Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[O:21]=[C:22]1[N:28]([CH2:29][CH2:30][CH2:31][CH:32]=O)[CH2:27][CH2:26][CH2:25][O:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]([CH:4]([CH3:20])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:27][CH2:26][CH2:25][O:24][CH2:23][C:22]1=[O:21])[CH3:2]
Reactant: CCN[C@@H](C)Cc1ccc(S(=O)(=O)c2nccs2)cc1
Reactant: O=CCCCN1CCCOCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCCCN1CCCOCC1=O)C(C)Cc1ccc(S(=O)(=O)c2nccs2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of ethyl-{(S)-1-methyl-2-[4-(thiazole-2-sulfonyl)phenyl]ethyl}-amine (0.326 g, 1.02 mmole), 4-(3-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.22 g, 1.2 mmole), and sodium triacetoxyborohydride (0.3 g, 1.4 mmole) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was partitioned between 5% hydrochloric acid and diethyl ether. The aqueous phase was brought to pH 12 with 25% sodium hydroxide and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{ethyl-[2-(4-thiazole-2-sulfonylphenyl)-1-methylethyl]amino}butyl)-[1,4]oxazepan-3-one, 145, as an oil. Anal.: Calcd. for C23H34ClN3O4S2.1H2O: C, 51.72; H, 6.79; N, 7.87%. Found C, 51.71; H, 6.49 N, 7.82%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1C(=O)N([Cl:22])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccccc2c1Cl
Yield: 73 %

Procedure:
Ethyl 1H-indole-2-carboxylate (26.45 mmol, 1.0 equiv.) was dissolved in CCl4 (26 ml); NCS (29.10 mmol, 1.1 equiv.) was added and the mixture was heated for 16 h at boiling temperature. The resulting solid was filtered out, and the filtrate was washed with water (2×50 ml) and sat. NaCl solution (50 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in hexane). Yield: 73%
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[CH3:26][S:27][CH2:28]Br>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:13]4[N:12]([CH2:26][S:27][CH3:28])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c3[nH]c4cc(-c5ccccc5)nn4c(=O)c3cnc21
Reactant: CSCBr
Product: CCn1ncc2c1ncc1c(=O)n3nc(-c4ccccc4)cc3n(CSC)c12

Procedure:
By treating the product of Example 29 with methylthiomethyl bromide according to the procedure of Example 2, 3-ethyl-3,11-dihydro-9-phenyl-11-methylthiomethyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([CH3:8])=[N:5][CH:4]=1.[C-:9]#[N:10].[Na+].O>CN(C=O)C>[CH3:8][C:6]1[O:7][C:3]([CH2:2][C:9]#[N:10])=[CH:4][N:5]=1
Reactant: Cc1ncc(CBr)o1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(CC#N)o1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 5-(bromomethyl)-2-methyl-oxazole CAS [82190-68-9] (15 g, 85 mmol) in DMF (150 mL) was treated with NaCN (10.4 g, 213 mmol) at room temperature and the mixture stirred at 70° C. for 1 h. After this time the mixture was poured onto ice-cooled water (300 mL) and extracted with CH2Cl2 (5×200 mL). The combined organic extracts were then washed with brine, dried with Na2SO4 for 30 min, and the mixture concentrated to afford crude 2-methyl-5-oxazoleacetonitrile product CAS [1159511-94-0] (10 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([C:13]2[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=2)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[NH:17][N:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (15.4 g, 67.6 mmol), 5-cyclopropyl-1H-pyrazol-3-ylamine (10.0 g, 81.3 mmol) and diisopropylethylamine (17 μL, 102 mmol) in 1-butanol (150 mL) was heated to 80° C. for 1 h. The solid that formed was collected by filtration and washed with acetonitrile to give the desired product (15.8 g, 75%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[CH3:10])=[CH:4][N:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:9]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH3:10])=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)c(F)c1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)Nc2ccccc2)C(C)c2cnc(Cl)nc2)c(F)c1
Reaction time: 2.5 h

Procedure:
(±)-[1-(2,4-Dichloro-pyrimidin-5-yl)-ethyl]-(2-fluoro-4-methoxy-phenyl)-amine (0.45 g; 1.41 mmol) (from Example 8b supra) and phenyl isocyanate (165 μL; 1.52 mmol) (Aldrich) were combined in toluene (5 mL) and heated in an oil bath at 110–120° C. for 2.5 hours and then at 130° C. for 2.5 hours. After cooling, the reaction mixture was concentrated and triturated with hexanes. The solid residue was purified by flash chromatography (Biotage 40S; 30:70 ethyl acetate-hexanes) to give the intermediate (±)-1-[1-(2-chloro-pyrimidin-5-yl)-ethyl]-1-(2-fluoro-4-methoxy-phenyl)-3-phenyl-urea. (Yield 0.27 g; 43.2%).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[O:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]([NH2:32])[CH2:24][CH2:23]1>>[O:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]([NH:32][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1CCOc2ccccc21
Product: O=[N+]([O-])c1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Yield: 86.9 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (2.271 g, 7.0 mmol; HPLC: 4.446 min) and rac-chroman-4-ylamine (CAS 53981-38-7) (1.044 g, 7.0 mmol; 0.374 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (1.98 g, 87%, HPLC 2.031 min), MS (ISP) m/e=326.2 [(M+H)+].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>CS(C)=O.CS(C)=O.CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (14.5 g, 362.96 mmol) in dimethyl sulfoxide (250 mL) was added dropwise a mixture of (4-chlorophenyl)acetonitrile (316) (25 g, 164.98 mmol) and 1,4-dibromobutane (35.6 g, 164.98 mmol) dissolved in dimethyl sulfoxide:ether (1:1; 300 mL) at 0° C. The reaction mixture was stirred for 30 min at same temperature and at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with HCl (1N; 25 mL) and water (200 mL) and extracted with ethyl acetate (3×100 mL). The separated organic part was washed with water (3×100 mL) and brine (100 mL) and dried and concentrated to get a crude product which was purified by silica CombiFlash column (3-5% ethyl acetate in hexane used as eluent) to afford 1-(4-chlorophenyl)-cyclopentanecarbonitrile (317) (33.9 g, 100%) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]([N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]3=[O:19])[CH:10]=[N:11][CH:12]=2)=[CH:5][N:6]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27]>CC(O)C>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([NH:27][C:2]2[O:3][C:4]([C:7]3[CH:8]=[C:9]([N:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]4=[O:19])[CH:10]=[N:11][CH:12]=3)=[CH:5][N:6]=2)[CH:28]=1
Reactant: O=c1ccccn1-c1cncc(-c2cnc(Cl)o2)c1
Reactant: COc1ccc(C)c(N)c1
Solvent: CC(C)O
Product: COc1ccc(C)c(Nc2ncc(-c3cncc(-n4ccccc4=O)c3)o2)c1

Procedure:
5′-[2-(5-Methoxy-2-methyl-phenylamino)-oxazol-5-yl]-[1,3′]bipyridinyl-2-one 221 was prepared as described for I-f above from 5′-(2-Chloro-oxazol-5-yl)-[1,3′]bipyridinyl-2-one VIII-c (68 mg, 0.250 mmol), and 5-methoxy-2-methylaniline (35 mg, 0.250 mmol) in iPrOH (3 mL) to afford the title compound 221 after column chromatography (SiO2; eluting with 2% to 5% EtOH in DCM) as an orange solid (28 mg, 30%). (300 MHz, CDCl3) δ 8.83 (d, J=1.9 Hz, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.93 (t, J=2.1 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 7.30 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.78 (s, 1H), 6.68 (d, J=9.3 Hz, 1H), 6.55 (dd, J=8.3, 2.5 Hz, 1H), 6.30 (t, J=5.6 Hz, 1H), 3.81 (s, 3H), 2.25 (s, 3H). ESL MS m/z 375 (M+H)+. Retention time=2.99 min (method 1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[OH:18][C:19]1[C:24]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:23][C:22]([SH:29])=[CH:21][C:20]=1[C:30]([CH3:33])([CH3:32])[CH3:31]>>[OH:18][C:19]1[C:20]([C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:21][C:22]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:23][C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: CC(C)(C)c1cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc(C(C)(C)C)c1O

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 4-hydroxy-3,5-di-tert. butyl-thiophenol (m.p. 84.5°-86.0° C.).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[F:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][NH2:19])=[CH:15][CH:14]=1>C(O)C>[NH2:10][C:6]1[NH:19][N:18]([CH2:17][C:16]2[CH:20]=[CH:21][C:13]([F:12])=[CH:14][CH:15]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(F)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(F)cc2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 13 g of 4-fluorobenzylhydrazine, on stirring for 5 hours in ethanol at 60° and working up as described in Example 1, yield 13.2 g of the compound identified above as colorless crystals of melting point 148°, corresponding to 63% of theory.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@H:7]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9](=[O:17])[C@@H:8]2[CH2:18][CH2:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[OH:21])=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C@@H:20]([OH:21])[CH2:19][CH2:18][C@@H:8]2[C@@H:7]([C:5]3[S:6][C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([OH:29])[CH:35]=4)=[CH:3][CH:4]=3)[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]2=[O:17])=[CH:23][CH:24]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(Br)s2)N1c1ccccc1
Reactant: OB(O)c1cccc(O)c1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)s2)N1c1ccccc1
Yield: 83.6 %

Procedure:
(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (90.2 mg, 0.196 mmol) was coupled with 3-hydroxyphenyl boronic acid (32.2 mg, 0.233 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (12 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one (77.6 mg, 84% yield) as a clear foam; Rf 0.36 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CD3OD) δ 7.31-6.93 (m, 14H), 6.70 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 4.89-4.88 (m, 1H), 4.64-4.59 (m, 1H), 3.77 (br s, 2H), 3.25-3.21 (m, 1H), 1.97-1.83 (m, 4H) ppm; MS [M−OH]+ 456.0.
Reaction SMILES: [Na+].[CH3:2][Si:3]([CH3:17])([CH3:16])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]([O-:15])=O)[N:10]=[CH:9]1.[N:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.CN(C=O)C>CN(C1C=CN=CC=1)C.CCOC(C)=O>[N:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][C:13]([C:11]2[N:10]=[CH:9][N:8]([CH2:7][O:6][CH2:5][CH2:4][Si:3]([CH3:2])([CH3:17])[CH3:16])[CH:12]=2)=[O:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C[Si](C)(C)CCOCn1cnc(C(=O)[O-])c1
Reactant: Nc1ccccc1N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(C(=O)Nc2ccccc2N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A flask was charged with 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylate sodium salt (70 mg, 0.26 mmol) (as prepared in the previous step), 2-piperidin-1-yl-phenylamine (36 mg, 0.20 mmol), EDCI (60 g, 0.31 mmol), DMAP (25 mg, 0.20 mmol), and DMF (1 mL) and stirred for 3 h at RT. The reaction was diluted with EtOAc (10 mL) and washed with brine (2×10 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 5-g SPE cartridge (silica) with 30% EtOAc/hexane to give 80 mg (97%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C21H32N4O2Si, 401.2 (M+H), found 401.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH2:27][CH2:28][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])[CH2:30][CH:31]=4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:46])[CH:10]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:17]2[C:21]3[CH:22]=[C:23]([C:26]4[CH2:27][CH2:28][N:29]([C:32]([C@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])[CH2:30][CH:31]=4)[CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH3:16])=[C:11]([F:46])[CH:10]=1
Reactant: C[C@H](c1ccc(Cl)cc1F)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1F)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of the crude (R)-t-butyl 2-(4-(1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidine-1-carboxylate (0.092 g, 0.17 mmol) in dichloromethane (1.5 mL) and stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (15 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5-20% methanol in dichloromethane) to give the title compound as a white solid (0.024 g, 0.053 mmol, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.78-9.70 (m, 1 H), 9.32-9.22 (m, 1 H), 8.44-8.38 (m, 1 H), 7.68 (d, J=8.4 Hz, 1 H), 7.58 (s, 1 H), 7.51-7.41 (m, 3 H), 7.27 (d, J=8.4 Hz, 1 H), 6.17-6.13 (m, 2H), 4.61-4.54 (m, 1 H), 4.19-4.05 (m, 3 H), 3.89-3.85 (m, 1 H), 3.69-3.50 (m, 3 H), 2.52-2.34 (m, 1 H), 1.95 (d, J=6.8 Hz, 3 H), 1.90-1.70 (m, 3 H); MS: (ES) m/z calculated for C25H27ClFN4O [M+H]+453.2, found 453.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][N:27]=[C:28]([CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)[CH3:29])([CH3:25])([CH3:24])[CH3:23].Cl>CN(C)C=O>[C:22]([O:26][N:27]=[C:28]([CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][O:15][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])=[CH:5][C:4]=1[Cl:14])[CH3:29])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(COCCCCOS(C)(=O)=O)=NOC(C)(C)C
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 76.3 %

Procedure:
First, 0.55 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.30 g of potassium carbonate, 0.59 g of 4-(methanesulfonyloxy)butyloxyacetone O-tert-butyloxime, and 10 ml of N,N-dimethylformamide are placed in a reaction vessel. After stirring at 60° C. for 6 hours, the reaction mixture is poured into diluted hydrochloric acid, and extracted twice with ethyl acetate. The ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 0.71 g (yield, 77%) of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-butyloxyacetone O-tert-butyloxime, nD25.0 1.5170.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Sn:12](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[Sn:12]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
n-BuLi (7.6 mL, 18.9 mmol) was added dropwise at −10° C. under nitrogen atmosphere over a period of 30 minutes to an anhydrous tetrahydrofuran solution (20 mL) of 1-methyl-1H-imidazole (1.6 mL, 18.8 mmol), and the mixture was stirred for 2.5 hours. Next, a tetrahydrofuran solution (12 mL) of Bu3SnCl (5.1 mL, 18.8 mmol) was added dropwise over a period of one hour at −78° C., and then the mixture was raised to room temperature and stirred overnight. The title compound (5.48 g, 79%) was obtained by vacuum distillation (140-142° C., 0.5 mmHg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[I:13])(=[O:3])[CH3:2].[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>[Ni]>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:7][C:6]=1[I:13])(=[O:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Agent: [Ni]
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1I

Procedure:
lodination of 4-aminobenzonitrile 30 with ICI produces 4-amino-3-iodobenzonitrile 31. Acetylatation of 4-amino-3-iodobenzonitrile 31 results in compound 32, which can be reduced with Raney nickel to form 4-acetamido-3-iodobenzaldehyde 33. Reaction of compound 33 with thiosemicarbazide yields 4-acetamido-3-iodobenzaldehyde thiosemicarbazone 34, as illustrated below.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[C:6]([F:20])[C:5]([O:21][CH2:22][CH3:23])=[C:4]([O:24][CH2:25][CH3:26])[CH:3]=1.[Cu](C#N)[C:28]#[N:29]>CN(C)C=O>[C:28]([C:2]1[C:7]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])=[C:6]([F:20])[C:5]([O:21][CH2:22][CH3:23])=[C:4]([O:24][CH2:25][CH3:26])[CH:3]=1)#[N:29]
Reactant: CCOc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CCOc1cc(C#N)c(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Temperature: 155 °C
Yield: 0.1 %

Procedure:
A mixture of 2-(6-bromo-3,4-diethoxy-2-fluorobenzyl)isoindol-1,3-dione (1.00 g, 2.37 mol), copper cyanide (0.42 g, 4.74 mol) and N,N-dimethylformamide (5 mL) was stirred at 155° C. for ten hours. After the reaction mixture was extracted with a 10% aqueous solution of ethylene diamine and toluene, the resultant organic layer was washed sequentially with a 10% aqueous solution of ethylene diamine and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off to give crude crystals, which were washed with ethyl acetate to give 0.52 g of the title compound (yield: 60%) as slightly green crystals.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36]N)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: CS(=O)(=O)c1cccc(NN)c1
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-methanesulfonyl-phenyl)-hydrazine according to the method described for example 43. MS: M=477.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[F:25][C:26]([F:41])([C:37]([F:40])([F:39])[F:38])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[S:29](F)(=[O:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[O:15][S:29]([C:28]([F:33])([F:34])[C:27]([F:35])([F:36])[C:26]([F:25])([F:41])[C:37]([F:40])([F:39])[F:38])(=[O:31])=[O:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2cnccc2c1O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2cnccc2c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 3-hydroxy-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ester-(950 mg, 4.26 mmol) and DMAP (26 mg, 0.21 mmol) in DCM (12 ml) at 0° C. was added DIPEA (1.8 ml, 10.2 mmol) and nonafluorobutylsulfonyl fluoride (0.99 ml, 5.53 mmol). After 10 minutes the reaction mixture was warmed to room temperature and stirred for an additional 20 hours. The reaction mixture was diluted with DCM (30 ml) and washed with water (20 ml). The organic phase was dried over sodium sulphate, filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-SPE, pentane:diethyl ether, gradient 90:10 to 65:35) to afford the title compound as a colourless oil which crystallised on standing (678 mg, 31%): LCMS (method B). RT=4.49 min, M+H+=508.