Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[C:25]([Cl:30])=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)C)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:30].[Cl:30][C:25]1[C:24]([S:21]([N:12]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:10]([CH2:9][NH:7][CH3:6])=[CH:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution (3 mL) of tert-butyl{[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (70 mg) in ethyl acetate was added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-ethyl acetate to give the title compound (yield 29 mg, 49%).
Reaction SMILES: [Mg].II.[Br:4][C:5]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:6]=1[CH2:7]Br.[CH3:15][CH2:16][O:17]CC>>[Br:4][C:5]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:6]=1[CH2:7][CH2:15][CH2:16][OH:17]
Reactant: CSc1ccc(Br)c(CBr)c1
Reactant: CCOCC
Agent: II
Agent: [Mg]
Product: CSc1ccc(Br)c(CCCO)c1
Reaction time: 2 h

Procedure:
To a suspension of 25.0 g of magnesium ribbon in a solution of 0.5 g of iodine in 550 ml of anhydrous ether is added 5 ml of a solution of 296.0 g of 2-bromo-5-(methylthio)benzyl bromide in 250 ml of anhydrous ether. The reaction is initiated by gentle heating, and the remainder of the solution is then added dropwise so as to maintain a reflux. Subsequently, the mixture is heated and stirred under reflux for one hour, and then cooled to 10°. A stream of nitrogen gas that has been bubbled through a reservoir containing 48.0 g of ethylene oxide is introduced into the reaction mixture. The addition of the ethylene oxide requires two hours. The mixture is subsequently stirred as it warms to room temperature, is stirred for four hours at room temperature, and then hydrolyzed by pouring on a mixture of 1 kg of ice and 55.0 g of ammonium chloride. Extraction with ether, followed by conventional workup of the ether solution, yield 210.0 g of 3-(2 -bromo-5-(methylthio)phenyl)-1-propanol, bp, about 125°-127° (0.6mm).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:12])([CH3:11])[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].S(Cl)([Cl:15])=O>>[CH2:1]([O:3][C:4]([C:6]([CH3:12])([CH3:11])[CH2:7][C:8]([Cl:15])=[O:9])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(C)(C)CC(=O)O
Product: CCOC(=O)C(C)(C)CC(=O)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethoxycarbonyl-3,3-dimethylpropionic acid (1 g) and 3 ml of thionyl chloride was stirred at room temperature for 20 hours. The excess thionyl chloride was removed in vacuo to afford 1.1 g of 3-ethoxycarbonyl-3,3-dimethylpropionyl chloride.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[N:36]=[CH:37][C:30]=12)[C:24]([O:26]C)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.[CH3:46][C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[C:30]2[CH:37]=[N:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[C:31]=2[N:32]=[CH:33][N:34]=1)[C:24]([NH:53][C:50]1[CH:49]=[CH:48][C:47]([CH3:46])=[CH:52][N:51]=1)=[O:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:8])[CH3:2]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(F)c1C
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(F)c2C)nc1

Procedure:
Prepared using a procedure analogous to that described for Intermediate AE1 using (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AF4) and 5-methylpyridin-2-amine. 1H NMR (400 MHz, DMSO) d 0.88 (9H, s), 1.96 (3H, d), 2.24 (3H, s), 3.75 (4H, m), 4.08-4.02 (1H, m), 4.14 (1H, m), 5.99 (1H, m), 7.50-7.29 (9H, m), 7.63-7.54 (5H, m), 7.89 (1H, d), 8.17 (1H, s), 8.51 (1H, s), 8.55 (1H, s), 10.94 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=5[F:17])[C:6]=4[CH:18]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)c(F)c1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)c(F)c1

Procedure:
The title compound, off-white solid (29 mg, 22%), MS (ISP) m/z=407.4 [(M+H)+], mp 133° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(2,4-difluoro-phenyl)-1H-benzo[d]imidazole (intermediate K) (100 mg, 324 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (79.2 mg, 356 μmol).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:6][C:7]([C:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH:10]=1)=[O:8])[CH3:5].[Cl-].[NH4+]>C1COCC1.C1COCC1.C1(C)C=CC=CC=1.[Cu]I>[CH2:4]([O:6][C:7]([CH:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][CH:10]1[CH3:1])=[O:8])[CH3:5]
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)CCN(C(=O)OC(C)(C)C)CC1C
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 5.18 g (27.18 mmol) CuI in 85 mL anhydrous THF at −78° C. was added 24 mL (34 mmol) of a 1.4 M solution of methyl magnesium bromide in THF/toluene dropwise under an atmosphere of nitrogen, the reaction was left to warm up to −15° C. and then stirred at this temperature for 45 minutes. It was cooled again at −78° C. and a solution of 3.85 g (13.59 mmol) 5-oxo-2,5,6,7-tetrahydro-azepine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 30 mL anhydrous THF was added dropwise. The resulting reaction mixture was stirred at −78° C. for 30 minutes and then left to warm up to room temperature over a period of 60 minutes. 100 mL saturated aqueous ammonium chloride was added and the resulting mixture was extracted with EtOAc (3×150 mL), the organic layers were combined, washed with H2O (2×200 mL) and saturated brine (200 mL) and dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 8:2) to give crude material that was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>ClCCl.CN(C)C=O>[Cl:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(CO)ccc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(CCl)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of (4-fluoro-3-methoxyphenyl)methanol (Claudi, et al., J. Med. Chem. 1990, 33(9):2408) (0.90 g, 5.76 mmol) in anhydrous dichloromethane (10 mL) was added thionyl chloride (0.84 mL, 12 mmol) and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo to afford 4-(chloromethyl)-1-fluoro-2-methoxybenzene (0.73 g, 72%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.05-6.86 (m, 3H), 4.53 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=3)[C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[NH:11][C:10]2=[O:20])=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(4-chloro-2-fluoro-5-hydroxyphenyl)6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (2.5 g) was added to an ice cooled con. nitric acid (50 ml). After stirring for 1 hr, the reaction mixture was poured into ice-cold water. The yellow crystals were collected by filtration to afford the title compound (0.9 g). The filtrate was extracted by ethyl acetate (200 ml) and washed with brine. The organic phase was dried over anhydrous sodium sulfate. After removal of the solvent, 0.6 g of title compound was obtained as yellow crystal.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4](P(OCC)(=O)OCC)[NH:3]1.[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:20]=1[CH:21]=[C:4]1[NH:3][C:2](=[O:1])[NH:6][C:5]1=[O:7])([O-:18])=[O:17]
Reactant: O=Cc1cc(N2CCCC2)ccc1[N+](=O)[O-]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Product: O=C1NC(=O)C(=Cc2cc(N3CCCC3)ccc2[N+](=O)[O-])N1

Procedure:
Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-(1-pyrrolidinyl)benzaldehyde analogous to the procedure of Example (2-1), m.p. 289° C. (dec.), crystallized from DMF-H2O.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].Cl[S:24]([OH:27])(=[O:26])=[O:25].O>C(Cl)Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[S:19][C:20]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:21][N:22]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)c(Cl)c1Cl
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(S(=O)(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 60 °C
Yield: 46.3 %

Procedure:
3,4-Dichloro-5-methyl-N-[1-(1,3-thiazol-2-yl)piperidin-4-yl]-1H-pyrrole-2-carboxamide (Example 329; 692 mg, 1.93 mmol) was dissolved in anhydrous DCM. Chlorosulfonic acid (513 μl, 7.7 mmol) was added slowly and the mixture was heated at 60° C. for 2 h. The mixture was cooled to 0° C. and water was added, whereupon a brown solid separated. This was filtered and washed well with water, dried in vacuo to give the title compound (393 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]([O:42][CH2:43][C@H:44]1[CH2:46][O:45]1)([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][C:33]([O:42][CH2:43][C@H:44]1[CH2:46][O:45]1)([CH3:32])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:36]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(Cn1ccc(N)n1)OC[C@H]1CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.56 g, 1.2 mmol), 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine (0.27 g, 1.12 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 0.912 g, 2.4 mmol) and iPr2NEt (1.5 mL, 8.4 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by column chromatography (25-80 g Analgix column, 1-100% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (222 mg, 28%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H37Cl2F2N5O3S+H [(M+H)+]: 660.2315. found: 660.2312.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7](=[O:17])[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7](=[O:17])[CH:6]=1)[NH2:3]
Reactant: CC(C)Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
Hydrazine hydrate (6.5 ml) was added to a solution of 6-Chloro-1-isobutyl-3-methylpyrmidine-2,4(1H,3H)-dione (10 g) in ethanol (40 ml). The mixture was heated at reflux for 5 hours, cooled to room temperature and then evaporated under reduced pressure. The residue was crystallized from ethanol to give the subtitle compound (6.7 g). Mass: 213.00 (M+H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH2:10][CH:11]=[CH2:12]>>[CH2:12]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH:10]=[CH2:9]
Reactant: C=CCCB(O)O
Reactant: O=Cc1ccc(Br)s1
Product: C=CCCc1ccc(C=O)s1
Yield: 54.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromo-2-formylthiophene (191 mg, 1.0 mmol) in place of 5-bromo-2-formylfuran and 3-butenylboronic acid (150 mg, 1.5 mmol) in place of hexylboronic acid to give 5-(3-butenyl)-2-formylthiophene (91 mg, 55%). Used without further characterization.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[C:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH2:58])[CH3:57])=[CH:51][CH:50]=2)=[CH:43][CH:42]=1)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[C:48][C:49]2[CH:50]=[CH:51][C:52]([CH2:55][CH:56]([NH:58][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH3:57])=[CH:53][CH:54]=2)=[CH:43][CH:42]=1)[CH3:39]
Reactant: CCOc1ccc(C#Cc2ccc(CC(C)N)cc2)cc1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)NC(C)Cc1ccc(C#Cc2ccc(OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.41 mg (0.10 mmol) butanoic acid are dissolved in 300 μL DMF together with 32.1 mg (0.10 mmol) TBTU and 50.0 μL (0.30 mmol) DIPEA and the mixture is stirred at r.t. for 5 min. 27.9 mg (0.10 mmol) 1-(4-((4-ethoxyphenyl)ethynyl)phenyl)propan-2-amine (I64) are added and the reaction mixture is stirred at 40° C. over night. The mixture is filtered through a plug of alox, eluted with DMF/MeOH (9/1) and the solvent is removed in vacuo. The residue is purified by HPLC.
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a stirring solution of 2 (0.77 g, 2.24 mmol) in CH2Cl2 (25 mL) at 0° C., was added, drop wise, TFA over 15 min. The pale yellow, reaction was stirred at 0° C. for 1 h then allowed to stand at RT for 15 min. The reaction was concentrated to a viscous oil, redissolved in CH2Cl2 (20 mL) and reconcentrated to a gummy solid. The crude product was crystallized from ether/hexanes to afford the title compound (3) as a white solid (0.30 g, 41%). 1H NMR (300 MHz, DMSO-d6): δ 1.59 (s, 8H), 2.29 (br s, 4H), 6.52 (d, J=16 Hz, 1H), 7.15-7.39 (m, 7H), 7.59 (d, J=16 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 12.41 (s, 1H). LRMS (APCI): m/z 433 (M+H)+. Anal. Calcd for C23H24O2: C, 83.07; H, 7.30. Found: C, 82.73; H, 7.25.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=C[C:21](C#N)=[C:20](N=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=2)[C:13](=[O:40])[C@@H:12]1[CH2:41][CH2:42][S:43][CH3:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:45]1[CH:50]=[N:49][CH:48]=[N:47][CH:46]=1.C(O)(=O)C>C(O)C>[NH2:45][C:50]1[C:21]2[C:46](=[CH:23][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[C@@H:12]([CH2:41][CH2:42][S:43][CH3:44])[C:13]3=[O:40])=[CH:19][CH:20]=2)[N:47]=[CH:48][N:49]=1
Reactant: c1ncncn1
Reactant: CSCC[C@H]1C(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CSCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Yield: 39 %

Procedure:
To a solution of 4-benzyloxycarbonyl-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-3-(S)-(2-methylsulfanyl-ethyl)-piperazin-2-one (1.17 g, 2.67 mmol) in 15 ml of ethanol is added 1,3,5-triazine and glacial acetic acid (3.1 ml, 53.4 mmol). The resulting solution is refluxed for 20 hours, concentrated under vacuum. The residue is dissolved in ethyle acetate, washed with 1N hydrochloric acid, a saturated aqueous NaHCO3 solution, water, brine. The solution is dried over MgSO4, concentrated. The resulting crude product is purified by column chromatography eluting with a gradient of 5% MeOH:CH2Cl2 to 10% MeOH:CH2Cl2. The title compound (489 mg, 39% yield) is obtained as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]2[CH3:31])=[CH:12][CH:11]=1>C(Cl)Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:19][C:18]([C:1](=[O:3])[CH3:2])=[C:17]2[CH3:31])=[CH:14][CH:15]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
Acetyl chloride (120 41, 1.67 mmol) was slowly added to a stirred slurry of aluminum chloride (223 mg, 1.67 mmol) in methylene chloride (15 ml) at -5° C. After 30 minutes, a solution 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl)-1H-pyrrole (Example 1) (500 mg, 1.52 mmol) in methylene chloride (20 ml) was added. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was poured over ice-water and extracted with methylene chloride. The organic fraction was washed with brine, dried (MgSO4), filtered and concentrated. The crude yellowish solid (570 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]ethanone (170 mg, 30%) as a white solid: mp (DSC) 211° C. Anal Calc'd. for C20H18NSFO3 ·0.25 H2O: C, 63.90; H, 4.96; N, 3.75. Found: C, 63.96; H, 5.04; N, 3.65.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][OH:12])[CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH2:11][C@H:3]1[O:4][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[O:1][CH2:2]1)(=[O:23])=[O:22]
Reactant: OC[C@H]1COc2cccnc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1COc2cccnc2O1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
A mixture of intermediate (2-a) (0.023 mol) and triethylamine (0.046 mol) in DCM (40 ml) was stirred at 0° C. A mixure of methanesulfonyl chloride (0.035 mol) in DCM (10 ml) was added dropwise. The mixture was stirred on an ice bath for 2 hours and then washed with H2O/NaCl. The organic layer was dried, filtered and the solvent was evaporated. The residue (oil) was solidified in DIPE. The precipitate was filtered off and dried, yielding 5 g of (S)-2,3-dihydro-1,4-dioxino[2,3-b]pyridine-3-methanol methanesulfonate (ester) (intermediate 3) ([α]D−27.89°; c=25.10 mg/5 ml in methanol; mp. 136° C.).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([CH:15]=O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[C@@H:17]1([NH:27][CH2:15][C:12]2[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:2]([OH:1])[C:14]=3[CH:13]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: N[C@H]1CCCc2ccccc21
Product: OC1c2ccccc2-c2ccc(CN[C@H]3CCCc4ccccc43)cc21

Procedure:
The product from Example 46B and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 45C to provide the title compound.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[N:7]=1.[Br:35]Br>C(O)(=O)C.O>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([Br:35])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:12][CH:13]=2)[N:7]=1
Reactant: BrBr
Reactant: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)cs1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-{[4-(2-aminothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (200 mg) was dissolved in a mixed solvent of acetic acid (10 ml) and water (5 ml), mixed with bromine (20 μl) under ice-cooling and then stirred at room temperature for 5 minutes. The reaction solution was concentrated under a reduced pressure, and the residue was dissolved in ethyl acetate (30 ml)-saturated sodium bicarbonate aqueous solution (20 ml). The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and mixed with 4 M hydrogen chloride in ethyl acetate solution (0.15 ml), and the thus precipitated solid was collected by filtration, dried and then recrystallized from methanol-ether, thereby obtaining 184 mg of N-{[4-(2-amino-5-bromothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (colorless powder).