Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[I:3].[OH:6][CH2:7][C@@H:8]1[CH:23]=[C:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[N:10]([CH3:11])[CH2:9]1.O.N>CS(C)=O>[I:3][C:15]1[NH:16][C:17]2[C:24]3[C:14]=1[CH2:13][C@@H:12]1[C:22]([C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:23][C@@H:8]([CH2:7][OH:6])[CH2:9][N:10]1[CH3:11]
Reactant: C[Si](C)(C)I
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: N
Solvent: O
Solvent: CS(C)=O
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(I)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2.3 g of trimethyliodosilane are portionwise added to 20 ml of dimethylsulfoxide and the mixture is stirred at room temperature for 5 minutes. Then, a solution of 1 g of lysergol in 15 ml of dimethylsulfoxide is added, the reaction mixture is stirred for 15 minutes, then poured into water and made alkaline by adding aqueous ammonia up to a pH value of 8 to 9. The precipitate is filtered off, wash 3 times with 20 ml of water each and dried to give the title compound in a yield of 1.1 g (0.002913, mole, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[C:13]([OH:18])=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.[Ag]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:16](=[O:17])[CH:15]=[CH:14][C:13](=[O:18])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C=CC(=O)c2[nH]c(-c3ccc(Cl)cc3)nc21
Yield: 20.2 %

Procedure:
A mixture of 1.0 g of 2-(4-chlorophenyl)-1H-benzimidazole-4,7-diol, 4 g of sodium sulfate and 1.3 g of silver oxide was stirred in p-dioxane for 12 hours and then filtered. The filtrate was evaporated and the residue crystallized from ethanol, giving 200 mg of the desired product as an orange solid, mp 270°-272° C. (dec.).
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[N:48]=[C:49]([NH:52][C:53](=[O:55])[CH3:54])[S:50][CH:51]=4)[CH:36]=3)[CH2:12]1)[C:8](=[O:56])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:53]([NH:52][C:49]1[S:50][CH:51]=[C:47]([C:37]2[CH:36]=[C:35]([O:34][C@@H:11]3[CH2:10][C@@H:9]4[N:13]([C:14](=[O:33])[C@@H:15]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][C@H:23]5[C@:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:56])[CH2:24]5)[CH2:12]3)[C:44]3[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=3)[N:38]=2)[N:48]=1)(=[O:55])[CH3:54]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4csc(NC(C)=O)n4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4csc(NC(C)=O)n4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3csc(NC(C)=O)n3)nc2c1
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3csc(NC(C)=O)n3)nc2c1

Procedure:
Step 29i) Following an analogous experimental and purification procedure to Step 1i, (1S,4R,6S,14S,18R)-7-cis-18-[2-(2-Acetylaminothiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-14-tert-butoxycarbonylamino-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic ethyl ester (180 mg, 0.228 mmol) in 14 mL of THF and 3.5 mL of MeOH was reacted with 92 mg (2.3 mmol) of LiOH in 7 mL of H2O to afford (1S,4R,6S,14S,18R)-7-cis-18-[2-(2-Acetylaminothiazol-4-yl)-7-methoxyquinolin-4-yloxy]-14-tert-butoxycar-bonylamino-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (150 mg, 86%): 1H NMR (500 MHz, CD3OD, some minor broadening due to rotomers) δ 11.29 (s, 9H), 1.41 (m, 7H), 1.62 (m, 2H), 1.84 (m, 1H), 1.96 (m, 1H), 2.18 (m, 1H), 2.24 (s, 3H), 2.50 (m, 1H), 2.62 (m, 1H), 2.68 (m, 1H), 3.96 (s, 3H), 4.11 (s, 1H), 4.29 (s, 1H), 4.65 (s, 2H), 5.51 (s, 3H), 7.05 (s, 1H), 7.37 (s, 1H) 7.55 (s, 1H), 7.95 (s, 1H), 8.12 (s, 1H): LC-MS m/e 763 (retention time: 3.09, method D, except gradient time increased from 2 to 4 min). Step 29j: Preparation of Compound 28, Example 29, (1S,4R,6S,14S,18R)-7-cis-{18-[2-(2-Acetylaminothiazol-4-yl)-7-methoxyquinolin-4-yloxy]-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-14-yl}carbamic acid tert-butyl ester
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4].[CH2:27]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])[CH3:28]>C(O)C>[CH2:27]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4])[CH3:28]
Reactant: CCc1ccccc1Oc1ccc2c(O)c(C(=O)OC)nc(C#N)c2c1
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3CC)ccc2c1O
Temperature: 150 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
A mixture of 1-Cyano-7-(2-ethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.14 mmole) and 3-amino-2,2-dimethyl-propionic acid ethyl ester (41 mg, 0.43 mmole) in anhydrous ethanol (0.7 ml) was stirred at 130° C. for two hours and 150° C. for one hour before it was cooled to room temperature, concentrated and by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a colorless oil (20.3 mg): MS: (+) m/z 462.22 (M+1), (−) m/z 460.10 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:21]1([CH2:34][O:35][C:36]([NH:38][CH2:39][C:40](O)=[O:41])=[O:37])[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:40](=[O:41])[CH2:39][NH:38][C:36]([O:35][CH2:34][C:21]1[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:37])[CH2:9][CH2:10][N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(CCNCC(=O)OC(C)(C)C)c(=O)[nH]c1=O
Reactant: O=C(O)CNC(=O)OCc1cccc2c1Cc1ccccc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1cn(CCN(CC(=O)OC(C)(C)C)C(=O)CNC(=O)OCc2cccc3c2Cc2ccccc2-3)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
The product from Example 8 (3.78 g; 13 mmol) and N-(fluorenylmethyloxycarbonyl)glycine (5.9 g; 20 mmol) are dissolved in anhydrous N,N-dimethylformamide (160 ml) under a protective atmosphere of argon gas. N,N'-Dicyclohexylcarbodiimide (4.11 g; 20 mmol) is added in portions at 0° C. The mixture is stirred at room temperature for 21 h and the solid which has precipitated is subsequently filtered off with suction. The solution is then concentrated in vacuo, and subsequently distilled repeatedly with toluene, and the crude product is chromatographed on silica gel. (Eluent: toluene/ethanol, 30:1-20:1). Yield: 6.33 g (82%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[OH:14])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:17]=1.CC(C)([O-])C.[K+].O>CS(C)=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc2[nH]ccc2cc1O
Reactant: CC(=O)Nc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(Oc2cc3cc[nH]c3cc2OC(C)C)ccn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
6-Isopropoxy-1H-indol-5-ol described in Production Example 17-4 (165 mg, 0.863 mmol) and N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (442 mg, 2.59 mmol) were dissolved in dimethylsulfoxide (2.0 mL) under nitrogen atmosphere, then potassium tert-butoxide (194 mg, 1.73 mmol) was added at room temperature, and the mixture was heated and stirred at 160° C. for 3 hours. The reaction liquid was cooled to room temperature and water and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:2-1:3), and then the target fraction was concentrated under vacuum to obtain the title compound (116 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.C(O)(=O)C>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([NH:19][C:20]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=[CH:22][CH:21]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: Nc1ccnn1-c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)O)c1
Temperature: 150 °C
Yield: 25.5 %

Procedure:
A mixture of 2-bromo-5-methoxy benzoic acid (1.31 g, 5.7 mmol), potassium carbonate (859 mg, 6.2 mmol), 5-amino-1-phenyl-pyrazole (900 mg, 5.7 mmol), and copper (II) acetate (21 mg, 0.11 mmol) in DMF (12 mL) was heated (150° C.) in a sealed tube for 16 h. After cooling, the reaction mixture was diluted with water (5 mL), and then acidified to pH 4 with acetic acid. The mixture was extracted with dichloromethane (3×10 mL), and then the combined organic extracts were washed with water (2×10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. HPLC purification of the residue (YMC propack C18 column, 150×20 mm ID, 30%-80% acetonitrile in water gradient) afforded 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino] benzoic acid (450 mg, 26%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 13.33 (br s, 1H), 9.62 (br s, 1H), 7.64 (d, 1H), 7.34-7.58 (m, 6H), 7.00-7.11 (m, 2H), 6.30 (d, 1H), 3.69 (s, 3H); ES-MS m/z 310.1 (MH+); HPLC RT (min) 2.74.
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([PH2+]C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([CH:37]=O)=[CH:34][C:33]=2[C:39]=1[C:40]([CH3:43])([CH3:42])[CH3:41])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([CH:37]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:34][C:33]=2[C:39]=1[C:40]([CH3:41])([CH3:43])[CH3:42])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Reactant: CCCCCCC[PH2+]c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under nitrogen atmosphere, 2.6 ml of n-butyl lithium (1.6 M in n-pentane) was added dropwise to a suspension of 1.84 g of n-heptylphenylphosphonium bromide in 10 ml of tetrahydrofuran. After stirring at room temperature for 30 minutes, a solution of 1.0 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran synthesized in Example 2-2) in 10 ml of tetrahydrofuran was added dropwise. Then, the mixture was heated under reflux for 30 minutes, cooled and then combined with a saturated aqueous ammonium chloride solution and extracted with chloroform. The organic layers were dried over anhydrous magnesium sulfate, then concentrated, and the residue was purified by silica gel column chromatography (in chloroform) to give 1.14 g of 5-benzyloxy-4-t-butyl-2-(1-octenyl)benzofuran as a colorless oil (yield 91%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)nc1

Procedure:
Operations similar to those of Production Example 14 were conducted using 6-chloronicotinic acid and 4-fluorophenylboronic acid, to provide the title compound as white solid.
Reaction SMILES: [NH3:1].C[O:3][C:4]([P:6](=[O:15])([O:11][CH2:12][CH:13]=[CH2:14])[O:7][CH2:8][CH:9]=[CH2:10])=O>O1CCCC1>[C:4]([P:6](=[O:15])([O:11][CH2:12][CH:13]=[CH2:14])[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[NH2:1]
Reactant: N
Reactant: C=CCOP(=O)(OCC=C)C(=O)OC
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)C(N)=O
Temperature: 35 °C

Procedure:
A slight excess (5-10%) of gaseous ammonia is introduced into a stirring mixture of 11 parts of diallyl methoxycarbonylphosphonate (from triallyl phosphite and methyl chloroformate) and 200 parts of tetrahydrofuran. The temperature increases from 25° to 28° C. spontaneously. The mixture is then heated to 35° C. and maintained at this temperature for 2 hours. The slightly hazy solution is filtered, and solvent is removed from the filtrate at 50° C. under reduced pressure (15 mm.). The residual solid is recrystallized from benzene, giving 6 parts of white crystalline diallyl carbamoylphosphonate, m.p. 91°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.O.O.O.O.O.O.O.O.[Ba].ClCCCl.Cl.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39]Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@H]2O)cc1
Reactant: CN(C)CCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Ba]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
0.2 g of triethylbenzylammonium chloride, 3 g of trans-(+)-2-(4'-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one and 6.4 g of barium octahydrate were added under vigorous stirring to 60 ml of 1,2-dichloroethane and 7 ml of water. A solution of 3.2 g of 2-(dimethylamino)-ethyl chloride-hydrochloride in 5 ml of water was added dropwise to the above mixture during 5 minutes. Stirring was continued at room temperature for 1 hour and then for 1.5 hours at 70°. After cooling to room temperature the aqueous phase was separated and discarded and the 1,2-dichloroethane was removed under vacuum. The residue was dissolved in 50 ml of toluene and then extracted with 50 ml of 3% HCl. The acidic extract was treated with an excess of a sodium bicarbonate solution and then extracted with 50 ml of toluene. The toluene was removed under vacuum to yield 3.5 g of trans (+)-2-(4' methoxyphenyl)-3-hydroxy-5-(2'-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one; m.p. 115°-117°.
Reaction SMILES: [SH2:1].[NH2:2][C:3](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C.N1C=CC=CC=1>>[NH2:2]/[C:3](/[C:4]([CH3:7])([CH3:5])[CH3:6])=[C:8](\[C:9]#[N:10])/[C:11](=[S:1])[NH2:12]
Reactant: S
Reactant: CC(C)(C)C(N)=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)/C(N)=C(/C#N)C(N)=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With cooling, 1.52 g (4.50 mmol) of hydrogen sulphide are introduced as a gas into a mixture of 1.6 g (1.40 mmol) of (1-amino-2,2-dimethylpropylidene)propanedinitrile, 1.41 g (1.40 mmol) of triethylamine and 2.21 g (2.80 mmol) of pyridine. For 1 h, nitrogen is then passed through the reaction mixture, and the reaction mixture is then added to ice-water and extracted with dichloromethane. The combined organic phases are dried over Mg2SO4 and freed from the solvent under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(COC)OC.C(=O)(O)[O-].[Na+].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>[C:13]1([C:2]2[CH:3]=[C:4]([CH:11]=[O:12])[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc(Br)cc2ccoc12
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: O=Cc1cc(-c2ccccc2)cc2ccoc12
Yield: 36.1 %

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (600 mg), phenylboronic acid (326 mg) and tetrakis(triphenylphosphine)palladium (O) (176 mg) in dimethoxyethane (20 ml) and 8% sodium bicarbonate (10 ml) was heated at reflux for 16 h. Solvent was removed in vacuo, the residue was partitioned between chloroform (40 ml) and water (40 ml). The organic phase was washed with brine (50 ml), dried, filtered and the filtrate evaporated in vacuo to give a yellow oil. Purification by FCC eluted with hexane:ethyl acetate (1:0→10:1) gave the title compound as a pale yellow solid (214 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:30][C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1.O[C@@H](C)C(N1CCN(CC2C=CC3C(=CC=C(OC4C=CC(C5NN=CC=5)=CC=4)C=3)N=2)CC1)=O>>[OH:30][C:31]1([C:34]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]5[CH:20]=[CH:21][C:22]([C:25]6[NH:29][N:28]=[CH:27][CH:26]=6)=[CH:23][CH:24]=5)[CH:14]=4)[N:9]=3)[CH2:2][CH2:3]2)=[O:35])[CH2:33][CH2:32]1
Reactant: c1cc(-c2ccc(Oc3ccc4nc(CN5CCNCC5)ccc4c3)cc2)[nH]n1
Reactant: O=C(O)C1(O)CC1
Agent: C[C@H](O)C(=O)N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1
Product: O=C(N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1)C1(O)CC1

Procedure:
The title compound 15 is synthesized from intermediate F (35 mg, 0.076 mmol), and 1-hydroxy-1-cyclopropanecarboxylic acid (19 mg, 0.19 mmol) according to the procedure described for the synthesis of compound 13.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[CH:11]=1>C(#N)C.ClCCl>[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[C:11]=1[I:1]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1I

Procedure:
N-Iodosuccinimide (17.67 g) was added portionwise to a stirred solution of 5-amino-3-cyano-1-(2,4,6-trichlorophenyl)pyrazole (U.S. Pat. No. 5,232,940; 22.5 g) in acetonitrile (300 ml) and the resulting mixture stirred at room temperature for 1 hour, then evaporated under reduced pressure. The residue was partially purified by chromatography on silica gel (800 g), using an elution gradient of dichloromethane:ethyl acetate (100:0 to 0:100), to produce a pale brown solid which was further purified as follows. Trituration with hexane (25 ml ) provided a residue which was dissolved in dichloromethane (500 ml). This solution was washed with water (500 ml), the aqueous washing back-washed with ethyl acetate (500 ml) and the combined organic solutions dried (Na2SO4) and evaporated under reduced pressure to furnish the title compound as a pale brown solid. δ(DMSOd6): 6.28 (br.s,2H), 7.98 (s,2H). MS (thermospray): M/Z [M+H] 413.0; C10H4Cl3IN4+H requires 412.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[CH3:15][C:16]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])[CH3:17]>O1CCOCC1>[C:16]([O:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:21])([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCC(=O)O
Temperature: -20 °C
Yield: 51.9 %

Procedure:
Prepared as described for L2 from stirring 4-aminobutyric acid (3.94 g, 38.2 mmol) in 50% aqueous dioxane with triethylamine (8.0 mL, 57 mmol) and BOC-ON (10.4 g, 42.2 mmol). A yellow oil was obtained that solidified upon addition of hexanes and cooling to −20° C. to yield a cream solid (4.03 g, 51.8%). 1H NMR (d6-DMSO, 300 MHz): δ 1.36 (s, 9H, CH3), 1.57 (m, 2H, CH2), 2.17 (t, 2H, CH2), 2.90 (m, 2H, CH2), 6.80 (t, 1H, NH).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:25]([S:39](Cl)(=[O:41])=[O:40])=[CH:24]2.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:31])=[O:32])[C:25]([S:39]([N:17]1[CH2:18][CH2:19][N:14]([C:12]3[S:13][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH3:2])[CH:8]=4)=[CH:10][N:11]=3)[CH2:15][CH2:16]1)(=[O:41])=[O:40])=[CH:24]2
Reactant: Cc1cc(-c2cnc(N3CCNCC3)s2)ccn1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc(N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5n4S(=O)(=O)c4ccccc4)CC3)s2)ccn1
Reaction time: 3 h

Procedure:
A saturated solution of hydrochloride in methanol (12 ml) was added to 1-(t-butoxycarbonyl)-4-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine (400 mg) at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated under reduced pressure, whereby 1-[5-(2-methylpyridin-4-yl)thiazol-2-yl]piperazine hydrochloride was obtained as a white solid. In a solution of the resulting hydrochloride in methylene chloride (12 ml) was dissolved 5-chloro-1-phenylsulfonylindol-2-sulfonyl chloride (522 mg), followed by the addition of diisopropylethylamine (538 μl) at room temperature. After stirring for 3 hours, a saturated aqueous solution (50 ml) of sodium bicarbonate was added to the reaction. mixture to separate it into layers. The water layer was extracted with methylene chloride (2×15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=7:1), whereby the title compound (240 mg) was obtained as a foam.