Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].Cl.[NH2:6][CH2:7][C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:17]([CH:20]=[C:21](SC)[S:22]([CH3:24])=O)([O-:19])=[O:18]>CO>[CH3:24][S:22][C:21]1[NH:6][CH:7]=[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]=1[N+:17]([O-:19])=[O:18]
Reactant: NCC(=O)Cc1ccccc1
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSc1[nH]cc(Cc2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.42 h
Yield: 28.3 %

Procedure:
A solution of sodium methoxide (sodium (1.9 g, 0.084 mol) dissolved in methanol (100 ml) and a solution of 1-amino-3-phenylpropan-2-one hydrochloride (7.9 g, 0.042 mol) in methanol (100 ml) were simultaneously added dropwise, to a stirred solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (7.7 g, 0.042 mol) in methanol. The temperature was maintained at about 60° during the addition, which took 25 minutes. The solvent was then removed in vacuo, and the residual dark red oil was chromatographed on a silica gel column. Elution and recrystallisation with petroleum ether/ethyl acetate (7:3) gave 2-methylthio-3-nitro-4-benzylpyrrole (2.95 g, 28.5%) m.p. 190°-192.5°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[N:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[N:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1cnc(Cl)nc1
Reactant: CC1(C)OB(c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
The compound (600 mg, 1.08 mmol) obtained in Example 52-2), 2-chloro-5-methylpyrimidine (155 mg, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.05 mmol), tricyclohexylphosphine (36 mg, 0.13 mmol), and tripotassium phosphate (400 mg, 1.84 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL), and the mixture was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (100 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (30 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 20%) to obtain the title compound (348 mg, 62%) in a light yellow solid form.
Reaction SMILES: [C:1]([C:3]1(O[Si](C)(C)C)[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][C:8]2[N:7]([CH3:17])[N:6]=[C:5]([CH3:18])[C:4]1=2)#[N:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:3]1[C:4]2[C:5]([CH3:18])=[N:6][N:7]([CH3:17])[C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:2]
Reactant: CCOC(=O)C1CCc2c(c(C)nn2C)C1(C#N)O[Si](C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C#N)c2c(C)nn(C)c2CC1
Reaction time: 5 h
Yield: 53.1 %

Procedure:
A solution of ethyl 4-cyano-4,5,6,7-tetrahydro-1,3-dimethyl-4-(trimethylsilyloxy)-1H-indazole-5-carboxylate (28.1 g, 0.119 mol) in pyridine is mixed with phosphorus oxychloride (43.0 mL, 0.461 mol), stirred for 5 hours at reflux temperature and concentrated in vacuo. The resultant black residue is diluted with ethyl acetate and water and treated with sodium bicarbonate to pH 6. The phases are separated, the organic phase is set aside, and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with aqueous sodium bicarbonate and water, dried (MgSO4) and concentrated in vacuo to give a black residue. The residue is triturated under ethyl acetate to give the title product as a tan solid (15.5 g, 52.9%), identified by 1HNMR and IR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[CH2:24]1C[O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:26](=[O:27])[CH:25]=[CH2:24])=[CH:11][CH:10]=2)#[N:13]
Reactant: C1CCOC1
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C(C)C)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1.00 g (3.31 mmol) 6-amino-4-[(3-isopropylphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml hot DMF, added 12 ml THF, and chilled to 0° C. under N2. Added 507 μl (3.64 mmol) triethylamine and 303 μl (3.64 mmol) acryloyl chloride. Removed ice bath at 15 minutes and at 1 hour stripped solvent. Slurried residue with dilute sodium bicarbonate, collected solids and washed with water. Recrystallized from ethyl acetate and dried in vacuo, giving 366 mg of orange solid: mass spectrum (electrospray m/e): M+H=357.1.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[CH2:14](N)[CH:15]=[CH2:16]>>[CH2:16]([NH:6][C:4](=[S:5])[CH:3]([N:2]([CH3:13])[CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:15]=[CH2:14]
Reactant: CN(C)C(C(N)=S)c1ccccn1
Reactant: C=CCN
Product: C=CCNC(=S)C(c1ccccn1)N(C)C

Procedure:
2-Dimethylamino-2-(2-pyridyl)thioacetamide is reacted with allylamine by the procedure of Example 7 to give N-allyl-2-dimethylamino-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]
Reactant: CN1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
73 mg (0.73 mmol) of N-methylpiperazine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 110 mg (95%) of 2-[2-ethoxy-5-(4-methyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-α][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41]1([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][C:41]([C:37]4[S:36][CH:40]=[CH:39][CH:38]=4)([C:47]([NH2:49])=[O:48])[CH2:42][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2cccs2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccs4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(thiophen-2-yl) -piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:34][N:33]([CH3:35])[CH2:32]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:32][N:33]([CH3:35])[CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CC(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(Cn2nc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c3cc(OC(F)F)ccc32)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-((1-methylazetidin-3-yl)methyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 53.8 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for 15 h the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane solution was added. After 1 h, the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[5-difluoromethoxy-1-(1-methyl-azetidin-3-ylmethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (18 mg, 69%). MS (M+H)+=484; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=2.3 Hz, 2H), 7.93 (d, J=9.0 Hz, 1H), 7.87 (s, 1H), 7.38-7.46 (m, 2H), 7.20 (s, 1H), 4.76 (d, J=7.3 Hz, 2H), 4.55 (s, 2H), 3.48 (t, J=8.0 Hz, 1H), 2.36 (s, 3H), 1.50 (s, 9H), 1.05 (t, J=7.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH2:24](B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)Cc1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Product: CCOC(=O)c1nc(Cc2ccccc2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and benzylboronic acid: MS (m/z) 425.1 (M+1).
Reaction SMILES: Br[C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28]>CO>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Sc1ccccc1Br
Reactant: COC(=O)C1(Br)CCCCC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(Sc2ccccc2Br)CCCCC1
Temperature: 65 °C

Procedure:
To a solution of 715 mg (3.2 mmol) of methyl 1-bromocyclohexane-1-carboxylate (J. Med. Chem. 1970, 13, 317) in MeOH (5 mL) was added diisopropylethylamine (0.9 mL, 5.2 mmol) and 2-bromobenzenethiol (0.55 mL, 4.7 mmol). The solution was heated to 65° C. under nitrogen for 2 h, then cooled and partitioned between ethyl acetate and 1 M HCl. The organic phase was washed twice with 1 M NaOH and brine, then dried over MgSO4 and concentrated. Purification by flash chromatography (10% EtOAc/hexanes) gave methyl 1-[(2-bromophenyl)sulfanyl]cyclohexanecarboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:19][OH:20].C(O)C>N1C=CC=CC=1>[N:19](=[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)[CH3:2])[OH:20]
Reactant: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)Sc1ccccc1O2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
A mixture of 2-acetylphenoxathiin (J.A.C.S. 1936, 58, 717) (484 mg, 2 mmol), hydroxylamine hydrochloride (556 mg, 8 mmol), ethanol (8 mL) and pyridine (4 mL) was stirred at room temperature for 45 minutes. The ethanol was evaporated and the residue triturated with water until a solid was obtained. Filtration afforded the title oxime (465 mg) as a cream-colored solid, m.p.: 143°-148° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:9]([S:10][C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=3)=[O:17])[CH2:12]2)=[C:8]([C:28]([OH:30])=[O:29])[N:7]2[C@H:3]1[C@@H:4]([C@H:31]([OH:33])[CH3:32])[C:5]2=[O:6].[Na].[OH-].[Na+:36]>C(=O)(O)[O-].[Na+]>[CH3:1][C@H:2]1[C:9]([S:10][C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([O-:27])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)=[C:8]([C:28]([O-:30])=[O:29])[N:7]2[C@H:3]1[C@@H:4]([C@H:31]([OH:33])[CH3:32])[C:5]2=[O:6].[Na+:36].[Na+:36]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)O)c4)C3)[C@H](C)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CN[C@H](C(=O)Nc4cccc(C(=O)[O-])c4)C3)[C@H](C)[C@H]12

Procedure:
To the solution of sodium bicarbonate (2.5 g in 70 mL water) Ertapenem monosodium (15 g) was slowly added at 0-5° C., by maintaining pH around 7.5 using sodium hydroxide solution. The solution obtained was subjected to carbon treatment, followed by stirred with alumina and filtered. To filtrate, containing Ertapenem disodium was filtered through 0.2 micron filter paper and added into 2500 mL of cold IPA solution at 0-5° C. The solid obtained was filtered washed with IPA followed by acetone and IPE, dried under dry and wet nitrogen to yield Ertapenem disodium (Yield—8-12 g; sodium content: 9.2-10.5%; moisture content: 5-7%; pH: 7.5-8.0). The color of the reconstituted product was pale yellow.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=O)=[C:11]3[CH2:10][S:9]2)[CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C>O1CCOCC1.C(O)C.O.C(N(CC)CC)C>[C:23]([C:22]1[CH:21]=[C:20]([NH:19][C:16]([C:15]2[CH:14]=[CH:13][N:12]3[C:11]=2[CH2:10][S:9][CH:8]3[C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[O:18])[CH:33]=[CH:32][CH:31]=1)(=[O:24])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C(O)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Hydrochloride of the acid chloride derived from (+)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylic acid (24.5 g) is added, at a temperature between 60° and 72° C., to a solution of 3-aminobenzophenone (16.1 g) and triethylamine (16.5 g) in dioxane (420 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in ethyl acetate (750 cc). The solution obtained is washed 3 times with distilled water (800 cc in total), twice with a saturated aqueous sodium bicarbonate solution (600cc in total) and twice with distilled water (600 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. Crude product (36 g) is thereby obtained, which is dissolved in a boiling ethanol:water (85:15 by volume) mixture (200 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 3 hours. The crystals formed are separated by filtration, washed 3 times with an ethanol: water (85:15 by volume) mixture (75 cc in total) and 4 times with diethylether (200 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. (+)-N-(3-benzoylphenyl)-3-(3-pyridyl)-1H,2H-pyrrolo[1,2-c]thiazole-7-carboxamide in the hydrated state (20.7 g), in the form of cream-coloured crystals, m.p. 109° C. is thereby obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1)=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]7[CH2:64][CH2:63][CH2:62][CH2:61]7)[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](NC(=O)OC5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (30 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with cyclopentyl chloroformate (6.5 μL) and stirred for 2 hours. Triethylamine (12 μL) and cyclopentyl chloroformate (6.5 μL) are added and the mixture is stirred for 12 hours. Then triethylamine (24 μL) and cyclopentyl chloroformate (13 μL) are added and the mixture is stirred for 2 hours. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step.
Reaction SMILES: I[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[CH:4][CH:3]=1.[CH2:20]([OH:24])[CH2:21][C:22]#[CH:23]>[Pd](Cl)Cl.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[OH:24][CH2:20][CH2:21][C:22]#[C:23][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a slurry of 2-(4 iodo-benzyl)-isoindole-1,3-dione (2.0 g, 5.51 mmol), triphenylphosphine (14.4 mg, 0.055 mmol), and palladium chloride (5 mg, 0.028 mmol) in DEA (20 mL) was added DMF (4 mL) and copper iodide (11 mg, 0.055 mmol) followed by 3-butyn-1-ol (417 μL, 5.51 mmol). The reaction stirred at room temperature overnight under nitrogen atmosphere. The next day, the reaction mixture was concentrated and purified by flash column chromatography (2:1 Hexane:ethyl acetate) to yield the product as a yellow solid (0.76 g, 45% yield). 1H NMR (600 MHz, CDCl3): δ 7.86 (m, 2H), 7.76 (m, 2H), 7.36 (s, 4H), 4.83 (s, 2H), 3.80 (q, 2H, J=6.3 Hz), 2.68 (t, 2H, J=6.2 Hz), 1.80 (t, 1H, J=6.4 Hz); 13C NMR (150 MHz, CDCl3): δ 167.5, 135.5, 133.6, 131.5, 131.4, 128.0, 122.9, 122.5, 86.3, 81.5, 60.6, 40.8, 23.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Fc1ccc(-c2ccc(I)cc2)cc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C1=O
Yield: 6.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649 mmol) was reacted with 4′-fluoro-4-iodo-biphenyl (198 mg, 0.675 mmol), 1,4-dioxane (15 mL), copper iodide (0.0096 g, 0.0504 mmol), trans-1,2-diamino cyclohexane (0.0032 g, 0.0280 mmol) and potassium phosphate (0.359 g, 1.691 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3), followed by preparative HPLC afforded 12 mg of the product (12.35% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH:8](Cl)[CH:9]=[C:10]([Cl:12])[Cl:11])[CH2:3][C:4]([O:6]C)=[O:5].CC(C)(C=CC(Cl)(Cl)Cl)CC(OC)=O>>[CH3:1][C:2]1([CH3:14])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[O:6][C:4](=[O:5])[CH2:3]1
Reactant: COC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: COC(=O)CC(C)(C)C=CC(Cl)(Cl)Cl
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Yield: 11 %

Procedure:
The procedure of Example 11 was repeated except that a mixture of 26.0 parts of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate and 26.0 parts of methyl 3,3-dimethyl-6,6,6-trichloro-4-hexenoate (mole ratio=1:1) was used in lieu of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate to obtain 37.9 parts of methyl 2,2-dimethyl-3-(2',2'-dichlorovinyl) cyclopropanecarboxylate (yield 85% based on starting material; cis/trans ratio=29:71) and 4.6 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (yield 11% based on starting material). The latter compound 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (4.6 parts) was treated with 5.0 parts of a methanolic solution of hydrogen chloride (concentration of hydrogen chloride: about 50%) to obtain 5.5 parts of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate (yield 96% based on 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide).