Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[O:31]([C:33]([C:35]1[S:36][CH:37]=[CH:38][C:39]=1[S:40](Cl)(=[O:42])=[O:41])=[O:34])[CH3:32]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:40]([C:39]3[CH:38]=[CH:37][S:36][C:35]=3[C:33]([O:31][CH3:32])=[O:34])(=[O:41])=[O:42])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 2-(methoxylcarbonyl)thiophene-3-sulfonyl chloride (0.014 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 1001C for 30 minutes. The reaction was cooled to 25° C., diluted with ethyl acetate (40 mL), washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane/methanol to give the title compound (15 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.69 (m, 1 H) 3.89 (s, 3 H) 4.46 (m, 2 H) 7.50 (m, 4 H) 7.65 (d, J=8.82 Hz, 1 H) 8.01 (d, J=5.15 Hz, 1 H) 8.54 (dd, J=7.91, 1.65 Hz, 1 H) 8.88 (dd, J=4.60, 1.65 Hz, 1 H) 10.74 (s, 1 H) 14.06 (s, 1 H). MS (ESI−) m/z 630 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13](Br)(Br)([Br:15])[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:14][C:13]([Br:15])=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([CH3:10])[C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C=O)c(C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C=C(Br)Br)c(C)c1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere, 2,3-dimethylanisaldehyde (3.0 g, 18.3 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0° C. Carbon tetrabromide (9.10 g, 27.4 mmol) was added followed by a dropwise addition of triphenylphosphine (14.4 g, 54.9 mmol) in dichloromethane (100 mL). The reaction was allowed to stir at 1.5 h at 0° C. The reaction was concentrated in vacuo, and the resulting residue was suspended in a mixture of hexanes and chloroform (4:1). The solid was removed by filtration and discarded. The filtrate was concentrated in vacuo and flash column chromatographed on silica gel eluting with 0% to 40% ethyl acetate in hexanes to yield the desired product. 1H NMR (400 MHz) (CDCl3) δ 7.44 (s, 1H); 7.19 (d, J=8.0 Hz, 1H): 6.72 (d, J=8.0 Hz, 1H), 3.82 (s, 3H); 2.17 (s, 3H); 2.16 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:12][CH:13]=2)=[O:6])[CH2:4][CH2:3]1.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[N:10]=[CH:9][C:8]([N:7]3[C:5](=[O:6])[C:2]4([CH2:4][CH2:3]4)[NH:1][C:25]3=[O:27])=[CH:13][CH:12]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(Oc2ccc(NC(=O)C3(N)CC3)cn2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)NC4(CC4)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 1-amino-N-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)cyclopropanecarboxamide (Intermediate 105, 58 mg) in dry dichloromethane (2 mL) TEA (0.129 mL, 0.925 mmol) was added. The reaction mixture was cooled in an ice-bath, then a solution of triphosgene (24.72 mg, 0.083 mmol) in dry dichloromethane (0.500 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then the solution of triphosgene (24.72 mg, 0.083 mmol) in dry dichloromethane (0.500 mL) was added again. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was maintained in the ice-bath and quenched with water (10 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column 25 g SNAP column and cyclohexane/ethylacetate as eluents from 100:0 to 50:50. This afforded the title compound as a white solid (20 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]CC1C=CC=CC=1)=[O:6]>CO.[Pd]>[OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:6]
Reactant: O=C(NCCO)NCc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NCCO)NCc1ccccc1O
Reaction time: 2 h

Procedure:
59.6 g of N-(2-hydroxyethyl)-N'-(2-benzyloxybenzyl)-urea are dissolved in 600 ml of methanol and hydrogenated in the presence of 6 g of Pd/C-catalyst (5%). After 2 hours the hydrogenation ceases. The catalyst is suction-filtered, and the filtrate concentrated by evaporation in vacuo. The residue is recrystallised from 350 ml of ethyl acetate; the pure product melts at 100°-101°.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13]>C1COCC1>[OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:3]1
Reactant: OC1CNCC12CC2
Reactant: OCCCBr
Solvent: C1CCOC1
Product: OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.5 %

Procedure:
To a solution of 7-hydroxy-5-azaspiro[2.4]heptane (1.23 g, 11.0 mmol) in THF (40 mL) was added 3-bromopropanol (2.3 g, 16.65 mmol) and Et3N-(2.24 g, 22.2 mmol). The reaction mixture was stirred at rt for 12 hrs and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:50:2(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as orange oil (1.14 g, 60%).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>CO>[N:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3([C:3]([NH:19][NH2:20])=[O:2])[CH2:7][CH2:6]3)=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1(c2ccc3ncccc3c2)CC1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)C1(c2ccc3ncccc3c2)CC1
Yield: 99.9 %

Procedure:
A solution of 1-quinolin-6-yl-cyclopropanecarboxylic acid methyl ester (513 mg, 2.26 mmol) and hydrazine monohydrate (3.39 g, 67.7 mmol) in methanol (5 mL) was heated under reflux overnight. After cooling, the solvent was removed in vacuo to afford 513 mg (100%) of the title compound and used without further purification. LCMS (method A): [MH]+=228, tR=2.88 min.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH:35](O)[CH3:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH:35]([O:23][C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:11]([CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:10]=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=2)[N:18]=4)[CH3:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (300 mg, 0.96 mmol), 3-(1-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (213 mg, 1.06 mmol) and PPh3 (379 mg, 1.46 mmol) in dioxane (5 mL) was added DIAD (285 μL, 1.46 mmol) and the resulting yellow solution stirred at RT for 2 h. Further 3-(1-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (105 mg, 0.53 mmol), PPh3 (190 mg, 0.73 mmol) and DIAD (143 μL, 0.73 mmol) were added and the resulting mixture stirred for 2 h. The reaction mixture was partitioned between EtOAc and 1M NaOH, the organic phase dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) affording 3-{1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}azetidine-1-carboxylic acid tert-butyl ester (312 mg, 66%). LCMS: RT 3.76 min [M+H]+ 495.2
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][O:6][C:4]1=[O:5].[CH2:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>C(OCC)C>[CH2:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([S:1][CH2:2][CH:3]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][O:6][C:4]2=[O:5])=[O:24])=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH3:18]
Reactant: O=C1OCC(c2ccccc2)C1CS
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCc1ccc(C(=O)SCC2C(=O)OCC2c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
To a solution of 1.5 g of α-mercaptomethyl-β-phenyl-γ-butyrolactone in 30 ml of ethyl ether were added at room temperature 4.3 g of p-n-butylbenzoyl chloride and then 1.9 ml of pyridine. The mixture was kept at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was diluted with 100 ml of ethyl ether, washed with 10% hydrochloric acid, 10% aqueous sodium hydrogen carbonate and then satureated saline, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 2.1 g (yield 79%) of the title compound.
Reaction SMILES: C(OC(C1C=CC(C(O)=O)=CC=1)=O)CCCCCCC.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:43])[CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:42][CH:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[CH:29][CH:30]=1)=[O:43]
Reactant: CCCCCCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCOC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 46 %

Procedure:
To 10 ml of methylene chloride were added 85 mg (0.31 mmol) of 4-octyloxycarbonyl benzoic acid obtained in Example 32, 95 mg (0.31 mmol) of 4-hydroxy-4'-(2-methyloctanoyl) biphenyl and 20 mg of 4-dimethylamino pyridine, which was added with 70 mg (0.32 mmol) of N,N'-dicyclohexylcarbodiimide. This mixture was reacted by heating under reflux for 4 hours, and the precipitated solid was filtered off. The filtrate was concentrated and isolated by a column chromatography of silica gel to obtain 42 mg (yield 24%) of white (+)-4-(2-methyloctanoyl) biphenyl, 4-octyloxycarbonyl benzoic acid ester having the aforementioned physical and chemical properties.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=3[CH3:69])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:52][C:53]2[C:54]3[CH:61]=[N:60][N:59]([C:62]4[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=4[CH3:69])[C:55]=3[N:56]=[CH:57][N:58]=2)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1
Reactant: Cc1c(F)cccc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1-n1ncc2c(O[C@@H](COCCO)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (1.504 mL, 1.50 mmol) was added dropwise to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AF3) (600 mg, 0.83 mmol) in THF (15 mL) over a period of 1 minute and the resulting solution stirred at ambient temperature for 3 hours. Saturated ammonium chloride (20 mL) was added to the reaction mixture which was then diluted with EtOAc (25 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 60 to 100% EtOAc in isohexane then by chiral HPLC to afford the product (252 mg, 62%). 1H NMR (400 MHz, DMSO) δ 2.07 (3H, s), 3.53-3.62 (2H, m), 3.65-3.72 (2H, m), 4.06-4.22 (2H, m), 4.61-4.71 (1H, m), 5.96-6.05 (1H, m), 7.36-7.42 (1H, m), 7.44-7.55 (2H, m), 7.92-7.96 (1H, m), 8.08 (1H, d), 8.45 (1H, dd), 8.60 (1H, s), 8.71 (1H, s), 11.18 (1H, s); m/z (ESI−) (M−H)−=485; HPLC tR=2.29 min.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[N:13]=1>CC(C)=O>[Br:11][C:12]1[C:17]([O:18][CH2:1][O:2][CH3:3])=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[N:13]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)n1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc([N+](=O)[O-])nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
With cooling with ice, chloromethyl methyl ether (1.04 mL) and potassium carbonate (3.16 g) were added to an acetone (30 mL) solution of 2-bromo-6-nitropyridin-3-ol (1.0 g), and stirred overnight at room temperature. The reaction liquid was concentrated under reduced pressure, ethyl acetate was added to the residue and washed with water and saturated brine. The organic layer was dried with sodium sulfate, then filtered and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 50%, gradient) to give the intended product (1.16 g, 97%) as a brown solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH:22]2[CH2:23][CH2:24][CH:18]1[CH2:19][C:20](=[C:25]([C:28]([OH:30])=O)[C:26]#[N:27])[CH2:21]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Br:31][C:32]1[C:33]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:34]([Cl:38])[S:35][C:36]=1[Cl:37]>CN(C=O)C.CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH:22]2[CH2:23][CH2:24][CH:18]1[CH2:19][C:20](=[C:25]([C:26]#[N:27])[C:28]([NH:42][S:39]([C:33]1[C:32]([Br:31])=[C:36]([Cl:37])[S:35][C:34]=1[Cl:38])(=[O:40])=[O:41])=[O:30])[CH2:21]2)=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=C(C#N)C(=O)O)C2
Reactant: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=C(C#N)C(=O)NS(=O)(=O)c1c(Cl)sc(Cl)c1Br)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
120 μl of DIEA are added to a solution of 102 mg of 3-(carboxy-cyano-methylene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 162 mg of 4-bromo-2,5-dichloro-thiophene-3-sulfonamide, 583 μl of PPA in DMF (50%) and 43 mg of DMAP in 4 ml of DMA, and the mixture obtained is stirred at RT for 48 hours. From the mixture obtained solvent is removed in vacuo and the residue obtained is subjected to preparative HPLC on an RP-18 column. 3-[2-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-cyano-2-oxo-ethylidene]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in the form of a foam is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([NH:15]C(=O)C)=[N:12][C:11]=2[CH3:19])=[CH:6][C:5]=1[F:20])(=[O:3])[CH3:2].Cl>CCO>[NH2:15][C:13]1[S:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([F:20])[CH:6]=2)=[C:11]([CH3:19])[N:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(C)=O)c(F)c2)s1
Agent: Cl
Solvent: CCO
Product: CC(=O)c1ccc(-c2sc(N)nc2C)cc1F
Reaction time: 1.5 h

Procedure:
N-[5-(4-Acetyl-3-fluoro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (0.46 g, 0.171 mmol) in EtOH (15 ml) is treated with 6M HCl (3.14 ml) and heated using microwave radiation at 100° C. After 90 minutes, the solvent is removed in vacuo and the resulting solid is dissolved in water (25 ml). The pH is adjusted to pH 7 by addition of 2M NaOH. The yellow solid which precipitates is filtered and dried under vacuum to afford the title compound. (MH+ 251.22).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[C:14]([O:16]C)=O.[Cl:18][CH2:19][C:20]#[N:21]>Cl.O1CCOCC1>[Br:7][C:6]1[C:2]2[N:1]=[C:20]([CH2:19][Cl:18])[NH:21][C:14](=[O:16])[C:3]=2[S:4][C:5]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCCl
Reactant: COC(=O)c1sc(-c2ccccc2)c(Br)c1N
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(CCl)nc2c(Br)c(-c3ccccc3)sc12
Temperature: 110 °C
Yield: 58.6 %

Procedure:
A mixture of EXAMPLE 8A (1.47 g, 4.7 mmol), chloroacetonitrile (0.43 g, 5.7 mmol) in 4N hydrochloric acid in dioxane (10 mL) was stirred overnight at ambient temperature. The solvent was removed and the residue heated in N,N-dimethylformamide (15 mL) at 110° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with 1:1 ethyl acetate/hexanes to give 0.98 g (59%) of the title compound. 1H NMR (DMSO-d6) δ 13.13 (s, 1H), 7.75-7.78 (m, 2H), 7.56-7.60 (m, 3H), 4.64 (s, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[C:14]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.[OH-].[Na+:30]>O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[C:14]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[O-:22])=[N:3]1.[Na+:30]
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A suspension of the product of Example 29A (0.113 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.286 mL, 0.285 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.119 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.64 (m, 4 H) 0.91 (m, 1 H) 1.40 (m, 3 H) 1.68 (m, 1 H) 2.10 (m, 1 H) 7.30 (m, 3 H) 7.49 (m, 3 H) 7.64 (m, 1 H) 8.05 (m, 1 H) 15.44 (m, 1 H). MS (ESI−) m/z 395 (M−H)−.
Reaction SMILES: [ClH:1].CO[C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.C1C[O:39][CH2:38]C1>O1CCOCC1>[ClH:1].[CH3:13][O:12][C:11]1[C:10]([O:39][CH3:38])=[C:9]2[C:6]([CH2:7][CH:8]2[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]2[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]2)=[O:19])=[CH:5][CH:4]=1
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Reactant: C1CCOC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3ccc(OC)c(OC)c31)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by the product of Preparation 1 and of the THF by dioxane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([CH3:1])[CH:3]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C(=O)O)ccc1Oc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)c(C)c2)c(O)n1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A mixture of 3-methyl-4-phenoxybenzoic acid (114 mg, 0.5 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (285 mg, 0.75 mmol), triethylamine (0.2 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was washed with water (30 mL). The organic phase was separated, dried over sodium, filtered, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-4-phenoxybenzamide as a white solid (50 mg, 28%). LRMS (M+H+) m/z: calcd 362.16. found 362. HPLC purity (214 nm): 95%. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.24 (t, J=4.8 Hz, 1H), 8.83 (s, 1H), 7.68 (dd, J=9.6 Hz, J=2.1 Hz, 1H), 7.41-7.35 (m, 2H), 7.13 (t, J=7.5 Hz, 1H), 6.96-6.93 (m, 2H), 6.82 (d, J=8.4 Hz, 1H), 5.80 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.21 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O1CCCC1.O.[NH2:26][NH2:27]>O>[N:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:26][NH2:27])=[O:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(N2CCCCC2)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NNC(=O)c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 6-(1-piperidyl)nicotinate (5.00 g) in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (10 ml) was added hydrazine monohydrate (11.0 ml). The solution was refluxed for 6 hours, during which period additional hydrazine monohydrate (11.0 ml) was added to the mixture. After cooling to ambient temperature, the reaction mixture was added to water (100 ml) and then stirred for 20 minutes at ambient temperature. The resulting precipitates were filtered, washed with water, and dried to give 6-(1-piperidyl)nicotinoylhydrazine (3.44 g), as a white solid.
Reaction SMILES: CN([SiH](N(C)C)N(C)C)C.C=CC=C.[CH3:15][N:16]([Si:18]([N:26]([CH3:28])[CH3:27])([N:23]([CH3:25])[CH3:24])[CH:19]=[CH:20][CH:21]=[CH2:22])[CH3:17]>C1(C)C(C)=CC=CC=1>[CH3:15][N:16]([Si:18]([N:26]([CH3:27])[CH3:28])([N:23]([CH3:25])[CH3:24])[CH:19]=[CH:20][CH2:21][CH3:22])[CH3:17]
Reactant: C=CC=C[Si](N(C)C)(N(C)C)N(C)C
Agent: C=CC=C
Agent: CN(C)[SiH](N(C)C)N(C)C
Solvent: Cc1ccccc1C
Product: CCC=C[Si](N(C)C)(N(C)C)N(C)C
Temperature: 125 °C
Yield: 32 %

Procedure:
To a 1 liter autoclave, was added 250 g (1.5 mol) tris(dimethylamino)silane, 100 g xylene, 168 g (3.1 mol) 1,3-butadiene and 200 ppm RhCl(PPh3)3 (0.45 g) as the catalyst. After the autoclave was secured, the reaction was heated to 125° C. for four hours. The reactor was then cooled to room temperature. GC and GC/MS revealed that the major product formed was 1-tris(dimethylamino)silylbuta-1,3-diene in 65% yield. 1-tris(dimethylamino)silylbut-1-ene was also formed in 32% yield.