Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]([CH2:14][CH2:15][CH2:16][CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4]>C(O)C>[NH2:7][CH2:6][C:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:1][CH2:2][CH2:3][CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCC(C#N)(CCCC)c1ccccc1
Solvent: CCO
Product: CCCCC(CN)(CCCC)c1ccccc1

Procedure:
α,α-Dibutyl-benzeneacetonitrile ((2), 7.0 gm; 0.0237 mol) is dissolved in borane-THF complex (1.1 equiv.) at room temperature for 18 hours. Once reaction is complete, ethanol (50 ml) is added, and the reaction is evaporated to dryness. Once dry, the residue is suspended in 100 ml 1M HCl, and the suspension is evaporated to dryness on a rotary evaporator. This procedure is repeated three times. After the final evaporation, the white residue is dissolved in 1M NaOH (100 ml), and extracted with diethyl ether (2×150 ml). The extracts are combined, dried with Na2SO4, filtered and evaporated to dryness to yield 1-amino-2,2-dibutyl-2-phenylethane (3), wt=6.4 gm (90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.22 (s, br, 1H), 7.74-6.68 (m, 12H), 5.04-4.92 (m, 1H), 3.66-3.50 (m, br, 2H), 3.00-2.82 (br, 2H), 2.80-2.58 (m, br, 4H), 2.58-2.40 (m, br, 2H), 2.00-1.68 (m, br, 6H), 1.66-1.46 (m, br, 1H), 1.46-1.36 (br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 551.1 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=S)[C:13]([C:22](OCC)=[O:23])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[O:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][NH2:37])[CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(#N)C.[Hg](Cl)Cl>[N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]4=[N:37][N:36]([CH:32]5[CH2:33][CH2:34][CH2:35][O:30][CH2:31]5)[C:22](=[O:23])[C:13]4=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=S
Reactant: NNC1CCCOC1
Agent: Cl
Agent: Cl[Hg]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1C1CCCOC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 1-[4-(1H-pyrazol-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate (200 mg, 0.510 mmol) and (±)-tetrahydro-2H-pyran-3-ylhydrazine hydrochloride (172 mg, 1.13 mmol, 2.2 equiv) were dissolved in N,N-dimethylformamide (10 mL) and acetonitrile (10 mL). The solution was sparged under nitrogen, treated with potassium carbonate (708 mg, 5.12 mmol, 10 equiv) and mercury(II)chloride (139 mg, 0.51 mmol, 1 equiv) and stirred at ambient temperature for 14 hours. The mixture was poured into water and extracted with ethyl acetate (3×70 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate) to provide the titled compound as a dark red solid: 1H-NMR (400 MHz, CDCl3) δ 8.33-8.29 (1H, m), 7.88 (1H, d, J=2.5 Hz), 7.74 (1H, d, J=1.8 Hz), 7.66 (2H, d, J=8.7 Hz), 7.61-7.56 (3H, m), 7.40 (2H, d, J=8.6 Hz), 6.47 (1H, dd, J=2.4, 1.9 Hz), 5.85 (2H, s), 4.77-4.69 (1H, m), 4.06 (1H, ddd, J=10.8, 4.4, 1.6 Hz), 4.00 (1H, d, J=11.0 Hz), 3.84 (1H, ap t, J=10.6 Hz), 3.55-3.48 (1H, m), 2.31-2.19 (1H, m), 2.17-2.10 (1H, m), 1.92-1.83 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 427.1872 [(M+H)+; calculated for C24H22N6O2: 427.1877].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][NH2:15].S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:15][CH3:14])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CN
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Product: CNCc1ccc(F)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
1.9 g of 4-fluoro-3-trifluoromethylbenzaldehyde, 30 ml of methylamine and 2 g of magnesium sulfate were stirred at room temperature for 2 h, the excess methylamine for the most part evaporating. The reaction mixture was diluted with ether, filtered and concentrated in vacuo. The methylbenzimine thus obtained was dissolved in 30 ml of methanol and, after addition of 2.0 g of sodium borohydride, the mixture was stirred overnight. It was concentrated in vacuo, and the residue was treated with 20 ml of 10 percent hydrochloric acid and extracted twice with tert-butyl methyl ether. The aqueous phase was then rendered alkaline and extracted twice again with tert-butyl methyl ether. After concentrating these extracts, 1.0 g of N-(4-fluoro-3-trifluoromethylbenzyl)-N-methylamine was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:16]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2ccccc2)cc1
Yield: 78.9 %

Procedure:
4-Phenylphenol 64 (25.5 g, 0.15 mol), allyl bromide (20.0 g, 0.165 mol) and K2CO3 (41.5 g, 0.15 mol) in 75 ml of dry DMF were stirred at room temperature overnight. The reaction mixture was diluted with 500 ml of diethyl ether and washed with water. The ether layer was washed with brine, dried and concentrated to give a lightly brown solid that was recrystallized from hexane to give 24.9 g of 4-allyloxy-biphenyl 65. Step 2: 3-Allyl-biphenyl-4-ol 66.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:15]2([CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[S:14][CH:13]([CH:27]([N:35]2C(=O)C3=CC=CC=C3C2=O)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl.O>CN(C=O)C>[NH2:35][CH:27]([CH:13]1[NH:12][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:15]2([CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[S:14]1)[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29]
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(N)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
18.6 g (0.03 mole) of tert-butyl 4-benzyloxycarbonyl-8-phenyl-alpha-phthalimido-1-thia-3,8-diazaspiro[4.5]decane-2-acetate (obtained in 3.3) are suspended in 50 ml of N,N'-dimethylformamide. A solution containing 2 g (0.04 mole) of hydrazine hydrate in 20 ml of N,N-dimethylformamide is added dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm up to ambient temperature and stirred for 1 hour. The reaction mixture is then again cooled to 0° C. and slowly neutralized by the addition of 33.75 ml of 1N hydrochloric acid, whereafter it is stirred at ambient temperature for 2 hours after which time it solidifies. 300 ml of water are added, followed by extraction with chloroform. The organic phase is washed with water, dried with anhydrous sodium sulfate and evaporated to dryness. The residue is triturated with diethyl ether, filtered and the precipitate washed with diethyl ether. There are obtained 12.8 g of tert-butyl alpha-amino-4-benzyloxycarbonyl-8-phenyl-1 -thia-3,8-diazaspiro[4.5]decane-2-acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:30][C:29](O)([C:31]([O:33][CH3:34])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.CCN(S(F)(F)[F:42])CC>C(Cl)Cl>[F:42][C:29]1([C:31]([O:33][CH3:34])=[O:32])[CH2:28][N:27]([CH2:26][C:4]2[CH:5]=[CH:6][C:7]([C:8]3[S:9][C:10]4[C:15]([N:16]=3)=[CH:14][CH:13]=[C:12]([C:17]3([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:19][CH2:18]3)[N:11]=4)=[C:2]([F:1])[CH:3]=2)[CH2:30]1
Reactant: COC(=O)C1(O)CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(F)CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Reaction time: 0.17 h

Procedure:
To a solution of methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-3-hydroxyazetidine-3-carboxylate (0.0334 g, 0.068 mmol) at 0° C. in anhydrous DCM was added 1.0 mL was added DAST (0.011 mL, 0.082 mmol). The reaction mixture was stirred for 10 min. at which time the reaction was quenched carefully with water and extracted with DCM. The organics were dried over magnesium sulfate and concentrate in vacuo. Purification by silica gel afford methyl 3-fluoro-1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated 491.2; Observed: 492.0 (M++1).
Reaction SMILES: C(OC([N:8]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:9]1[N:10]=[CH:11][C:12]([C:36]2[CH2:41][CH2:40][CH:39](CS([O-])(=O)=O)[CH2:38][CH:37]=2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.[N-:54]=[N+:55]=[N-:56].[Na+]>CN(C=O)C>[N:54]([CH:39]1[CH2:40][CH2:41][C:36]([C:12]2[N:13]=[C:14]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:28])[C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:22][CH:21]=4)=[N:18][N:19]=3)[C:9]([NH:8][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])=[N:10][CH:11]=2)=[CH:37][CH2:38]1)=[N+:55]=[N-:56]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(CS(=O)(=O)[O-])CC4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N=[N+]=[N-])CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 94.8 %

Procedure:
To a solution of [4-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclohex-3-en-1-yl]methanesulfonate (138 mg, 0.18 mmol) in anhydrous DMF (1 mL) was added sodium azide (59 mg, 0.91 mmol) and the reaction mixture was heated at 70° C. under an atmosphere of nitrogen for 15 h. The reaction mixture was cooled to room temperature, quenched with water and diluted with EtOAc. An aqueous saturated brine solution was added, the layers were separated and the organic layer was washed twice more with an aqueous saturated brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to a brown oil to provide tert-butyl N-[[4-[5-[6-(4-azidocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (103 mg, 94%), which was used without any further purification in the next step. LC/MS m/z 604.7 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:27][CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 74.7 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)piperidin-4-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (423 mg, 75%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Cl:40][CH2:41][C:42]([N:44]=[C:45]=[O:46])=[O:43]>C1COCC1>[Cl:40][CH2:41][C:42]([NH:44][C:45](=[O:46])[NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)=[O:43]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: O=C=NC(=O)CCl
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(=O)NC(=O)CCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.38 mmol) in THF (15 mL) was added a solution of 2-chloroacetyl isocyanate (100 mg, 0.78 mmol) in THF (1 mL) dropwise under nitrogen. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the resulting residue was obtained 6-(3-(2-chloroacetyl)ureido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (203 mg, yield: 81%) without further purification. MS (M+H)+: 642.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[O:22])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chlorobenzoic acid (0.86 g, 5 mmol) in anhydrous CH2Cl2 (40 mL) was added 1-(trifluoromethyl)-3-isocyanatobenzene (1.03 g, 5.5 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCO3 (40 mL) was added and the mixture was stirred for 5 min. The organic layer was separated and aqueous was extracted with CH2Cl2 (3×20 mL). The combined organic solution was dried (Na2SO4). The solvent was removed in vacuo. The title compound was afforded as a white solid (1.68 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 88 %

Procedure:
A 0° C. solution of (2,4-difluoro-phenyl)acetic acid (14.5 g, 0.084 mol) in H2SO4 (60 mL) was treated drop-wise with 69% HNO3 (6 mL), stirred at 0° C. for 35 min, then poured into ice water. The aqueous layer was extracted with EtOAc, and the organic extracts were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give (2,4-difluoro-5-nitro-phenyl)acetic acid (16 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (t, J=8.0 Hz, 1H), 7.68 (m, 1H), 3.75 (s, 2H).
Reaction SMILES: [Cl:1]C(OCC)=O.[CH2:7]([S:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:16]=1[CH2:17]N(C)C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([S:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:16]=1[CH2:17][Cl:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(CN(C)C)c1SCc1ccccc1
Solvent: CCOCC
Product: COc1cccc(CCl)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Ethyl chloroformate (0.6 ml, 6.2 mmol) was added dropwise to an ice-cooled solution of 2-benzylthio-3-methoxy-N,N-dimethyl benzylamine (1.5 g, 5.2 mmol) in dry ether (40 ml). The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, and the residual solid was extracted several times with hexane. The extracts were evaporated to leave the title compound as a solid (1.29 g, 89%), mp 54°-55C. (Found: C,64.67; H,5.50; Cl,12.99. C15H15ClOS requires C,64.62; H,5.42; Cl,12.72%).
Reaction SMILES: [CH3:1][N:2]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]=[C:5]2[O:14][N:15]=[C:16]([CH3:17])[C:4]=12.[OH-].[K+:35]>O1CCCC1CCO>[CH3:1][N:2]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:3]1[C:8]([C:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]2[O:14][N:15]=[C:16]([CH3:17])[C:4]=12.[K+:35]
Reactant: CCOC(=O)c1cnc2onc(C)c2c1N(C)S(=O)(=O)c1ccc(Oc2ccncc2)cc1
Agent: OCCC1CCCO1
Agent: [K+]
Agent: [OH-]
Product: Cc1noc2ncc(C(=O)[O-])c(N(C)S(=O)(=O)c3ccc(Oc4ccncc4)cc3)c12

Procedure:
A mixture of 1.84 g (3.92 mmol) of the preceding ester and 4.71 ml of 1 N KOH in 10 ml of tetrahydrofuran-ethanol (1:1) was refluxed overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether and filtered to give 1.59 g of potassium 4-{methyl-[4-(4-pyridinyloxy)benzene-sulfonyl]amino}-3-methylisoxazolo[5,4-b]pyridine-5-carboxylate as a pale yellow solid. Following the procedure of Example 91, the preceding potassium salt (1.45 g) was reacted with hydroxylamine to give a solid. The solid was partitioned between 30 ml of CH2Cl2 and 30 ml of H2O and filtered. The CH2Cl2 layer was stirred with 2 N citric acid (aqueous phase-pH 6). The solid which precipitated was filtered off and suspended in H2O. The aqueous suspension was adjusted to pH 7 with 1 N NaHCO3 and filtered. The solid was again suspended in H2O and the pH of the aqueous suspension adjusted to pH 6 with 2 N citric acid. The mixture was stirred and filtered to give 0.66 g of 4-{methyl-[4-(4-pyridinyl-oxy)benzenesulfonyl]amino}-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid, hydroxyamide, m.p. 141° C. dec.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7].[Br:15]Br.Br>C(Cl)(Cl)Cl>[Br:15][CH:6]([CH3:7])[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCC(=O)c1ccccc1
Reactant: BrBr
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1ccccc1

Procedure:
A pinch of aluminium chloride ground beforehand in a mortar is added to 13.4 g (0.1 mol) of propiophenone in 100 ml of anhydrous chloroform, and a solution of 5 ml (0.1 mol) of bromine in 20 ml of chloroform is then added dropwise, with stirring. The mixture decolourises instantaneously. It is cooled in an ice bath and then stirred overnight to drive off the hydrobromic acid formed. The catalyst is filtered off and the solvent is driven off from the filtrate. 22 g of an oil remain, which is used as such in a subsequent step.
Reaction SMILES: C([O:8][CH:9]([CH3:30])[CH2:10][CH2:11][C:12]1[O:13][C:14]2[C:23]3[CH:22]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:15]=2[N:16]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][CH:9]([CH3:30])[CH2:10][CH2:11][C:12]1[O:13][C:14]2[C:23]3[CH:22]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(CCC(C)OCc4ccccc4)oc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nc(CCC(C)O)oc3c21
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
To a solution of N-(2-{2-[3-(benzyloxy)butyl]-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl}ethyl)acetamide (155 mg, 0.381 mmol) in methanol (4 mL) was added a 10% palladium-carbon powder (300 mg), and the mixture was stirred at 50° C. for 4 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (101 mg, yield 84%).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31](=O)[CH2:32][CH3:33]>>[CH2:32]([C:31]1[CH:30]=[CH:29][N:26]=[C:24]([NH:23][C:13]2[CH:14]=[CH:15][C:16]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:11]([O:10][CH3:9])[CH:12]=2)[N:25]=1)[CH3:33]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCC(=O)C=CN(C)C
Solvent: O=[N+]([O-])O
Product: CCc1ccnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (149 mg, 0.4 mmol) and 1-dimethylamino-pent-1-en-3-one using (64 mg, 0.5 mmol) using in analogous manner the procedure described in example 139. Obtained as a white solid (18 mg, 16%). MS ISP (m/e): 310.2 [(M+H)+]. NMR (CDCl3, 300 MHz): δ (ppm)=8.33 (d, 1H), 7.81 (d, 1H), 7.63 (s, 1H), 7.25 (s, 1H), 7.15 (d, 1H), 7.07 (dd, 1H), 6.87 (s, 1H), 6.67 (d, 1H), 3.87 (s, 3H), 2.71 (q, 2H), 2.30 (s, 3H), 1.33 (t, 3H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].CS[C:17]1[NH:18][CH2:19][CH2:20][CH2:21][C:22]=1[N+:23]([O-:25])=[O:24]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:18][CH2:19][CH2:20][CH2:21][C:22]=2[N+:23]([O-:25])=[O:24])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC1=C([N+](=O)[O-])CCCN1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCNC2=C([N+](=O)[O-])CCCN2)cs1
Reaction time: 8 h

Procedure:
A solution of 2-(2-guanidino-4-thiazolylmethylthio)ethylamine (0.8 g, 3.5 mmol) and 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.5 g, 2.9 mmol) in ethanol (50 ml) was refluxed for 3 hours then left to stand at room temperature overnight. The solvent was removed in vacuo and the residue chromatographed on a silica-gel column. The product was eluted with ethyl acetate/propan-2-ol (8:2) and recrystallised twice from methanol/ether. Yield: 0.16 g, 15%. M.P. 211°-212.5° C.