Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (500 mg, 1.88 mmol), DCC (467 mg, 2.26 mmol), and HOBT (346 mg, 2.26 mmol) in dry THF (15 ml) was stirred for 30 minutes at RT. Then (R)-quinuclidin-3-ol (288 mg, 2.26 mmol) was added portionwise and the reaction was stirred at RT for 16 hours. The solvent was evaporated, the residue was dissolved in EtOAc, and the insoluble was removed by filtration. The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to obtain (S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (600 mg, 85% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[NH:7][C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)[N:10]=1)([CH3:5])[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:53][O:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([C:63](O)=[O:64])[CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:4][C:3]([C:6]1[NH:10][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14]3)=[C:8]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:7]=1)([CH3:5])[CH2:2][NH:1][C:63]([CH:60]1[CH2:59][CH2:58][N:57]([CH2:56][CH2:55][O:54][CH3:53])[CH2:62][CH2:61]1)=[O:64]
Reactant: COCCN1CCC(C(=O)O)CC1
Reactant: CC(C)(CN)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCN1CCC(C(=O)NCC(C)(C)c2nc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A mixture of the product of Example 1, Step 6 (0.1 g, 0.29 mmol), 1-hydroxybenzotriazole (0.06 g, 0.44 mmol) and polymer bound 1,3-dicyclohexylcarbodiimide (0.4 g, 0.6 mmol, 1.52 mmol/g) in a 1:1 mixture of dichloromethane and DMF (4 ml) was stirred at room temperature for 30 min. A solution of 1-(2-methoxy-ethyl)-piperidine-4-carboxylic acid hydrochloride [WO 97/25309] (0.098 g, 0.44 mmol) in DMF (2 ml) was then added and the mixture stirred at room temperature overnight. The reaction mixture was then filtered, the solvent removed in vacuo and the crude residue purified by silica gel chromatography eluting with a 1:9:90 mixture of 0.88 ammonia solution:methanol:dichloromethane to give the title compound (0.12 g, 80%) as a yellow oil; MS(AP+) m/e 516 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:15])[CH3:2].C(NC(C)C)(C)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[N:3]([CH2:1][CH3:2])[CH2:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCNCc1cc(S(C)(=O)=O)ccc1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCN(Cc1cc(S(C)(=O)=O)ccc1O)C(=O)OCc1ccccc1

Procedure:
To 2-ethylaminomethyl-4-methanesulfonyl-phenol (0.229 g, 1.0 mmol) and diisopropylamine (0.94 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added benzyl chloroformate (0.16 mL, 1.1 mmol). Some over-acylation product was observed, so additional benzyl chloroformate (0.21 mL) was added to convert all of the product to the diacylated product. After aqueous work-up, the organic layer was concentrated, and the residue was dissolved in MeOH (10 mL) and treated with 1N aqueous LiOH (4 mL). Once the hydrolysis was complete, the mixture was worked-up, and the residue was purified to give the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([CH2:3][C:4]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: NCc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: N#CCC(=O)NCc1ccccn1
Reaction time: 5 h

Procedure:
To a solution of 6.8 g of cyanoacetic acid in 200 ml of acetonitrile was added a solution of 8.65 g of 2-aminomethylpyridine in 50 ml of acetonitrile, and to the resulting suspension there was added rapidly (with stirring) a solution of 18.5 g of dicyclohexylcarbodiimide in 50 ml of acetonitrile. After stirring 5 hours and standing overnight, the suspension was filtered. The filtrate was evaporated, and the crude residue was triturated with ether-ethyl acetate to give crystals, m.p. 78°-80°. Recrystallization from toluene yielded the 2-(cyanoacetylaminomethyl)-pyridine, m.p. 81°-82°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8].[N-:36]=[N+:37]=[N-:38].[Na+]>O.C(O)(C)C.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:31])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[NH:38][N:37]=[N:36][N:27]=3)[CH:24]=2)[C:19]([C:28](=[O:30])[CH3:29])=[CH:18]1)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(C#N)ccc12
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(-c3nnn[nH]3)ccc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 617 from (1R,3S,5R)-2-[2-(3-acetyl-6-cyano-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide (prepared as described in Example 616 (100.0 mg, 0.203 mmol), sodium azide (66.0 mg, 1.014 mmol) and zinc bromide (228.0 mg, 1.014 mmol) in water (2 mL) and isopropanol (1 mL). White solid. MS (LC/MS): 536.0 [M+H]+; tR (HPLC conditions k): 3.21 min.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=4)=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>O1CCOCC1>[P:1]([OH:3])([OH:8])([O:13][CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=4)=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])=[O:2]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4ccc(F)c(F)c4)s3)ncnc2cc1OCCCN1CCC[C@@H]1COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4ccc(F)c(F)c4)s3)ncnc2cc1OCCCN1CCC[C@@H]1COP(=O)(O)O
Yield: 70 %

Procedure:
Di(tert-butyl) ((2R)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl phosphate (450 mg, 0.58 mmol) in dioxane (20 ml) was treated with a solution of HCl (4N) in dioxane (940 μl) at ambient temperature for 15 hours. The solid was recovered by filtration, washed with dioxane, dried in vacuo at 50° C. to yield the title compound (270 mg, 63% yield):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Yield: 88.4 %

Procedure:
125 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohexyl)benzene and 120 g of zinc powder or granules are suspended in 1300 ml of ethanol. 220 ml of acetic acid are added dropwise at boiling heat. The precipitate is filtered off with suction and washed with ethanol, and the filtrate is concentrated under reduced pressure. The residue is taken up in hydrochloric acid and extracted with toluene. The aqueous phase is rendered alkaline using 50% strength sodium hydroxide solution, the precipitate is filtered off with suction and the filtrate is extracted with toluene. The organic phase is dried using sodium sulfate and concentrated. 98 g of the title compound are obtained as a crystallizing oil.
Reaction SMILES: Cl[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26]CC2C=CC=CC=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].C([O-])=O.[NH4+]>CO.[Pd]>[OH:26][C:24]1[CH:23]=[C:18]([CH:17]=[C:16]([O:15][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:14])[N:8]([CH3:13])[CH2:9][CH2:10][O:11][C:12]=3[CH:2]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc(O)cc(Oc2ccc3c(c2)OCCN(C)C3=O)c1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of methyl 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(phenylmethyl)oxy]benzoate (8.8 g, 18.8 mmol), and ammonium formate (11.87 g, 188 mmol) in methanol (190 mL) was placed under an atmosphere of argon and 10% palladium on charcoal (880 mg) added. The mixture was heated under relux for 2 hours, cooled to RT, filtered through Celite®, washed with methanol, and the filtrates evaporated in vacuo to a residue which was partitioned between water (150 mL) and ethyl acetate (200 mL). The organic layer was washed with brine, dried (MgSO4), evaporated in vacuo to a residue which was chromatographed on basic alumina, eluting with ethyl acetate then methanol, to give a solid which was crystallised from ethyl acetate and isohexane to give the desired compound (3.25 g). 1H NMR δ (CDCl3): 3.15 (s, 3H), 3.5 (t, 2H), 4.35 (t, 2H), 6.6 (dd, 1H), 6.75 (dt, 1H), 7.8 (t, 1H); m/z 344 (M+H)+
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[C:26]4([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:25][CH2:24][CH2:23][C:22]3=[O:32])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[C:40]1[O:41][C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=1>CN(C=O)C>[O:41]1[C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=[C:40]1[N:29]1[CH2:30][CH2:31][C:26]2([N:21]([CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH:13]=[CH:12][N:11]4[S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[C:22](=[O:32])[CH2:23][CH2:24][CH2:25]2)[CH2:27][CH2:28]1
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCNCC5)cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(c4nc6ccccc6o4)CC5)cccc32)cc1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To the stirred solution of 1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecan-2-one (TFA salt) (300 mg, 0.55 mmol) in DMF (6 mL) were added K2CO3 (380 mg, 2.75 mmol) and 2-chloro benzoxazole (101 mg, 0.66 mmol). The mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude mixture water was added and extracted with ethyl acetate. The organic layer was dried over anhydride sodium sulfate, filtered and concentrated to obtain a solid which was purified by flash column chromatography (eluent: 3% methanol in chloroform) to yield the title compound (250 mg, 80%). [LCMS RtE=1.75 min, [M+H]+=569.1].
Reaction SMILES: Cl.[Si]([O:9][CH2:10]/[C:11](/[CH3:43])=[CH:12]\[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([N:23]([C:28]1[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:36]2[C:31]([CH:32]3[CH2:42][CH:33]3[CH2:34][O:35]2)=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25])(=[O:22])=[O:21])(C(C)(C)C)(C)C>CO>[F:19][C:17]1[CH:16]=[CH:15][C:14]([S:20]([N:23]([C:28]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:36]3[C:31]([CH:32]4[CH2:42][CH:33]4[CH2:34][O:35]3)=[CH:30][CH:29]=2)[C:24]([O:26][CH3:27])=[O:25])(=[O:22])=[O:21])=[C:13](/[CH:12]=[C:11](/[CH3:43])\[CH2:10][OH:9])[CH:18]=1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C(/C)CO[Si](C)(C)C(C)(C)C)ccc2c1OCC1CC21
Agent: Cl
Solvent: CO
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C(/C)CO)ccc2c1OCC1CC21
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added to a solution of methyl (1aRS,7bSR)-5-(N-{2[(Z)-3-(tert-butyldimethylsilanyloxy)-2-methylprop-1-enyl]-4-fluorobenzenesulfonyl]-N-methoxycarbonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 202, 0.385 g) in methanol (20 mL) and the mixture was left at room temperature for 45 minutes. The solution was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl (1aRS,7bSR)-5-{N-[4-fluoro-2-((Z)-3-hydroxy-2-methylprop-1-enyl)benzenesulfonyl]-N-methoxycarbonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.314 g) as a white foam.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]=12.[Cl:26]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:26][C:3]1[N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Cl)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
3-Imidazo[1,2-a]pyridin-6-ylmethyl-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 10, 33.6 mg, 0102 mmol) was dissolved in DCM (1 mL) with N-chlorosuccinimide (15 mg, 0.112 mmol). The RM was stirred at rt for 22 h. The solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and the acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and it was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4, filtered and concentrated to afford the white title compound (tR 0.7 min (conditions 2), MH+=364).
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH3:15])[CH3:14])[CH2:8][N:7]=1)([S:4][CH3:5])[CH3:3].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH3:3][C:2]([C:6]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH3:15])[CH3:14])[CH2:8][N:7]=1)([S:4]([CH3:5])=[O:24])[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC(C)(C)C1=NCN(C(C)C)C(=O)O1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CN=C(C(C)(C)S(C)=O)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.5 g of 6-(1-methyl-1-methylmercaptoethyl)-3-isopropyl-3,4-dihydro-2H-1,3,5-oxadiazin-2-one (Example 1) are dissolved in 100 ml of chloroform. The resultant solution is cooled to -10° C., and a solution of 9.5 g of m-chloroperbenzoic acid in 120 ml of chloroform is then added dropwise. The reaction mixture is subsequently stirred for 1 hour at room temperature and then concentrated. The residual crude product is recrystallised from a 1:1 mixture of ethyl acetate and hexane, affording the title compound of the formula ##STR7## with a melting point of 120-°121° C. (compound 2).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:30]#[N:31])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:30]#[N:31])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1ccc(C(=O)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
p-Anisoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 1.8740 g of p-anisoyl chloride (99%, Aldrich) (10.98 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.7 mL of trimethylsilyl cyanide (13 mmol) were added to a 100-mL round bottom flask. To this solution, 0.27 mL of tin (IV) chloride (2.3 mmol) was added. The reaction was stirred for 2 hr at room temperature. During the 2 hr, the color of the solution changed from clear to dark brown. After the 2 hr of stirring, the reaction was quenched with 75 mL of ice-cold water and then extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield 1.592 g (90%) of p-anisoyl cyanide as a dark orange solid: IR (CHCl3) (partial) 3020, 2220, 1675, 1600 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1.[Na].Cl[C:17]1[C:18]([N+:34]([O-:36])=[O:35])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=[CH:20]2>C1COCC1>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH:10]=[CH:9][C:8]=1[O:11][C:17]1[C:18]([N+:34]([O-:36])=[O:35])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[N:21]=[CH:20]2
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Reactant: C[Si](C)(C)CCOCn1ncc2c([N+](=O)[O-])c(Cl)ccc21
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Oc2ccc3c(cnn3COCC[Si](C)(C)C)c2[N+](=O)[O-])c(OC)c1

Procedure:
To methyl-3-methoxy-4-hydroxyphenylacetate (0.062 g, 0.32 mmol) in dry THF (5 mL) under nitrogen was added sodium hexamethyldisylazide (1M solution in THF) (312 μl, 0.31 mmol). After 10 min. stirring at room temperature 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (93 mg, 0.28 mmol) in 5 mL of THF was added. The resulting mixture was stirred at reflux for 5 days. After that time the mixture was quenched with water and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The desired product was isolated by chromatography (10% ethyl acetate/hexane). 1H NMR (400 MHz) (CDCl3) δ 8.40 (s, 1H); 7.70 (d, J=9.1 Hz, 1H); 7.05 (d, J=9.1 Hz, 1H); 6.95 (m, 2H), 6.84 (dd, J=1.5, 8.0 Hz, 1H); 5.75 (s, 2H); 3.82 (s, 3H), 3.62, s, 3H); 3.62 (s, 2H); 3.57 (t, J=8.0 Hz, 2H); 0.89 (t, J=8.0 Hz, 2H); 0.0 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:24][C@H:20]2[CH2:21][CH2:22][CH2:23][N:19]2[C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)OC1(C)C

Procedure:
[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl][4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone was prepared as described in Example 14 from 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid and (R)-(−)-1-(2-pyrrolidinylmethyl)pyrrolidine.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:30])[C:17]([O:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18]>CN(C)C=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:16]([CH3:30])[C:17]([O:19][CH2:20][CH2:21][S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC(Br)C(=O)OCCSCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(O)cc1)C(=O)OCCSCc1ccccc1
Temperature: 25 °C

Procedure:
12.1 g of hydroquinone were dissolved in 60 ml of dry dimethylformamide, and while blowing a slow stream of nitrogen into the solution, 31.7 g of potassium carbonate were added thereto at room temperature whilst stirring. Then the mixture was heated to 90° to 95° C. for one hour with stirring. The mixture was cooled to 60° C., and 30.3 g of 2-benzylthioethyl 2-bromopropionate were added dropwise thereto. After the addition was completed, the mixture was further heated to 90° C. for 2 hours. After cooling the reaction mixture to room temperature, it was poured into ice-water and adjusted to pH 7. Then it was extracted with 100 ml of chloroform. The organic phase was dried and the chloroform was distilled off under reduced pressure. The end product of 2-benzylthioethyl 2-(4-hydroxy-phenoxy)-propionate was obtained in a yield of 25.2 g in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH:9]=2)[CH:7]=1.[Sn](Cl)Cl.Cl>CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:10]2[CH:9]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])[N:13]=[C:12]([NH2:14])[N:11]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Nc2ccc([N+](=O)[O-])cc2)nc(N)n1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(N)cc2)nc(N)n1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
A mixture of the title compound of Example 11 (0.060 g, 0.16 mmol) and tin (II) chloride (0.19 g, 1.0 mmol) in a solution of 1.0 M hydrochloric acid and methanol (1:10, 15 ml) was heated under reflux for 2 hours. After evaporation of volatiles under reduced pressure, the residue was treated with aqueous sodium hydroxide solution (1.0 M, 10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.035 g, 64% yield) as a white powder. 1H NMR (DMSO-d6) δ 3.84 (s, 3H, CH3), 4.83 (s, 2H, NH2), 6.08 (s, 2H, NH2), 6.54 (d, 2H, J=8.7 Hz, Ar), 6.58 (s, 1H, Ar), 7.13 (d, 1H, J=8.9 Hz, Ar), 7.25 (d, 2H, J=8.7 Hz, Ar), 7.41 (dd, 1H, J=8.9 Hz, J-2.8 Hz, Ar), 7.89 (d, 1H, J=2.8 Hz, Ar), 8.67 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:18])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Br-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:18])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:20][CH2:21][CH3:22]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [Br-]
Product: CCC=C(c1cccnc1)C(C)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone and propyltriphenylphosphonium bromide there is obtained 3-(2,4-dichloro-β-methyl-α-propylidenephenethyl)-pyridine