Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C.[NH2:62][C@H:63]([CH2:67][S:68][S:69][C:70]([CH3:73])([CH3:72])[CH3:71])[C:64]([OH:66])=[O:65]>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:20]([NH:62][C@H:63]([CH2:67][S:68][S:69][C:70]([CH3:73])([CH3:72])[CH3:71])[C:64]([OH:66])=[O:65])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)SSC[C@@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)SSC[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid (Fmoc-Trp-OH) (1.26 g, 2.96 mmol) and N-hydroxysuccinimide (341 mg, 2.96 mmol) in methylene chloride (5.9 mL) were mixed with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI.HCl) (568 mg, 2.96 mmol) at 0° C., and the reaction solution was stirred at room temperature for 16 hours. N-Ethyl-N-isopropyl propane 2-amine (DIPEA, 517 μL, 2.96 mmol) and (S)-2-amino-3-(tert-butyldisulfanyl)propanoic acid (H-D-Cys(StBu)-0H) (Compound SP641) (620 mg, 2.96 mmol) were then mixed at 0° C., and the reaction solution was stirred at room temperature for 5 hours. After washing with 1 N hydrochloric acid, the organic layer was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was crude purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Fmoc-Trp-D-Cys(StBu)-OH) (Compound SP642).
Reaction SMILES: [NH:1]([C:8]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH:1]([C:8]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]([C:10](=[O:11])[CH:9]=1)=[CH:17][C:16]([F:18])=[C:15]([Cl:19])[N:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (2.3 g, 5.7 mmol) and t-BuOK (1.28 g, 11.4 mmol) in dioxane (80 mL) was stirred at 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue provided 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (1.0 g, 50%) as a light yellow solid: LCMS RT: 2.60 min, MH+: 366.8. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]1[C:21]2[C:12](=[CH:13][C:14]3[CH:15]4[CH2:25][CH2:24][CH2:23][CH:16]4[C:17](=O)[NH:18][C:19]=3[CH:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>COCCOC>[C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]1[C:21]2[C:12](=[CH:13][C:14]3[CH:15]4[CH2:25][CH2:24][CH2:23][CH:16]4[C:17](=[S:43])[NH:18][C:19]=3[CH:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)C1CCc2cc3c(cc21)NC(=O)C1CCCC31
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)C1CCc2cc3c(cc21)NC(=S)C1CCCC31

Procedure:
A solution of 100 mg (0.21 mmol) of 7-(N-tert-butoxycarbonyl-3-chlorobenzyl-amino)-1,2,3,3a,7,8,9,10b-octahydro-dicyclopenta[c,g]quinolin-4-one and 96 mg (0.23 mmol) of Lawesson's reagent in 10 ml of DME is stirred for 2 hours at room temperature. After concentration by evaporation, the residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 70 mg of product.
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH2:3][CH3:4].[CH3:7][S:8]([C:11]1[S:15][C:14]([N:16]=[C:17]=[O:18])=[N:13][N:12]=1)(=[O:10])=[O:9].NN>C(Cl)Cl>[CH2:1]([N:5]([C:17]([NH:16][C:14]1[S:15][C:11]([S:8]([CH3:7])(=[O:10])=[O:9])=[N:12][N:13]=1)=[O:18])[NH2:6])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: CCCCNN
Agent: NN
Solvent: ClCCl
Product: CCCCN(N)C(=O)Nc1nnc(S(C)(=O)=O)s1
Temperature: 25 °C

Procedure:
A solution of n-butylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-n-butyl-4-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 97.7 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (83.6 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[NH:17][C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[N:17]([CH3:28])[C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: COc1c2c(c(NC(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c2c(c(N(C)C(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide (0.073 g, 0.196 mmol) in 2 mL DMF was added Cs2CO3 (0.084 g, 0.25 mmol) and methyl iodide (0.044 mL, 0.7 mmole) and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was partitioned between CHCl3 and 10% KHSO4, the organic was dried with Na2SO4, filtered and evaporated to give the crude product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[O:16][C:17]([CH2:20]Cl)=[N:18][N:19]=3)=[CH:13][N:12]3[CH:22]=[CH:23][N:24]=[C:11]3[C:10]=2[Cl:25])=[C:4]([F:26])[CH:3]=1.[I-].[K+].[NH3:29]>O1CCCC1>[NH2:29][CH2:20][C:17]1[O:16][C:15]([C:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:26])=[C:10]([Cl:25])[C:11]3[N:12]([CH:22]=[CH:23][N:24]=3)[CH:13]=2)=[N:19][N:18]=1
Reactant: N
Reactant: Fc1cc(Br)ccc1Nc1c(-c2nnc(CCl)o2)cn2ccnc2c1Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: NCc1nnc(-c2cn3ccnc3c(Cl)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(4-Bromo-2-fluoro-phenyl)-[8-chloro-6-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-7-yl]-amine (38 mg, 0.083 mmol) was dissolved in tetrahydrofuran (1 mL). Potassium iodide (14 mg, 0.083 mmol) was added and then ammonia (7 M solution in methanol, 0.30 mL, 2.08 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (gradient of 20:1 dichloromethane/methanol to 5:1) to yield the desired product (26 mg, 71%) as a yellow solid. MS ESI (+) m/z 437, 439 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.33 (s, 1H), 8.17 (d, 1H), 7.70 (d, 1H), 7.51 (dd, 1H), 7.16 (d, 1H), 6.65 (t, 1H), 3.94 (s, 2H). 19F (376 MHz, DMSO-d6)−128.3 (t).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>O1CCOCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[CH:5]=[O:6])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=Cc1cc(-c2ccncc2)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To 3-bromo-5-(trifluoromethyl)benzaldehyde (1.0 g, 3.95 mmol) in 1,4-dioxane (15 ml), pyridine-4-boronic acid) (583 mg, 4.74 mmol), sodium carbonate (2M aqueous solution) (1.67 gms in 7.9 ml water) and Pd(PPh3)4 450 mg, 0.39 mmol) was added and heated at 90° C. for 5 h. Then reaction mixture was diluted with ether, washed with water, brine and dried. Volatiles were removed under vacuum and the crude residue was column chromatographed (50% ethylacetate/50% hexanes) to yield 250 mg of 3-(pyridin-4-yl)-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCCCC2)n(-c2ccccc2)c2ccccc12
Yield: 50 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with piperidine as described in Example 2 to give, after flash chromatography, the title compound (50% yield). NMR (CDCl3) 10.23 (1H, s), 8.29 (1H, d), 7.59 (2H, m), 7.50 (1H, m), 7.40 (2H, d), 7.22 (1H, m), 7.11 (1H, t), 6.98 (1H, d), 3.25 (4H, m), 1.53 (2H, m), 1.42 (4H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH2:40][C:39](=[O:41])[NH:38][N:37]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[NH:37][N:38]=[C:39]([O:41][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:40]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCC5CCN(CCS(C)(=O)=O)CC5)c(OC)cc34)n[nH]2)cc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (115 mg, 0.28 mol) and 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (65 mg, 0.33 mol), (prepared as described for the starting material in Example 10), in DMF (1.5 ml) containing potassium carbonate (60 mg, 0.42 mol) was heated at 100° C. for 30 minutes. After cooling, water was added. The precipitate was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in methylene chloride/methanol and pentane was added. The precipitate was collected by filtration, washed with pentane and dried under vacuum to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (120 mg, 75%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.Cl.[N:26]([O-])=O.[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[N:26][N:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cn2ccnc2)cc1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-n2nnc3ccc(Cn4ccnc4)cc32)cc1
Temperature: 0 °C
Yield: 49 %

Procedure:
A mixture of 1.6 parts of 4-(1H-imidazol-1-ylmethyl)-N2 -phenyl-1,2-benzenediamine, 20 parts of acetic acid and 1.08 parts of concentrated hydrochloric acid was cooled in an ice bath at 12°-16° C. A solution of 0.83 parts of sodium nitrite in 7 parts of water was added dropwise. Upon complete addition, the reaction mixture was allowed to reach room temperature while stirring. The reaction mixture was poured into alkaline ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel first using a mixture of trichloromethane and methanol, saturated with ammonia, (97.5:2.5 by volume) and then a mixture of ethyl acetate, methanol and methanol, saturated with ammonia (92:2.5:2.5 by volume) as eluents. The pure fractions were collected and the eluent was evaporated. The residue was taken up in a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 0.81 parts (49.0%) of 6-(1H-imidazol-1-ylmethyl)-1-phenyl-1H-benzotriazole; mp. 110.1° C. (compound 72).
Reaction SMILES: [NH2:1][C:2](=[O:37])[C:3](=[O:36])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:25]=[C:24]3[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C:23]3=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[ClH:38]>ClCCl.O1CCOCC1>[ClH:38].[NH2:1][C:2](=[O:37])[C:3](=[O:36])[CH:4]([NH:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH:25]=[C:24]2[CH2:26][NH:27][CH2:28][C:23]2=[N:22]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)nc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CNC2
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 2-(3-(4-amino-3,4-dioxo-1-phenylbutan-2-ylcarbamoyl)-pyridin-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (50 mg, 0.099 mmol) in dichloromethane (10 mL) 4004 of 4M HCl in dioxan were added and stirred over night at room temperature. The mixture then was concentrated, the remainder treated with MTB and the remaining solid then further purified by chromatography over Chromabond RP-C18 (eluent: water/acetonitrile) to give 30 mg of the titel compound; ESI-MS [M+H]+: 405.1. 1H-NMR (400 MHz, DMSO), δ[ppm]: 10.41 (broad), 8.93 (m, 1H), 8.54 (m, 1H), 8.21 (m, 1H), 8.06 (m, 1H), 7.85 (m, 1H), 7.71 (m, 1H), 7.49 (m, 1H), 7.26 (m, 5H), 5.33 (m, 1H), 4.35-4.16 (m, 5H), 3.12 (m, 1H), 2.84 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]#[N:14])=[C:6](Cl)[C:5]=1[N+:16]([O-:18])=[O:17])[CH3:2].[NH3:21].C(COC)OC>C(O)C>[CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH2:21])[C:7]([C:13]#[N:14])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: N
Reactant: CCN(CC)c1c([N+](=O)[O-])cc(C#N)c(Cl)c1[N+](=O)[O-]
Solvent: CCO
Solvent: COCCOC
Product: CCN(CC)c1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Reaction time: 72 h

Procedure:
A solution of 4.33 g. (0.0144 mole) of N,N-diethyl-3-chloro-2,6-dinitro-4-cyanoaniline, 6.40 g. (0.0288 mole) of a 7.66% solution of ammonia in absolute ethanol, and 15 ml. of dimethoxyethane was sealed in a Pyrex reaction tube and alloed to stand at room temperature for 72 hours. The contents were distilled to dryness at reduced pressure and extracted with 100 ml. of boiling chloroform. The filtered chloroform extract was evaporated to dryness and the residual orange solid taken up in hot 95% ethanol. Upon cooling, the product crystallized and was isolated by filtration to give 1.51 g. (37.3%) or an orange, crystalline solid melting at 142°-145°C. Recrystallization from 95% ethanol gave the desired product, m.p. 145.5°-146.5°C.
Reaction SMILES: [C:1]([O:7]CC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][Si:11](C(O)C)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:1]([O:7][Si:11]([CH3:13])([CH3:12])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(O)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)O[Si](C)(C)C
Yield: 82.5 %

Procedure:
A solution of ethyl acetoacetate (2.60 g. 20 mmol; Aldrich) and trimethylsilylethanol (2.51 g, 21.1 mmol, Fluka) in toluene (100 ml) was heated and slowly distilled at 80°-100° with a Vigreaux column (1.7 cm×7 cm), removing most of the solvent over a period of 10 h. The residue was distilled under a reduced pressure with a Vigreaux column (1.7 cm×7 cm to obtain 3.34 g (16.5 mmol, yield 82.7%) of the title compound as a colourless oil: Rf 0.32 (20% ETOAc/Hex); bp 85°-88° C. (0.3 Torr); ir (neat) max : 1740 (ketone) and 1720 (ester) cm-1 ; 1Hmr (CDCl3) : 0.07 (9H, s, SiMe3), 1.00 (2H, `t` J=8 Hz, SiCH2), 1.93 (0.45H, s, MeC(OH)=), 2.28 (2.55H, s, MeCO), 3.12 (0.15H, s, OH of the enol form), 3.43 (1.7H, s, COCH2), 4.2 (2H, `t` J=8 Hz, CO2CH2), and 4.95 (0.15H, s, vinyl proton of the enol form) ppm;
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(/C=C/c2ccccc2)ccc1C(=O)O)c1ccccc1
Reaction time: 7 h

Procedure:
0.37 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 2 mL of methanol and 2 mL of tetrahydrofuran containing 0.18 g of methyl 2-(benzamido)-4-((E)-2-phenylvinyl)benzoate at room temperature, and stirred at the same temperature for 7 hours. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. Solid substances were separated by filtration and purified with silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to obtain 65 mg of 2-(benzamido)-4-((E)-2-phenylvinyl)benzoic acid as white solid.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>>[Cl:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([C:7]1[CH:6]=[CH:5][C:2]([O:3][CH3:4])=[C:1]([O:9][CH3:10])[CH:8]=1)=[O:15]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: COc1ccccc1OC
Product: COc1ccc(C(=O)C(C)(C)CCl)cc1OC
Temperature: 70 °C
Yield: 93 %

Procedure:
A 50 mL round bottom flask equipped with a stir bar was charged with veratrole (1.3 mL, 10 mmol) and 3-chloropivaloyl chloride (1.4 g, 10 mmol). To this mixture was added polyphosphoric acid (20 g). The mixture was heated at 70° C. for 2 h. [The progress of the reaction was followed by removing an aliquot for mini workup and NMR analysis.] The material was added to a mixture of ice water (100 mL)/EtOAc (100 mL) and stirred until the polyphosphoric acid had dissolved. The phases were separated and the EtOAc phase was washed with sat. NaHCO3 (100 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was used as is in the next step. Amount obtained: 2.4 g, 9.3 mmol, 93% yield. LC-MS (ESI) m/e 257 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 6H) 3.83 (s, 2H) 3.93 (s, 3H) 3.95 (s, 3H) 6.87 (d, J=8.44 Hz, 1H) 7.37 (d, J=1.95 Hz, 1H) 7.48 (dd, J=8.42, 1.98 Hz, 1H). Step 2
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([S:24][C:25]4[CH:41]=[CH:40][C:28]5[N:29]=[C:30]([NH:32]C(=O)OC(C)(C)C)[S:31][C:27]=5[CH:26]=4)=[N:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([S:24][C:25]4[CH:41]=[CH:40][C:28]5[N:29]=[C:30]([NH2:32])[S:31][C:27]=5[CH:26]=4)=[N:22][N:23]=3)[N:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Temperature: 20 °C
Yield: 36.1 %

Procedure:
4×0.1 cm3 of trifluoroacetic acid (containing 10% of anisole) are added to a mixture of 127 mg of 1,1-dimethylethyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate in 5 cm3 of dichloromethane stirred at 20° C., this addition taking place over 7 h, until the starting product has disappeared. The reaction mixture is then concentrated under reduced pressure, so as to recover 186.5 mg of yellow powder which is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60A; 32-63 μm), elution being carried out with a gradient of dichloromethane then dichloromethane/methanol: 99.5/0.5, 99/1, 98.5/1.5, 98/2, 97.5/2.5, 97/3. 36.6 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine are thus obtained in the form of a whitish powder, the characteristics of which are as follows: