodium bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating the reaction mixture to reflux for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.1 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 1/1) to give 5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]-1,3-benzodioxole (1.46 g, 47%) as a white solid: mp 200-202° C. Anal. Calc'd. for C18H15N2SO5F3.0.25 PhCH3: C, 52.55, H, 3.80, N, 6.21. Found: C, 52.73, H, 3.78, N, 6.01.
Reaction SMILES: [CH:1]1CCCCC=1.[O:7]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[C:9]([C:16]2[NH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=2)=[N:8]1>>[CH3:1][N:17]1[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=[C:16]1[C:9]1[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[O:7][N:8]=1
Reactant: C1=CCCCC1
Reactant: O=[N+]([O-])c1cnc(C2=NOC3CCCCC23)[nH]1
Product: Cn1c([N+](=O)[O-])cnc1C1=NOC2CCCCC12

Procedure:
Following the same procedure as in Example 30, the hydroxamoylchloride prepared as in Example 7 is reacted with cyclohexene. The product, 2-(3a,4,5,6,7,7a-hexahydro-1,2-benz-isoxazol-3-yl)-5-nitroimidazole has a melting point of 119°-121° C.
Reaction SMILES: ClC1C=CC([C:8]2([C:11]([C:13]3([C:16]4[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=CC=1.CC1[N:25]=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[S:27]C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH:8]1([C:11]([C:13]2[CH:15]=[CH:14][C:20]([C:19]3[S:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[N:25][C:18]=3[CH3:17])=[CH:21][CH:16]=2)=[O:12])[CH2:9][CH2:10]1
Reactant: O=C(C1(c2ccc(Cl)cc2)CC1)C1(c2ccc(Cl)cc2)CC1
Reactant: CC(=O)Nc1nc(C)cs1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)C3CC3)cc2)s1
Temperature: 150 °C

Procedure:
Dry, degassed DMF (90 ml) was added to 4-chlorophenylcyclopropyl ketone (5.0 g, 27.6 mmol), N-(4-Methyl-thiazol-2-yl)-acetamide (3.6 g, 23.1 mmol), Bis(tri-t-butylphosphine) palladium (0) (1.18 g, 2.31 mmol) and caesium carbonate (15.03 g, 46.1 mmol), and the reaction mixture heated to 150° C. for 4 hours. The reaction mixture was filtered through celite and the filtrate reduced in vacuo. The material was purified by column chromatography using as eluant 2:1 to 1:2 Iso-hexane:EtOAc gradient. (M+H) 259.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)(=O)C>[C:23]([N:13]1[CH2:14][CH2:15][N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]2[NH:12]1)(=[O:25])[CH3:24]
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (207 mg) in acetic acid (2 ml) was added acetic anhydride (75 mg) with ice cooling. The solution was stirred at ambient temperature for 1 hour and concentrated in vacuo. The residue was dissolved in water (3 ml) and the solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with dichloromethane and the extract was dried and concentrated in vacuo. The residue was crystallized from ethyl acetate to give 2-acetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (195 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[C:30]([O:31][CH3:32])=[CH:29][C:24]2[NH:25][C:26](=[O:28])[S:27][C:23]=2[CH:22]=1>>[CH3:32][O:31][C:30]1[C:21]([NH:20][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][C:23]2[S:27][C:26](=[O:28])[NH:25][C:24]=2[CH:29]=1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CN(C)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2sc3c(c12)CCC(C(=O)N(C)C)C3

Procedure:
30 mg (101 μmol) (RS)-4-chloro-N,N-dimethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 85a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 5.8 mg (12%) of the title compound.
Reaction SMILES: [CH:1]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH:1]12[CH2:2][CH:6]3[CH:7]([CH2:8][CH2:9]1)[CH:10]([CH2:3][CH2:4][CH2:5]3)[CH2:11]2
Reactant: C1CC2C3CCC(CC3)C2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C1CC2CC3CCC2C(C1)C3
Temperature: 0 °C
Yield: 41.9 %

Procedure:
A solution of 15 g (0.1 mole) of tricyclo[5.2.2.02,6 ] -undecane (I) in 100 ml of methylene chloride was agitated at 0°C. Then, 1.3 (0.01 mole) of anhydrous aluminum chloride was added to the solution, and the mixture was heated and refluxed under agitation for 1 hour. The reaction mixture was allowed to cool and then poured over 100 ml of ice water. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The methylene chloride extract was combined with the organic layer, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and then dried over anhydrous sodium sulfate. Methylene chloride was distilled off, and the residue was subjected to fractionation. The highest boiling point fraction (boiling at 111° to 112°C. under 36 mmHg) was separated, whereby 6.3 g (yield: 42%) of tricyclo[5.3.1.03,8 ]-undecane was obtained.