Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:7]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][C:5](=[S:15])[N:4]1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([N:38]=[C:39]=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]>O1CCCC1>[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]([O:1][N:2]=[C:3]2[C:7]([CH3:14])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:6][C:5](=[S:15])[N:4]2[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NO
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=NOC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-hydroxyimino-5-methyl-5-phenyl-3-phenylamino-thiazolidine-2-thione (0.19 g), triethylamine (0.06 g) and 3,4-dichlorophenylisocyanate in tetrahydrofuran (3 ml) was stirred for 2 days at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (chloroform) to yield 4-(3,4-Dichlorophenylcarbamoyl)oxyimino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (0.13 g) having a melting point of 95-96° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[O:5][C:6]=1Br.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:10][C:8]([C:4]1[O:5][C:6]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[C:2]([Br:1])[CH:3]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)c1cc(Br)c(Br)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Br)c(-c2ccncc2)o1
Yield: 54.7 %

Procedure:
tert-Butyl 4,5-dibromo-2-furancarboxylate (H. Muratake et al, Chem. Pharm. Bull., 1997, 45, 799) (9.78 g, 30 mmol), 4-pyridyl boronic acid (M. Lamothe et al, J. Med. Chem., 1997, 40, 3542) (4.06 g, 33 mmol), potassium carbonate (24.8 g, 180 mmol), triphenylphosphine (786 mg, 3 mmol) and palladium (II) acetate (337 mg, 1.5 mmol) were dissolved in ethylene glycol dimethyl ether (150 ml) and water (75 ml). The mixture was heated at reflux for 18 hours with vigorous stiring, cooled then filtered through celite pad, which was thoroughly washed with ethyl acetate. The filtrate was then washed with saturated sodium bicarbonate solution, water (×3) and brine, then dried over magnesium sulfate. The solution was evaporated in vacuo and the residue purified by silica gel chromatography to afford the title product (5.32 g, 55%); MS (AP−) m/e 323/325 [M−H]−.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26].Cl>C(#N)C>[CH2:25]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH3:26]
Reactant: CCI
Reactant: CS(=O)(=O)c1cccc(N2CCNCC2)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCN(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 1-[2-fluoro-3-(methylsulfonyl)phenyl]piperazine (0.13 g, 0.52 mmol), acetonitrile (4 ml), potassium carbonate (0.14 g, 1.1 mmol) and iodoethane (0.48 ml, 0.52 mmol). Yield: 0.09 g (60%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 214-216° C. MS m/z (relative intensity, 70 eV) 286 (M+, 59), 272 (14), 271 (87), 201 (11), 57 (bp).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([CH:8]2[O:12]CCO2)[CH:5]=[CH:4][C:3]1=O.[CH3:14][N:15]1C=CC=C(C2OCCO2)C1=O.Cl>O1CCCC1>[C:14]([C:3]1[N:2]=[CH:7][C:6]([CH:8]=[O:12])=[CH:5][CH:4]=1)#[N:15]
Reactant: Cn1cccc(C2OCCO2)c1=O
Reactant: Cn1cc(C2OCCO2)ccc1=O
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)cn1
Reaction time: 12 h
Yield: 100 %

Procedure:
The 73:27 mixture (933 mg, 5.15 mmol) of 1-methyl-5-(1,3-dioxolan-2-yl)-2(1H)-pyridone and 1-methyl-3-(1,3-dioxolan-2-yl)-2(1H)-pyridone was dissolved in tetrahydrofuran (10.0 mL). To this, 1N hydrochloric acid (10.0 mL) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 12 hours. Then, the reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and thereby 6-cyano-3-pyridinecarboxaldehyde (364 mg, yield: 100%) was obtained. The residue was purified by preparative thin-layer chromatography (ethyl acetate) to give 1-methyl-5-formyl-2(1H)-pyridone (309 mg, yield: 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 99.4 %

Procedure:
A mixture of 10.0 g (0.033 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 4.5 g (0.033 mole) of 3-chloro-N,N-dimethylpropanamide, 14.0 g (0.132 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 ml of N,N-dimethylformamide was heated on a steam bath for 16 h. The mixture was poured into 2 L of water and extracted three times with 500 ml portions of ethyl acetate. The ethyl acetate fractions were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a glass. Upon trituration with petroleum ether (30°-60° C.) the glass solidified to yield 13.2 g (100%) of a yellow solid. A portion of this solid was recrystallized from ethyl ether to give the title compound as a white solid, mp 134°-135° C.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].Cl>O1CCCC1>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:20]1[O:19][N:18]=[CH:17][C:16]=1[CH2:3][CH2:2][C:1]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1ccc(-c2oncc2CCl)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
To a solution of diethyl malonate (3.38 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 770 mg) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(2,4-difluorophenyl)isoxazole (2.20 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was acidified by pouring into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate-hexane to give a colorless prism (2.10 g, yield 87%) of 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionic acid. melting point: 125–126° C.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[CH3:20][O:21][CH:22]=[CH:23][C:24]([O:26][Si](C)(C)C)=[CH2:25]>ClCCl.[I-].[Zn+2].[I-]>[Si:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([CH2:25][C:24](=[O:26])[CH:23]=[CH:22][O:21][CH3:20])[NH:8][C:7]1=[O:9])[CH3:11])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC=CC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 15 h
Yield: 43 %

Procedure:
(3R,4R) 4-acetoxy-3-[(1R)-(1-(tert-butyldimethylsilyloxy)ethyl)]azetidin-2-one (2 g, 56.96 mM) was dissolved in dichloromethane (150 ml) at ambient temperature and 4-methoxy-2-trimethylsilyloxybut-1,3-diene (1.5 ml, 7.65 mM) added followed by zinc iodide (2.2 g, 17 mM). The reaction mixture was shielded from light and stirred for 15 hours. The mixture was then washed with a 5% aqueous solution of sodium bicarbonate (30 ml) and then water (30 ml). The organic phase was dried with magnesium sulphate and the solvent evaporated. The residue was purified by chromatography on silica, eluting with ethyl acetate/dichloromethane (1:1) to give (3S,4R) 3-((1R)-1-(tert-butyldimethylsilyloxy)ethyl)-4-(4-methoxy-2-oxobut-3-en-1-yl)azetidin-2-one (0.96 g, 43%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:30]=[CH:29][C:23]2[NH:24][C:25](=[O:28])[CH2:26][O:27][C:22]=2[CH:21]=1>C(O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:19][C:20]3[CH:30]=[CH:29][C:23]4[NH:24][C:25](=[O:28])[CH2:26][O:27][C:22]=4[CH:21]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Reactant: Cc1ccc(CC2CCN(C(=O)CCl)CC2)cc1
Solvent: CCO
Product: Cc1ccc(CC2CCN(C(=O)CNc3ccc4c(c3)OCC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-methyl-benzyl)-piperidin-1-yl]-ethanone (Example 227a) and 7-amino-4H-benzo[1,4]oxazine-3-one according to the method described in Example 206. Melting Point: 206-208° C. (ethanol)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=1.CCN(CC)CC.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:22])(=[O:23])[N:20]([CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reactant: COc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(/C=C/c2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 81, step A) (75 mg, 0.17 mmol) in acetonitrile (2 mL), in a pressure vessel, is added 2-bromo-6-methoxypyridine (32 mg, 0.17 mmol), NEt3 (0.05 mL, 0.34 mmol), Pd(OAc)2 (8 mg, 0.034 mmol), and 2-(di-t-butylphosphino)biphenyl (20 mg, 0.068 mmol). The vessel is sealed and stirred at 100° C. for 18 h. The reaction is cooled to RT and filtered through Celite. The solvent is removed under reduced pressure and the crude material purified by column chromatography using a gradient of 0-35% EtOAc/hexanes as eluent to afford the title compound as a yellow oil: (M+H)+=552.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([CH:19]=2)[CH:17]=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21].[NH:22]1[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([CH:19]=2)[CH2:17][N:22]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]
Reactant: O=C(O)C1CNC1
Reactant: CCC(Nc1ccc(C)c(C=O)c1)c1ccc(Cl)c(C)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(Nc1ccc(C)c(CN2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of INT 9 (200 mg, 0.66 mmol) and azetidine-3-carboxylic acid (67 mg, 0.66 mmol) in MeOH (6.5 mL) was added HOAc (0.038 mL, 0.66 mmol) followed by NaCNBH3 (42 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to afford the title compound Example 4.
Reaction SMILES: [F:1][C:2]([F:18])([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[CH:19](OC)(OC)OC.C(O)(=O)C>CO>[F:1][C:2]([F:18])([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]2[O:13][CH:19]=[N:15][N:14]=2)=[CH:10][CH:9]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: NNC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Reactant: COC(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)C(F)(F)Oc1ccc(-c2nnco2)cc1
Temperature: 120 °C
Yield: 5.1 %

Procedure:
A mixture of 4-(perfluoroethoxy)benzohydrazide (3.17 g, 11.7 mmol) in trimethyl orthoformate (11.6 mL, 106 mmol) and acetic acid (0.13 mL, 2.35 mmol) was heated at 120° C. for 5 hours. The reaction was diluted with MeOH (15 mL) and poured into a beaker containing ice water (150 mL). The white precipitate was vacuum filtered and dried in a vacuum oven to provide 166 mg of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazole as an off-white solid. An orange precipitate had formed in the aqueous filtrate and was collected by vacuum filtration and adsorbed onto silica gel. Purification by flash chromatography (0-40% EtOAc/hexanes) provided 2.02 g of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazole as an off-white solid giving a combined yield of 2.186 g (67%): mp 87-89° C.; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.28-8.05 (m, 2H), 7.40 (d, J=8.9 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −85.98, −87.82; ESIMS m/z 280 ([M+H]+).
Reaction SMILES: C(O[C:6](=[O:41])[CH2:7][NH:8][C:9]([C:11]1[N:15]2[C@:16]([CH3:40])([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[C:17](=[O:27])[N:18]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:14]2=[N:13][CH:12]=1)=[O:10])(C)(C)C.Cl.O1CCOCC1.[NH:49]1[CH2:53][CH2:52][C@@H:51]([C:54]2[N:55]=[N:56][NH:57][N:58]=2)[CH2:50]1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([N:18]2[C:17](=[O:27])[C@@:16]([CH3:40])([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:33][CH:34]=3)[N:15]3[C:11]([C:9]([NH:8][CH2:7][C:6](=[O:41])[N:49]4[CH2:53][CH2:52][C@@H:51]([C:54]5[N:55]=[N:56][NH:57][N:58]=5)[CH2:50]4)=[O:10])=[CH:12][N:13]=[C:14]23)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reactant: C1C[C@@H](c2nn[nH]n2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NCC(=O)N3CC[C@@H](c4nn[nH]n4)C3)n21
Reaction time: 14 h
Yield: 66.3 %

Procedure:
{[(R)-7-(3,5-Dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-acetic acid tert-butyl ester (0.061 g, 0.1 mmol) was dissolved in CH2Cl2 (0.5 mL) and 4N HCl/dioxane (1 mL) added. The solution was agitated on an orbital shaker for 14 h and then concentrated in vacuo. The resulting residue was dissolved in DMA (2 mL), and (R)-5-pyrrolidin-3-yl-2H-tetrazole (0.21 g, 0.15 mmol), HOAt (0.041 g, 0.3 mmol), triethylamine (0.09 mL, 0.6 mmol) and HATU (0.057 g, 0.15 mmol) were added. The reaction mixture was agitated for 14 h and then concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and water (0.1 mL) and purified via reverse phase HPLC purification to afford 0.045 g of (3R)-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-N-{2-oxo-2-[(3R)-3-(2H-tetrazol-5-yl)pyrrolidin-1-yl]ethyl}-3-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide as a white solid, m/z 680.1 [M+1]+
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:1][CH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: OCC1(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,1-Bis(hydroxymethyl)cyclopropane (1.0 g, 0.0098 mol), triethylamine (TEA) (2.0 mL, 0.015 mol), and 1H-imidazole (0.13 g, 0.0020 mol) were dissolved in anhydrous DCM (15 mL) and the solution was cooled to 0° C. A solution of tert-butyldimethylsilyl chloride (1.55 g, 0.0103 mol) in DCM (5 mL) was added drop-wise and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3×). The organic extract was dried (magnesium sulfate), filtered, and concentrated in vacuo. The crude product was identified by 1H NMR and used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]=[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:21]O.OS(O)(=O)=O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[CH:19][CH:20]=1)([O:3][CH3:21])=[O:2]
Reactant: CO
Reactant: O=C1Nc2ncccc2C1=Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C=C2C(=O)Nc3ncccc32)cc1
Yield: 90 %

Procedure:
A solution of 3-(4-carboxybenzylidene)-7-azaoxindole (2.663 g, 10 mmol), methanol (3.2 g, 0.1 mol) and H2SO4 95% (1 g) in benzene (100 ml) was heated in a Soxhlet apparatus for 10 h. To dry the distillate continuously, the cap of the Soxhlet contained anhydrous MgSO4. After cooling, water was added, the organic phase repeatedly washed with water and then evaporated under vacuum. Thus almost pure title compound was obtained in about 90% yield.
Reaction SMILES: [CH2:1]([CH2:7][C:8]([NH2:10])=[S:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(OCC)(=O)C>N1C=CC=CC=1>[C:11]([NH:10][C:8](=[S:9])[CH2:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: NC(=S)CCc1ccco1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC(=S)CCc1ccco1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
8.56 g (0.05 mol) of 2-furfurylthioacetamide, 5.61 g (0.055 mol) of acetic anhydride, and 6.11 g (0.05 mol) of N,N-dimethyl-aminopyridine were dissolved in 50 ml of pyridine. The mixture was stirred at 80° C. for 16 hours. The solvent was distilled away from the reaction mixture, and the residue thus obtained was added to ethyl acetate and washed successively with water, 1N hydrochloric acid, water three times, and brine. A resultant organic extract layer was dried, and the solvent was distilled away therefrom, so that N-acetyl-2-furfurylthioacetamide was obtained in a yield of 7.11 g (60%).
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=C(OCC3CCCC3)C=C(Br)C=2)=CC=1C)C.[CH2:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:31]#[CH:32].[CH2:39]([O:41][C:42](=[O:79])[CH2:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51][C:52]2[CH:57]=[C:56](C#CC3C=CC(CO)=CC=3)[CH:55]=[C:54]([O:68][CH2:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74](Cl)=[CH:73][CH:72]=3)[CH:53]=2)=[CH:47][C:46]=1[CH3:78])[CH3:40]>>[CH2:39]([O:41][C:42](=[O:79])[CH2:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51][C:52]2[CH:57]=[C:56]([C:32]#[C:31][CH2:30][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:55]=[C:54]([O:68][CH2:69][CH2:70][CH:71]3[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76]3)[CH:53]=2)=[CH:47][C:46]=1[CH3:78])[CH3:40]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CCCC3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (260 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine (203.6 mg; 1.63 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 80 mg (28%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.19 min
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:17](O)=[O:18].C(Cl)(=O)C(Cl)=O.[CH3:26][O:27][C:28](=[O:50])[C@@H:29]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH:30]([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:26][O:27][C:28](=[O:50])[C@@H:29]([NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[CH:45][C:46]([NH:49][C:17]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[C:2]=3[CH3:1])=[O:18])=[CH:47][CH:48]=2)=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1c(C(=O)O)oc2cccc(-c3ccccc3)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5ccccc5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To 60 mg (0.24 mmol) 3-methyl-4-phenyl-benzofuran-2-carboxylic acid was added 1 mL of oxalyl chloride and the mixture was refluxed for 1 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 1 mL of dichloromethane and was added to a mixture of 129 mg (0.36 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, 87 mg (0.714 mmol) of 4-(dimethylamino)pyridine and 2 mL of in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 41 mg (29% yield) of (S)-3-methyl-2-{4′-[(3-methyl-4-phenyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.[N:27]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(OP(C#N)(=O)OCC)C.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:30]3[CH2:31][CH2:32][CH2:33][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:29]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)O)cc4)cnc3N)[nH]c2c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)[nH]c2c1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]benzoic acid (108 mg, 0.3127 mmol) in DMSO (1 mL) were added tert-butyl 1,4-diazepane-1-carboxylate (187.9 mg, 0.9381 mmol), diethylcyanophosphonate (124.7 mg, 114.3 μL, 0.6879 mmol) and DIPEA (121.2 mg, 163.3 μL, 0.9381 mmol). The reaction mixture was heated at 80° C. overnight, allowed to cool and filtered and the resultant taken on to the next step without further purification (122 mg, 75% Yield).