Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[CH3:18][Mg]Br>O1CCCC1.[Cu]I>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH:9]([C:12]#[N:13])[C:10]#[N:11])[CH3:18])=[CH:14][CH:15]=1
Reactant: C[Mg]Br
Reactant: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(c1ccc(OC(F)(F)F)cc1)C(C#N)C#N
Yield: 60 %

Procedure:
Using 1.19 g of (4-(trifluoromethoxy)benzylidene)malononitrile, 20 ml of tetrahydrofuran, a catalytic amount of copper (1) iodide, and 12.5 ml of a solution of methyl magnesium bromide in tetrahydrofuran (about 1 M, available from Tokyo Kasei Kogyo Co., Ltd), and according to the process described in REFERENCE PRODUCTION EXAMPLE 2, there was obtained 0.76 g of (1-(4-(trifluoromethoxy)phenyl)ethyl)malononitrile (the intermediate (10)).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH2:31][S:32]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39](=[O:44])[CH2:38]2)(=[O:34])=[O:33].N1CCCCC1>C(O)C>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[C:25]=1[CH2:31][S:32]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39](=[O:44])/[C:38]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1])(=[O:34])=[O:33].[CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][CH:3]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: 25 °C
Yield: 321.6 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (67.2 mg, 0.19 mmol) were dissolved in 2.5 ml of ethanol, and added with 42 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2), and dried to obtain the title compound (Z)-2-(5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-ylidene)methyl)-3-methyl-5-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 68 (93 mg, yield 77.5%) as an orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(NCCCC)CCC>>[N:22]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Reactant: C1CCNCC1
Solvent: CCCCNCCCC
Product: Cc1cccn2cc(-c3ccc(OCCCN4CCCCC4)cc3)nc12

Procedure:
This compound was prepared according to the procedure described in Example 1 of U.S. Pat. No. 4,727,145 or J. Med. Chem. 188, 31, 2221 et seq., above using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and piperidine instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively. Analysis: Calc'd for C22H27N3O 3HCl 1H2O; C, 6.76; H, 55.41; N, 8.81. Found: C, 6.63; H, 55.02; N, 8.55.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.Cl>CN(C)C=O.O.O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[C:4]1=[O:18]
Reactant: O=C1NC(=O)C2(N1)C(=O)Nc1ccccc12
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (1.5 g., 50% w/w dispersion in mineral oil) was added continuously to a solution of spiro[imidazoline-4,3'-indoline]-2,2',5-trione (2.17 g.) in N,N-dimethylformamide (40 ml.) and water (20 ml.). The resultant mixture was stirred for 30 minutes and then a solution of 3,4-dichlorobenzyl chloride (1.95 g.) in tetrahydrofuran (5 ml.) was added dropwise during 10 minutes. The solution obtained was stirred at room temperature for two hours and then poured into water (150 ml.). The mixture was acidified with concentrated hydrochloric acid and then extracted with ether (2×100 ml.). The combined extracts were washed with water (3×100 ml.), then with saturated sodium chloride solution (100 ml.), dried (MgSO4) and evaporated. The residual solid was dissolved in chloroform and purified by chromatography on silica (25 g.) using an increasing concentration of ethyl acetate in cyclohexane as eluant. Evaporation of the ethyl acetate rich fractions gave 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5 -trione identical with that obtained in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][S:10](=[O:12])(=[O:11])[NH2:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1F
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1ccccc1F
Yield: 38.2 %

Procedure:
This compound was prepared according to the procedure of Example 56. A mixture of 11.2 g (0.1 mole) of 2-fluorophenol and 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate in 50 ml of toluene gave 7.3 g (38%) of the title compound as a white solid, mp 63°-64° (benzene).
Reaction SMILES: C(C1C=CC=CC=1[OH:11])CCC.[C:12]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCCc1ccccc1O
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccccc1O

Procedure:
The procedure of Example 5 was repeated in all respects except 2-butylphenol was substituted for 4-t-butylphenol. 40% bleach number=0.5, 100% bleach number=4.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)N.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][O:45][CH3:46])[N:38]=[CH:37][N:36]=[C:35]2[S:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([S:47][C:35]3[C:34]4[C:39](=[CH:40][C:41]([O:42][CH2:43][CH2:44][O:45][CH3:46])=[C:32]([O:31][CH3:30])[CH:33]=4)[N:38]=[CH:37][N:36]=3)[CH:49]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Agent: NC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react carbamate phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 154A (151 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (107 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours the reaction was concentrated to dryness. The resulting solid was triturated with 1:1 dichloromethane/hexane and the solid removed by filtration to give 26 mg. 1H (DMSO-d6) 9.23 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 7.79 (s, 1H), 7.55 (m, 4H), 7.40 (m, 5H), 7.25 (s, 1H), 6.35 (s, 1H), 4.33 (m, 2H), 3.99 (s, 3H), 3.75 (m, 2H), 3.34 (s, 3H), 1.25 (s, 9H); LCMS (ESI) m/z 599 (M+H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[NH:5]1>C(O)(=O)C>[F:3][C:4]1([CH:12]([Br:1])[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[NH:5]1
Reactant: BrBr
Reactant: CSC1=NC=CC(F)(CC(=O)c2ccccc2)N1
Solvent: CC(=O)O
Product: CSC1=NC=CC(F)(C(Br)C(=O)c2ccccc2)N1
Yield: 99.7 %

Procedure:
Bromine (1.22 g, 7.6 mmol) in acetic acid (5.6 ml) is added to a solution of 4-Fluoro-2-(2-methylthio-4-pyrimidyl)acetophenone (2 g; 7.6 mmol) in acetic acid (40 ml. The initially thick precipitate is almost dissolved after 20 min, filtered and the filtrate evaporated to dryness. The residue is taken up in a saturated solution of NaHCO3 and extracted three times with tert.butyl methyl ether. The combined organic phases are dried over Na2SO4 and evaporated to dryness to yield 2.6 g (100%) of a brown oil, which is used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:17][CH:12]([N:13]([CH3:16])[CH:14]2[CH3:15])[CH2:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.[C:18]([Cl:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C1C=CC=CC=1>[ClH:26].[C:18]([O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:17][CH:12]([N:13]([CH3:16])[CH:14]2[CH3:15])[CH2:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1N(C)C2CCCC1(c1cccc(O)c1)C2
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1N(C)C2CCCC1(c1cccc(OC(=O)c3ccccc3)c1)C2
Product: Cl
Reaction time: 0.75 h
Yield: 76.4 %

Procedure:
0.35 g of 1-(3-hydroxyphenyl)-6,7-dimethyl-6-azabicyclo [3,2,1]octane is dissolved in 4 ml of pyridine, and a solution of 0.28 g of benzoyl chloride in 2 ml of benzene is added thereto under ice-cooling. The mixture is stirred for 45 minutes. Then, the mixture is concentrated under reduced pressure. The residue thus obtained is washed with ether and then recrystallized from a mixture of ethylacetate and acetone. 0.43 g of 1-(3-benzoyloxyphenyl)-6,7-dimethyl-6-azabicyclo[3,2,1]octane hydrochloride is obtained. M.p. 207° - 209°C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.C(/[B:10]1[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]1)=C\C>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:2]1(=[CH:1][B:10]2[O:18][C:15]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:13])[O:11]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1CCCC1
Reactant: C/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CC1(C)OB(C=C2CCCC2)OC1(C)C
Yield: 34.4 %

Procedure:
A solution of methylcyclopentane (100 mg, 1.22 mmol), and trans-1-propenylboronic acid pinacol ester (204 mg, 1.22 mmol) in dry dichloromethane (6 mL) was bubbled with nitrogen for 5 minutes. Grubbs Catalyst, 2nd generation (52 mg, 0.06 mmol) was added and the reaction mixture was refluxed overnight. The solution was concentrated in vacuo and the residue was purified by preparative TLC (cyclohexane/ethyl acetate 90/10) to provide 2-(cyclopentylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21a) (88 mg, 0.42 mmol, 35%)
Reaction SMILES: [B-](F)(F)(F)F.[CH:6]1[CH:12]=[CH:11][CH+:10][CH:9]=[CH:8][CH:7]=1.CO.[C:15](=O)(O)[O-:16].[Na+]>O>[CH3:15][O:16][CH:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: c1ccc[cH+]cc1
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1C=CC=CC=C1

Procedure:
1-methoxy-1,3,5-cycloheptatriene can be produced from cycloheptatrienyl tetrafluoroborate (I) as described in Conrow K 1963 Organic Synthesis 43, 101. The reaction of (I) with methanol and sodium bicarbonate in water gives 7-methoxy-1,3,5-cycloheptatriene (II), (reference Conrow K1961, J. Am. Chem. Soc. 83,2342). The 1-methoxy-1,3,5-cycloheptriene can be made by the thermal isomerisation of (II) by heating at 150° for 2.5 hours in nitrogen atmosphere in the presence of antioxidants and absence of water, as described by T. NOZOE and K., Takahashi, Bull Chem. Soc. Japan, 38, 665, 1965. Pratt, J. T. Reaction of Cycloheptatriene, PHD Thesis, University of Washington, Seattle, Wash. 1964.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C([Li])CCC.[C:29](O)(=O)[C:30](O)=[O:31]>CCCCCC.C(N=CC)(C)(C)C.ClP(=O)(OCC)OCC.O1CCCC1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:29][CH:30]=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)O
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: CC=NC(C)(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=CC=O)c2ccc(C)cc2)cc1
Reaction time: 30 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction was worked up after 30 hours. The following reagents were used: 4,4'-dimethylbenzophenone (21 g), diisopropylamine (32.2 mL). 1.55M n-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (17.6 mL) and tetrahydrofuran (200 ml). The work up, varied only in that the oxalic acid catalyzed hydrolysis was done overnight at room temperature, furnished 23 g of crude product which was crystallized from hexane to give 18.1 g of 3,3-bis(4-methylphenyl)-2-propenal, mp 92°-93.5° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].O.CC(O)C>[OH-].[Na+].C1C=CC=CC=1>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:3][CH:2]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 77.4 %

Procedure:
A vigorously stirred mixture of 34 g (0.25 mol) of 4-tolylboronic acid and 34 g (0.17 mol) of 2-bromo-1-nitrobenzene in a mixture of 170 mL of 5N sodium hydroxide, 57 mL of water, 215 mL of 2-propanol and 1080 mL of benzene was treated with 11.9 g of (tetrakis)triphenylphosphine palladium(0). The two-phase mixture was heated at reflux for three hours. The cooled reaction mixture was filtered through Celite and the filter cake washed with fresh benzene. The organic layer was separated and washed with water (3×), dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum and the residue (46.1 g) purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (20:1), to give 28.05 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[C:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)(Cl)Cl.O>[C:18]([N:23]1[CH2:28][CH2:27][N:26]([CH:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:10]2)[CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1ccc2c(c1)CC(Cl)c1ccccc1S2
Reactant: CCOC(=O)N1CCNCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
100 g of 2,10-dichloro-10,11-dihydro-dibenzo[b,f]thiepin in 300 ml of chloroform are heated at reflux for 24 hours together with 182 g of 1-carbethoxy-piperazine. The mixture is then diluted with chloroform and water. The organic phase is washed several times with water and dried over magnesium sulphate. After filtration, the filtrate is concentrated under reduced pressure and the residue crystallised from acetone/hexane. There is obtained 1-carbethoxy-4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine of melting point 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH2:33][C:34](Cl)=O)=[CH:28][CH:27]=3)[CH:20]=[N:19]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:34]([CH2:33][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][C:23]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)=[CH:32]4)=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: Cn1cc(-c2cnc3ccc(CC(=O)Cl)cc3c2)cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
(6-Chloro-pyridazin-3-yl)-hydrazine (190 mg, 1.315 mmol) was dissolved in dimethylformamide followed by the addition of triethylamine (3 eq). This mixture was stirred for 5 minutes. The mixture became dark green and then was cooled 0° C. A solution of [3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl]acetyl chloride (375 mg, 1.315 mmol) in dimethylformamide was added dropwise and the reaction mixture turned dark yellow, and stirred for one hour. After such time mixture was concentrated to dryness then taken up in acetic acid (10 mL) and stirred at 60° C. for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water, and the aqueous phase further extracted with ethyl acetate. The combined organics purified via flash column chromatography (SiO2, CH2Cl2, methanol gradient 0 to 10%) to return the title compound (217 mg, 42% yield). Analytical data presented in Table 2.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][C:14](=[O:32])[CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH2:29]O)[CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[CH3:12].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:32])[CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:20]=[CH:21][C:22]([CH:25]([CH2:29][O:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=2)[CH:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=1)[CH3:12]
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CO)C(C)C)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1ccc(C(COc2cc(C)c(Br)c(C)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromo-3,5-dimethyl-phenol (818 mg, 4.07 mmol) and 3-[4-(1-hydroxymethyl-2-methyl-propyl)-benzoylamino]-propionic acid ethyl ester (1.0 g, 3.26 mmol) in anhydrous toluene (15 mL) is degassed and filled with nitrogen 3 times. Tributylphosphine (1.21 mL, 4.89 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (1.23 g, 4.89 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is loaded on a silica gel column and purified using hexanes/ethyl acetate. MS (ES): 488.2 [M+H]−.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].O>ClCCl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)=[C:1]=[S:2]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(N=C=S)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thiophosgene (4.1 mL, 54 mmol) was added al at once to a mixture of diethyl 4-aminobenzylphosphonate (12.04 g, 50 mmol), sodium bicarbonate (8.33 g, 99 mmol), water (100 mL), and dichloromethane (250 mL), and the mixture was stirred at room temperature for about 2 hours. The organic and aqueous layers were separated, the organic layer dried over magnesium sulfate, filtered, and concentrated to give the product isothiocyanate as a brown oil. This was used directly in the next step.
Reaction SMILES: C([O:3][C:4](=[O:31])[C@H:5]([CH3:30])[CH2:6][C@H:7]([NH:21][C:22](=[O:29])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:29])[CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:6][C@@H:5]([CH3:30])[C:4]([OH:31])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)Cc1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (2 mL, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)-pentanoic acid. HPLC Retention time 1.23 minutes (condition A); MS 408.3 (M+1); 1H NMR (400 MHz, MeOD-d4) δ ppm 1.16 (d, J=7.07 Hz, 3H), 1.50 (m, 1H), 1.96 (m, 1H), 2.52 (m, 1H), 2.72 (dd, J=7.71 Hz, 7.58 Hz, 1H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1H), 3.64 (d, J=1.26 Hz, 2H), 4.20 (m, 1H), 6.82 (m, 1H), 6.89 (m, 1H), 7.21 (m, 3H), 7.32 (m, 1H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].CN([CH:26]=[O:27])C>>[CH2:11]([O:12][C:26](=[O:27])[C:2]([CH2:3][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1)=[CH2:7])[CH3:10]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=C(CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O)C(=O)OCC
Temperature: 18 °C

Procedure:
A suspension of 2.50 g (7.98 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1.15 ml (7.98 mmol) of ethyl 2-(bromomethylacrylate) in 80 ml of DMF was treated at −20° C. with 0.38 g (8.78 mmol) of NaH (55% in oil) and warmed up naturally to 18° C. (2.5 h). After cooling (0° C.) additionally 0.12 ml (0.80 mmol) of ethyl 2-(bromomethylacrylate) was added and after 30 min no starting material was left, based on TLC. The reaction was extracted with aqueous 10% KHSO4/ether (3×), the organic phases were washed with a aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to give 3.51 g (quantitative, 90% purity) of the crude title compound as light yellow viscous oil, which was used directly in the next step. MS: 425.1 (MH+, 2Cl).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH:12]1[O:16][CH2:15][CH2:14][O:13]1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:13]1[CH2:14][CH2:15][O:16][CH2:12]1.[CH2:9]([O:8][P:1]([CH2:20][CH:19]=[CH:18][C:17]([CH3:23])=[CH:22][CH:21]=[O:13])([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: Cc1ccccc1
Reactant: BrC1OCCO1
Reactant: CCOP(OCC)OCC
Product: C1COCO1
Product: CCOP(=O)(CC=CC(C)=CC=O)OCC

Procedure:
Triethyl phosphite (2.56 g, 15.44 mmol) in dry toluene (10 ml) and bromodioxolane (H) (3 g, 12.87 mmol) in toluene (10 ml) were introduced in succession into a 50-ml two-necked flask fitted with a thermometer and a condenser.