Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([C:9]3[CH2:13][C:12]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[O:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1([CH3:32])[O:26]B(O)[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]1=2.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:11]1[C:12]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:13][C:9]([C:7]2[NH:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:22]([OH:26])([CH3:32])[CH3:21])=[CH:3][C:4]=3[N:8]=2)=[N:10]1
Reactant: Brc1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Reactant: CC1(C)OB(O)c2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CC(C)(O)c1ccccc1-c1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Yield: 9 %

Procedure:
Using the procedure for step D in Example 1, the title compound was prepared from 3-(5-bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene (150 mg, 0.449 mmol, as prepared in the previous step) and 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (2.0 eq., 145 mg, 0.898 mmol, prepared as described in US2007/259936) and (dppf)PdCl2.DCM (0.10 eq., 36.6 mg, 0.045 mmol) in 9% yield (16.4 mg). 1H-NMR (400 MHz, d4-MeOH) δ: 7.82 (dd, J=8.1, 1.3 Hz, 1H), 7.53-7.68 (m, 1H), 7.47 (br. s., 1H), 7.35 (td, J=7.6, 1.6 Hz, 1H), 7.19-7.24 (m, 2H), 7.05 (dd, J=7.6, 1.3 Hz, 1H), 3.28 (s, 2H), 1.69-1.90 (m, 6H), 1.46-1.65 (m, 4H), 1.33 (s, 6H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C24H27N3O2: 390.2 (M+H). found: 390.4.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[C:16]([NH:20][C:21]([NH:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 0.92 g of (2R)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride and 0.6 cm3 of tert-butyl isothiocyanate in 10 cm3 of ethanol is cooled to a temperature in the region of 0° C. and 0.56 cm3 of triethylamine is then added. The mixture is stirred for 18 hours at room temperature and is then heated at a temperature in the region of 60° C. for 2 hours; the suspension thus dissolves. 0.6 cm3 of tert-butyl isothiocyanate is added and heating is continued for 3 hours, after which the reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 50° C. The yellow oil obtained is dissolved in 50 cm3 of ethyl acetate, after which the organic solution is washed with twice 50 cm3 of sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.2 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-nitrobenzyl)-ethyl]thiourea are obtained in the form of a yellow oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4, δ in ppm): 1.39 (s: 9H); 2.98 (limiting AB: 2H); 3.38 (limiting AB: 2H); 4.48 (mt: 1H); 7.60 (t, J=8 Hz: 1H); 7.74 (broad d, J=8 Hz: 1H); 8.09 (broad d, J=8 Hz: 1H); 8.16 (broad s: 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[S:15]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:32]([O:31][P:27]([CH2:26][N:14]([S:15]([C:18]1[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1)(=[O:17])=[O:16])[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([C:3](=[O:4])[CH2:2][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[CH:6]=[CH:7]2)(=[O:34])[O:28][CH2:29][CH3:30])[CH3:33]
Reactant: C1COCCN1
Reactant: CCOP(=O)(CN(c1ccc2c(ccn2C(=O)CCl)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN(c1ccc2c(ccn2C(=O)CN2CCOCC2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
125 mg diethyl {[[1-(2-chloro-acetyl)-1H-indol-5-yl]-(3,5-dichloro-phenylsulphonyl)-amino]-methyl}-phosphonate are dissolved in 2 ml dimethylformamide, combined with 34 mg potassium carbonate and 22 μl morpholine and stirred overnight at ambient temperature. The mixture is divided between ethyl acetate and water. The organic phase is washed with saturated sodium chloride solution and dried on magnesium sulphate. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (ethyl acetate/methanol 30:1 to 10:1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[O:16]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>C(O)(C)C>[ClH:2].[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][N:4]=[C:3]2[NH:27][C:26]1[CH:25]=[CH:24][C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)c1ccccc1
Product: Nc1ccc2ncnc(Nc3ccc(Oc4ccccc4)cc3)c2c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A suspension of crude 4-chloro-6-nitroquinazoline hydrochloride (5 mmol) (Morley J. S. and Simpson J. C. E., J. Chem. Soc., 1948:360) was refluxed under nitrogen with stirring in isopropanol (10 mL) containing 4-phenoxyaniline (926 mg, 5 mmol) and N,N-dimethylaniline (1.215 g, 10 mmol) for 3 hours. The mixture was allowed to cool to 25° C., and the precipitate was collected by Buchner filtration, rinsed with isopropanol (2×10 mL) and dried at 60° C. in a vacuum oven to give 6-amino-4-(4-phenoxyanilino)quinazoline hydrochloride (1.702 g, 86%) as an orange solid; mp 293-294° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Al+3].[Cl-].[Cl-].[Cl-].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.Cl[CH2:21]CCl>>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([C:16](=[O:17])[CH2:15][CH2:14][C:13]([O:18][CH3:21])=[O:19])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)O1
Reactant: ClCCCl
Reactant: Oc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCC(=O)c1ccc(O)c(F)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of 2-fluorophenol (22.4 g, 200 mmole) in 1,2-dichloroethane (250 ml) at 0° there was added AlCl3 (54 g, 400 mmole) and then succinic anhydride (20 g, 200 mmole). The reaction mixture was heated at 85° C. for 18 hours, then cooled, poured on ice and stirred for several hours at room temperature. The layers were separated and the aqueous layers extracted with CH2Cl2. The combined extracts were washed with water, dried (MgSO4) and evaporated to a semi-solid which was taken up in a solution of methanolic HCl (500 ml, approximately 3N). After standing for 24 hours the solution was poured into water, extracted with CH2Cl2, washed with water, dried and evaporated to a small volume. The crude product was purified by chromatography on silica gel to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](CC#N)=[CH:11][C:10]2=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-:25].[Na+].[CH2:27]([OH:29])[CH3:28]>>[N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:28][C:27]([OH:25])=[O:29])=[CH:11][C:10]2=[O:22])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCc1cc(=O)n(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)Cc1cc(=O)n(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12

Procedure:
1-(4-Nitrobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetonitrile (0.5g.) was added to a solution of sodium hydroxide (0.2g.) in ethanol (50ml.) and the mixture was heated under reflux for 5 hours. The ethanol was evaporated under reduced pressure and the residue was treated with 2N hydrochloric acid (100ml.). The precipitate thus formed was separated off and recrystallised from ethanol to give 1-(4-nitrobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid (0.42g.) m.p. 208°-210° C., (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:13])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: ClCCc1ccc(Cl)cc1
Temperature: 58 °C
Reaction time: 2.5 h

Procedure:
Into a 250-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 2-(4-chlorophenyl)ethanol (25.026 g, 160 mmol) N,N-dimethylformamide (0.621 mL, 7.99 mmol) was added and the mixture was heated to 58° C. Thionyl Chloride (12.25 mL, 168 mmol) was charged over 1 h while the temperature was maintained at <65° C. Upon completion of the addition, the mixture was stirred at 60 to 64° C. for 2.5 h, and then allowed to gradually cool to room temperature and stirred overnight to give a clear, golden oil.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:27](O)=[O:28])[CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl.[C:31]([S:37][CH2:38][CH2:39][NH2:40])(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].Cl.C(SCCN)(=O)C.Cl.C(SCCN)(=O)C1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]([NH:4][C@H:5]([C:27]([NH:40][CH2:39][CH2:38][S:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH2:6][S:7][C:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)SCCN
Reactant: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(=O)SCCN
Agent: Cl
Agent: NCCSC(=O)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)(C)C
Yield: 86 %

Procedure:
The coupling reaction of 7 (7.4 mmol) with S-pivaloylcysteamine hydrochloride [(compound obtained according to the same methods as those described by T. Wieland and E. Bokelman, Ann. Chem., 1952, 576, 20-34, during the syntheses of S-acetylcysteamine hydrochloride and S-benzoylcysteamine hydrochloride) M.p.=212-213° C.] is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 30%). 11 is collected in the form of a colorless foam with a yield of 86%. Rf (AcOEt/petroleum ether, 7/3): 0.5. [α]D20=+8.5° (c 1.29, CHCl3).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.CC1[O:46][C:47]([CH3:53])=[CH:48][C:49]=1[C:50](O)=[O:51].Cl.CN(C)[CH2:57][CH2:58][CH2:59]N=C=NCC>C(#N)C>[CH3:53][C:47]1[O:46][C:58]([CH3:57])=[CH:59][C:48]=1[CH2:49][C:50]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:51]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C(=O)O)c(C)o1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c(C)o1
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2,5-dimethyl-3-furoic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford 2-(2,5-dimethyl-furan-3-yl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.65 g, 73%) as a white solid: mp 193-195° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.45 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.23 (s, 3H), 2.46 (s, 3H), 2.54-2.63 (m, 2H), 2.85-2.97 (m, 1H), 4.85 (d, J=5.9 Hz, 2H), 5.14-5.20 (dd, J=5.3 and 12.6 Hz, 1H), 6.49 (s, 1H), 7.67-7.86 (m, 3H), 8.54 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 12.98, 13.08, 21.96, 30.92, 37.53, 48.85, 104.86, 115.84, 121.77, 126.99, 131.48, 132.99, 134.76, 139.69, 149.11, 154.47, 163.32, 166.96, 167.54, 169.81, 172.74; Anal. Calcd. for C21H19N3O6: C, 61.61; H, 4.68; N, 10.26. Found: C, 61.66; H, 4.37; N, 9.99.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[C:17](#[N:20])[CH:18]=[CH2:19]>O1CCCC1>[C:1]([C:4]1([CH2:19][CH2:18][C:17]#[N:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Reactant: C=CC#N
Solvent: C1CCOC1
Product: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21

Procedure:
Five hundred g. of 9-carbamoylfluorene was slurried in 13 liters of tetrahydrofuran under nitrogen, and the mixture was stirred and heated to 50°. Fifty ml. of Triton B was added, followed by 131 g. of acrylonitrile. The mixture was stirred at 50° for 6 hours, and 65 g. of additional acrylonitrile and 25 ml. of Triton B were added. The mixture was stirred at 50° overnight.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[S:8][C:7]([C:9](=[NH:11])[NH2:10])=[N:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.O=[C:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Br:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[NH:10][C:9]([C:7]2[S:8][C:4]([O:3][CH3:2])=[CH:5][N:6]=2)=[N:11]1
Reactant: COc1cnc(C(=N)N)s1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Yield: 59 %

Procedure:
5-methoxythiazole-2-carboximidamide hydrochloride (3.3 g, 17 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (3.46 g, 17 mmol) and ethyl 3-oxobutanoate (2.2 g, 17 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (4.56 g, 59%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=1)=[O:4]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CCCNS(C)(=O)=O)s1
Yield: 97.6 %

Procedure:
A solution of 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.0 g, 10.9 mmol) in EtOAc (100 mL) and MeOH (50 mL) was hydrogenated with 10% palladium on carbon (680 mg) at 50 psi for 7 h. The solution was filtered through a pad of Celite® with the aid of MeOH and was concentrated in vacuo to provide the title compound as an off-white solid (2.95 g). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H), 7.23 (d, 1H), 4.29 (m, 1H), 3.85 (s, 3H), 3.18 (q, 2H), 2.93 (m, 5H), 1.96 (m, 2H).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])=O.Cl.[C:20]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21].C(O)(=O)C.C(OCC)(=O)C>ClCCCl>[C:20]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:25][N:26]([CH2:1][CH2:3][CH2:4][CH2:5][C:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:27][CH2:28]1)(=[O:22])[CH3:21]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=CCCCC12CCCc3cccc(c31)NC2=O
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)C1(c2ccccc2)CCN(CCCCC23CCCc4cccc(c42)NC3=O)CC1
Yield: 23.6 %

Procedure:
2a-(3-Formylpropyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (180 mg, 0.72 mmol), 4-acetyl-4-phenylpiperidine hydrochloride (190 mg, 0.79 mmol), acetic acid (430 mg, 7.2 mmol) and sodium triacetoxyborate (310 mg, 1.4 mmol) were stirred in 1,2-dichloroethane (3 ml) at a room temperature for 20 hours. The reaction solution was mixed with ethyl acetate (80 ml), washed with sodium hydroxide aqueous solution (1 N) and saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 74 mg of the title compound (0.17 mmol, 24% in yield).
Reaction SMILES: I[CH2:2][C@@H:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[CH:5]=[CH:4]1.[CH2:15]([O:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:24]=1[N:30]1[S:34](=[O:36])(=[O:35])[N:33]([CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:32](=[O:43])[CH2:31]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[N:30]1[CH2:31][C:32](=[O:43])[N:33]([CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[S:34]1(=[O:35])=[O:36])[CH2:2][C@@H:3]1[NH:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[CH:5]=[CH:4]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1N[C@@H](CI)C=Cc2ccccc21
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@H]3C=Cc4ccccc4C(=O)N3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from (R)-3-iodomethyl-2,3-dihydrobenzo[c]azepin-1-one and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2cccc(O)c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cccc(O)c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-hydroxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4]1.[CH2:12](Br)[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.[I-].[Na+].O1CCC[CH2:22]1>>[CH2:12]([CH2:22][O:11][CH2:10][CH2:9][N:6]1[CH2:7][CH2:8][O:3][CH2:4][CH2:5]1)[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: OCCN1CCOCC1
Reactant: BrCC1CCCO1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: C1COC(CCOCCN2CCOCC2)C1
Yield: 56 %

Procedure:
To a suspension of 25 g sodium hydride in 500 g tetrahydrofuran, 131 g of 2-morpholino ethanol and 182 g of tetrahydrofurfuryl bromide were successively added dropwise. Thereafter, 1 9 of sodium iodide was added to the solution, which was heated under reflux for 100 hours. After cooling, the reaction solution was washed with an aqueous saturated sodium chloride solution, concentrated in vacuum, and purified by vacuum distillation, whereby 120 g of 4-[2-(tetrahydrofurfurylmethoxy)ethyl]morpholine, designated [B-43], was obtained (boiling point 97° C./24 Pa, yield: 56%).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[CH:10]=[C:9]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])[S:8][C:7]=2[C:6]([CH3:34])([CH3:33])[CH2:5][CH2:4]1.[CH:36]([CH:38]=[CH:39][C:40]([CH3:47])=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=O.CO.O>C1OCCC1>[CH3:47][C:40]([CH:39]=[CH:38][CH:36]=[C:12]([C:9]1[S:8][C:7]2[C:6]([CH3:33])([CH3:34])[CH2:5][CH2:4][C:3]([CH3:2])([CH3:35])[C:11]=2[CH:10]=1)[CH3:13])=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CC(c1cc2c(s1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=C(C)C=CC=O
Agent: [Br-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)C=CC=C(C)c1cc2c(s1)C(C)(C)CCC2(C)C
Yield: 83.3 %

Procedure:
4.50 g of [1-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)ethyl]triphenylphosphonium bromide and 1.3 g of ethyl 5-formyl-3-methylpenta-2,4-dienoate are dissolved in 70 ml of butylene oxide and the solution is heated at reflux for 2 hours. The cooled mixture is poured into a methanol/water mixture (6:4) and extracted several times with hexane. The hexane phase is washed three times with water, dried and evaporated. After filtration of the crude product over silica gel (eluting agent hexane/ether 9:1), there are obtained 2.4 g of ethyl 3-methyl-7-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)-2,4,6-octatrienoate as a pale yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=O)[CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([NH2:22])=[O:19])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reaction time: 12 h

Procedure:
6-Chloro-3-[(2-fluoro-4-iodophenyl)amino]pyridazine-4-carboxylic acid (144 mg, 0.37 mmol.) and 1,1′-carbonylbis(1H-imidazole) (119 mg, 0.73 mmol) were suspended in N,N-dimethylformamide (1.00 ml). The mixture was stirred over night (12 hr). Solid ammonium acetate (31 mg, 0.40 mmol) then added. The reaction was stirred for another 5 h. Water (0.5 mL) was then added into the mixture. The desired product was precipitated and was collected by vacuum filtration. LC/MS [7.39 min; 393 (M+1)].