Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:4]([NH:8]C(=O)[O-])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:13].Cl>CCO.O1CCOCC1.[Pd]>[ClH:13].[CH:1]1([C@H:4]([NH2:8])[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: ClC(Cl)Cl
Reactant: COC[C@@H](NC(=O)[O-])C1CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC[C@@H](N)C1CC1
Yield: 100 %

Procedure:
To a solution of (S)-1-cyclopropyl-2-methoxyethylcarbamate (4.36 g, 17.5 mmol) from Part D in EtOH (80 mL) and CHCl3 (3 mL) in a Parr bottle was added 4 N HCl in dioxane (5 mL) and Pd/C (476 mg, 10%, wet, Degussa type). The mixture was placed on a Parr shaker under H2 atm at 45 psi for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated then reconcentrated from hexanes (2×) to afford (S)-1-cyclopropyl-2-methoxyethanamine hydrochloride (2.65 g, 100% yield) as a white solid: mp 190-192° C.; [α]25D +14.3 (c 0.446, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.41 (s br, 3H), 3.68 (d, J=5.6 Hz, 2H), 3.39 (s, 3H), 2.64-2.60 (m, 1H), 1.20-1.13 (m, 1H), 0.71-0.58 (m, 3H), 0.32-0.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 72.1, 59.2, 57.5, 10.7, 4.2, 4.1; LRMS (ESI) m/e 231.2 [(2M+H)+, calcd for C12H27N2O2 231.2].
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:5][CH2:4]1.B1([O-])O[O:38]1.O.O.O.O.[Na+]>CO.O>[OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=2)[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH2:21])=[O:38])=[CH:22][CH:23]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C#N)cc1
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C(N)=O)cc1
Temperature: 50 °C

Procedure:
A solution of 4-{5-[4-hydroxymethyl-4-(3-trifluoromethoxy-benzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile (71 mg, 0.142 mmol; Example 31) and sodium perborate tetrahydrate (92.8 mg, 0.6 mmol) in a mixture of methanol (2.5 mL) and water (1 mL) was heated at 50° C. for 7 h. The resultant mixture was concentrated under vacuum, and the residue was partitioned between chloroform and dilute hydrochloric acid (0.5M). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:11])([CH3:10])[CH2:12][C:13]([OH:21])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C2C(=O)OC(C)(C)OC2=O)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(C)(C)CC(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 107.8 %

Procedure:
The 5-(2-(3-methoxyphenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione 85.C (0.313 g, 1.1 mmol) was dissolved in DMF (1.50 mL, 19 mmol). To the solution was added water (0.15 mL, 8.3 mmol). The resulting solution was then heated to 100° C. and stirred for four hours. The reaction was cooled to room temperature and then diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were then washed with 1N lithium chloride solution (1×20 mL) and brine (1×20 mL) and dried over magnesium sulfate. The filtrate was then concentrated to give crude 3-(3-methoxyphenyl)-3-methylbutanoic acid 85.D (0.247 g, 111% yield) that was used directly in the following reaction. MS ESI (pos.) m/e: 226.1 (M+H2O)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:34]([O:36]C)=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:8][C:9]1[C:10]([C:34]([OH:36])=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(NCCCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCNc1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 8-(benzyloxy)-5-(6-(tert-butoxycarbonylamino)hexylamino)-1,6-naphthyridine-7-carboxylate (Example 1.1; 0.58 g; 1.08 mmol) was dissolved in a mixture of water (2 ml) and methanol (2 ml). NaOH (100 mg; 2.7 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. H2O and HCl 2 N were added until pH=4-5 was reached. The mixture was extracted with EtOAc (2×). The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:37])C.C(O)C.[OH-].[Na+].Cl>C1COCC1>[CH:31]1([CH2:30][CH2:29][O:28][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:38])=[O:3])=[C:8]([CH3:37])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCC3CCCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(OCCC3CCCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (110 mg; 0.208 mmol) was dissolved in THF (2 mL), ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 105 mg. HPLC-MS: m/z: 500.1 (M)+; Rt: 3.20 min.
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:34]O>C(O)C>[CH2:18]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC
Reactant: OO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
The general procedure of Example 11 is followed using 100 grams (0.19 mol) of dihexadecylamine (451 eq. wt., 88% secondary amine, 30.2 grams (0.44 mol) of 50% aqueous hydrogen peroxide solution and 400 ml of ethanol. After stirring for 48 hours, the reaction mixture is filtered to give the above-named product which is twice recrystallized from 500 ml of chloroform. The desired product is obtained in a yield of 29.4 grams (32%) as white needles melting at 97°-99° C.
Reaction SMILES: C[Si](Cl)(C)C.[C:6]([C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)#[N:7].O.C(=O)([O-])[O-:18].[Na+].[Na+]>C(O)C>[C:6]([C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)(=[O:18])[NH2:7]
Reactant: N#Cc1cc(CO)ccn1
Reactant: O=C([O-])[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cc(CO)ccn1
Temperature: 50 °C
Reaction time: 5.5 h

Procedure:
Trimethylsilyl chloride (27 mL) and a suspension of 2-cyanopyridine-4-methanol (1.6 g, 11 mmol, Reference compound 11-1) in ethanol (20 mL) were added to ethanol (14mL) at room temperature under a nitrogen atmosphere, and then the mixture was stirred at 50° C. for 5.5 hours. The mixture was allowed to stand, and water (27 mL) and sodium carbonate (2.3 g, 22 mmol) were added thereto. The solvent was evaporated under reduced pressure, ethanol (100 mL) was added thereto, and the resulting insoluble matter was filtered out. The filtrate was evaporated under reduced pressure, then the resulting residue was dried at 50° C. under reduced pressure to the title reference compound including inorganic salt.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](C2C=CC=CC=2C(O)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2].[OH:24]O>C1COCC1>[OH:24][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC[C@H](C)COc1ccc(-c2ccccc2C(=O)O)cc1C#N
Reactant: OO
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc(O)cc1C#N

Procedure:
A mixture of compound 47 (3.00 g, 0.014 mol), hydrogen peroxide (30%, w/v, 150 ml) and THF (200 ml) was heated under reflux for 3 h. The water/THF mixture was removed in vacuo and the oily residue was dissolved in diethyl ether and washed with water. The ether was dried (MgSO4) and evaporated in vacuo to give a viscous, fawn oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:32]([O:34][CH:35]([O:47][CH2:48][CH3:49])[CH2:36][C@@H:37]([NH2:46])[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH3:33]>>[CH2:48]([O:47][CH:35]([O:34][CH2:32][CH3:33])[CH2:36][C@@H:37]([NH:46][C:29](=[O:30])[C@H:27]([CH3:28])[NH:26][C:24](=[O:25])[C@H:19]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH:18][C:16](=[O:17])[C@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH3:49]
Reactant: CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)[C@@H](C)CC
Reactant: CCOC(C[C@@H](N)CC(=O)OC(C)(C)C)OCC
Product: CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CC(OCC)OCC)[C@@H](C)CC

Procedure:
Starting from 0.22 g (0.5 mmol) of ethoxycarbonyl-L-tyrosyl-L-isoleucyl-L-alanine (Example 3, Step A6) and 0.13 g (0.5 mmol) of (3R)-3-amino-4-t-butoxycarbonyl-butyraidehyde diethyl acetal (Example 1, Step B4) and using proportional amounts of reagents and solvents, the components are coupled and the end product isolated according to the process described in Example 1, Step A1.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:44])[C@H:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][C@H:35]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:44])=[O:33])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 87-89° C.; MS m/e 696 (M+);
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:34][C:2]([F:1])([F:33])[CH:3]([C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Nc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 85 °C
Yield: 65.2 %

Procedure:
To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenylamino)isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1.[BrH:23]>O>[Br:23][CH2:4][C:3]([CH2:6][OH:5])([CH2:2][OH:1])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: Br
Reactant: O=C(c1ccccc1)c1ccc(OCC2(CO)COC2)cc1
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OCC(CO)(CO)CBr)cc1

Procedure:
Suspend (4-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}phenyl)(phenyl)methanone in a mixture of 48% aq. HBr and water and heat the mixture to reflux for 1 hour. Extract the product into dichloromethane, and evaporate the solvent, the solid residue may be recrystallised from ethanol to provide {4-[3-bromo-2,2-bis(hydroxymethyl)propoxy]phenyl}(phenyl)methanone.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[O:5])[CH3:2].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+]([O-])=O)[C:17]=1[C:18]#[N:19])([O-:15])=[O:14]>>[C:18]([C:17]1[C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=[CH:21][C:20]=1[O:10][CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7][NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])#[N:19]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCNC(=O)NCC(C)(C)CO
Product: CCNC(=O)NCC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 47 %

Procedure:
Prepared as in Example 215c from 1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)urea (Example 227d) and 2,6-dinitrobenzonitrile in 47% yield. MS 321 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH2:16][Br:17]
Reactant: CC(=O)N(C(C)=O)c1cc(C)c(Cl)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N(C(C)=O)c1cc(CBr)c(Cl)cc1F
Yield: 7.9 %

Procedure:
A mixture of 7.8 g (0.032 mole) of 2-chloro-4-fluoro-5-diacetylaminotoluene, 6.2 g (0.035 mole) of N-bromosuccinimide, 0.5 g of benzoyl peroxide, and 200 ml of carbon tetrachloride was heated at reflux for two days. This mixture was filtered, and the filtrate was washed with water. The filtrate was dried, and the solvent was evaporated under reduced pressure. The residue was passed through a column of silica gel, eluting with ethyl acetate/heptane (1/4). Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 0.82 g of 2-chloro-4-fluoro-5-diacetylaminobenzyl bromide. The nmr was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:16]=1[C:17]([NH:13][C:10]1[S:11][C:12]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=1)=[O:18]
Reactant: Nc1nc2cccc([N+](=O)[O-])c2s1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: Cc1cc(C)c(C(=O)Nc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 75 °C
Yield: 65.6 %

Procedure:
To 0.089 g (0.46 mmol) of 7-nitro-1,3-benzothiazol-2-amine in 1 mL of pyridine was added 0.17 g (0.91 mmol) of 2,4,6-trimethylbenzoyl chloride. The mixture was heated to 75° C. for 18 h and the volatiles were removed in vacuo. The residue was washed with water and 1 N hydrochloric acid, dissolved in ethyl acetate, dried over sodium sulfate, filtered, concentrated in vacuo and the resulting crude solid was purified by flash chromatography eluting with 25% ethyl acetate/hexanes mixture to give 0.103 g (66%) of the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].N1C(C)=CC=CC=1C.[CH3:17][C:18]([CH3:30])([O:20][C:21]([NH:23][C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26])=[O:22])[CH3:19]>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:29][C@@H:24]([C:25]([O:27][CH3:28])=[O:26])[NH:23][C:21]([O:20][C:18]([CH3:30])([CH3:17])[CH3:19])=[O:22]
Reactant: Nc1ccccc1S
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@H](CSc1ccccc1N)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a mixture of 2-amino-thiophenol (1.9 g., 15.4 mmole), methylene chloride (15 ml.), and 2,6-lutidine (1.8 ml., 1.0 eq.) at -20° (chloroform dry ice) is added 2-[[(1,1-dimethylethoxy)carbonyl]amino]-2-propenoic acid, methyl ester (3.0 g., 1.0 eq.) dropwise over 5 minutes. After one hour the cooling bath is removed and the reaction mixture is stirred for an additional 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, brine, dried (MgSO4), and evaporated. The residue (4.1 g.) is chromatographed on silica (125 g.) eluting with hexane/ethyl acetate (5:1) to give 2.5 g. of S-(2-aminophenyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-cysteine, methyl ester as an oil after evaporation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[NH2:21][CH2:22]CN.O>CN(C)C=O>[C:22]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)#[N:21]
Reactant: NCCN
Reactant: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Br)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(C#N)c1

Procedure:
A mixture of ethyl 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate (0.2 g) and cuprous cyanide (0.07 g) in dry N,N-dimethylformamide (1 ml) was stirred and heated under reflux for 8 h. The hot reaction mixture was poured into a stirred solution of 1,2-diaminoethane (0.3 ml) and water (1.5 ml). The reaction mixture was filtered, and the residue was washed with hot benzene 2×8 ml. The organic layer was separated, and the residue was washed with more hot benzene (10 ml). The benzene solutions were combined, dried (MgSO4) and concentrated to afford a brown oil. The oil was purified using `flash` chromatography and chloroform/methanol 9:1 as eluant. The product fractions were combined and concentrated to afford ethyl 3-[3-cyano-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate as a brown oil. I.R. (CHCl3 film) vC=N: 2230 cm-1
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOc1ccc(CCl)cc1
Reactant: CCCCCCCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCOc1ccc(CCl)cc1

Procedure:
This compound was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (6.36 g, 53.4 mmol), 4-octyloxybenzyl alcohol (12.4 g, 52.5 mmol), CH2Cl2 (150 mL).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])#[N:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[C:1]([C:3](=[CH:13][N:14]([CH3:16])[CH3:15])[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)c1ccsc1
Product: CN(C)C=C(C#N)C(=O)c1ccsc1

Procedure:
2-Cyano-3-dimethylamino-1-thien-3-ylpropen-1-one was prepared from 3-cyanoacetyl thiophene (7.64 g,50.56 mmol) and dimethylformamide dimethylacetal (20 mL, 152 mmol) as a yellow solid (6.6 g), m.p. 134°. δH (CDCl3) 8.27 (1H, dd, J 3.0, 1.3 Hz), 8.00 (1H, s), 7.61 (1H, dd, J 5.0 Hz), 7.27 (1H, dd, J 5.0,3.0 Hz), 3.48 (3H, s) and 3.29 (3H, s).
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=O)[NH2:2].N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](C(N)=O)CC1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound prepared in Example 21 (0.84 g, 4.6 mmol) in pyridine (20 mL) was added imidazole (1.0 g, 4.6 mmol) and phosphorusoxychloride (1.0 mL) in one portion at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 h whereupon the reaction was quenched with water and extracted with ethyl acetate. The organic extract was washed with 2 M hydrochloric acid, dried and concentrated to give the title compound (0.76 g, 99%) as a white solid.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][C:33]([S:36](=[O:38])(=[O:37])[NH2:39])=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (400 mg, 1.02 mmol) is coupled to 4-bromobenzene-sulfonamide (241 mg, 1.02 mmol) using Method A. On filtration of the cooled reaction mixture through celite and removal of the solvents in vacuo, the crude residue obtained is used in the next synthetic step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[N:11][C:12]([NH:15][NH2:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:17][CH2:18][C:19](OC)(OC)OC>Cl.CCOCC>[Cl:17][CH2:18][C:19]1[N:11]2[N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:14]=[CH:13][C:12]2=[N:15][N:16]=1
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Reactant: COC(CCl)(OC)OC
Agent: Cl
Solvent: CCOCC
Product: ClCc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reaction time: 0.17 h
Yield: 80 %

Procedure:
(Step 3-i) N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (4.0 g, 17 mmol)) was taken up in HCl/Et2O (20 mL) and stirred for 10 min. The reaction mixture was concentrated, taken up in DMF (20 mL), and 2-chloro-1,1,1-trimethoxyethane (5.2 g, 34 mmol) was added. After stirring for 3 hours, a precipitate began to form. After one hour additional stirring, the reaction mixture was filtered to give the product, 3-(chloromethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine, as a white solid. (4 g, 13.6 mmol, 80% yield): 1H-NMR (500 MHz, DMSO-d6) 10.40 (s, 1H), 8.19 (d, J=9.8 Hz, 1H), 8.13 (t, J=1.8 Hz, 1H), 7.68 (dd, J=1.7, 8.2 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.28 (d, J=9.9 Hz, 1H), 7.11-7.09 (m, 1H).