Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[C:10]3[S:18][CH:19]=[CH:20][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([C:29](Cl)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.[OH-].[Na+].Cl>O1CCCC1CO>[NH:17]1[C:11]2[C:10]3[S:18][CH:19]=[CH:20][C:9]=3[N:8]([C:6]([C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:29]([C:24]4[C:23]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:30])=[CH:3][CH:4]=3)=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=[N:16]1
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cc1)c1ccccc1-c1ccccc1
Yield: 57.5 %

Procedure:
As described for Example 2, 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine (297 mg) is reacted with 0.542 g of [1,1'-biphenyl]-2-carbonyl chloride to give 0.70 g of bis acylated product. A mixture of this product in 13 ml of tetrahydrofuran-methanol (9: 4) and 2.3 ml of 1N NaOH is stirred for 18 hours at room temperature. To the mixture is added 2.3 ml of 1N HCl and the solvent removed. The mixture is triturated with 50 ml of CH2Cl2, filtered and the solid washed with CH2Cl2 and water to give 0.27 g of off-white crystals, m.p. 280°-284° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][C:65]([F:68])([F:67])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.3 %

Procedure:
To a solution of 200 mg (0.94 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 300 mg of TBTU (0.94 mmol) in 15 ml DMF, were added 0.8 ml (4.68 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 329 mg (0.94 mmol) (4-tert-butyl-benzyl)-[2-(3-trifluoromethoxy-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 160 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; diethylether/heptane 1:1) to give 130 mg off-white foam (23%). MS (ISP) 547.4 (M+H)+.
Reaction SMILES: [C:1]([O:4]CC1CS[C@@H]2C(N[C:31]3[NH:32][C:33]4[C:39]([NH:40]C(=O)C)=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)C(=O)N2C=1C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O)(=O)[CH3:2].C(Cl)[Cl:46]>>[NH2:40][C:39]1[C:33]2[NH:32][CH:31]=[N:35][C:34]=2[CH:36]=[CH:37][CH:38]=1.[C:1]([Cl:46])(=[O:4])[CH3:2]
Reactant: CC(=O)Nc1cccc2nc(NC3C(=O)N4C(C(=O)OC(c5ccccc5)c5ccccc5)=C(COC(C)=O)CS[C@H]34)[nH]c12
Reactant: ClCCl
Product: CC(=O)Cl
Product: Nc1cccc2nc[nH]c12

Procedure:
The diphenylmethyl 3-acetoxymethyl-7-(4-acetylaminobenzimidazol-2-yl)aminoceph-3-em-4-carboxylate used as starting material may be obtained by reaction of the corresponding 4-aminobenzimidazole derivative in dry methylene chloride with excess acetyl chloride and purifying the product by chromatography on silica using CH2Cl2 /MeOH/HOAc 97:1:2 v/v/v as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.I[CH2:17][CH3:18].[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:10]([CH2:17][CH3:18])[S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NC(C)c1cncc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCN(C(C)c1cncc(Br)c1)S(=O)(=O)CC

Procedure:
In analogy to the procedure described for the preparation of intermediate A-42, N-(1-(5-bromopyridin-3-yl)ethyl)ethanesulfonamide (intermediate A-37) was reacted with iodoethane in presence of NaH (60% in mineral oil) to give the title compound as a yellow oil. MS: 321.0 and 323.1 (M+H+).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8](S(O)(=O)=O)=[CH:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1>>[CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[OH:16])[CH:11]=1
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1
Solvent: O=C(Cl)c1ccccc1
Product: Oc1cccc2ccccc12

Procedure:
In an aqueous solvent, 23.9 parts of 7-amino-4-hydroxynaphthalene-2-sulfonic acid is condensed with 14.1 parts of benzoyl chloride according to a normal method to obtain a naphthol derivative.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.O>C(#N)C>[Br:29][C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 2.63 mmol) obtained in Example 3 in acetonitrile (30 mL) was added N-bromosuccinimide (468 mg, 2.63 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 1.10 g (yield: 91%) of the title compound. Melting point: 191-193° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[C:15]1([CH2:21][CH2:22][NH:23][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-phenylethylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To a solution of tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-(2-Phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 52 mg; 13C-NMR (CD3OD, rotamers): δ 27.1, 28.5, 34.9, 36.6, 40.2, 40.4, 44.1, 44.2, 44.4, 53.3, 54.2, 54.6, 114.0, 114.1, 126.2, 126.6, 127.2, 127.4, 128.3, 128.6, 128.79, 128.82, 129.7, 138.5, 139.5, 158.96, 159.0, 172.7, 173.1
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH2:29])=[O:28])[C:21]([O:34][CH3:35])=[CH:20][N:19]=1.C(O)(C)C>C1COCC1.C(OCC)C>[CH3:35][O:34][C:21]1[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH2:29])=[O:28])=[N:23][C:18]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:10]=2)=[N:19][CH:20]=1
Reactant: Nc1cccc(CCN2CCOCC2)c1
Reactant: COc1cnc(Cl)nc1Nc1ccccc1C(N)=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cnc(Nc2cccc(CCN3CCOCC3)c2)nc1Nc1ccccc1C(N)=O
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
3-[2-(4-Morpholinyl)ethyl]aniline (103 mg; 0.5 mmoles) was dissolved in THF (2 mL) and treated with 1 mL of a solution of 1M HCl in ethyl ether. The mixture was stirred for 5 min and then concentrated in vacuo. The residue was treated with 2-{[2-chloro-5-(methoxy)-4-pyrimidinyl]amino}benzamide (139 mg; 0.5 mmoles) and isopropanol (4 mL). The suspension was stirred in a vial, which was sealed and heated at 100° C. for 24 h. Upon cooling, the solid was collected by filtration, washed with cold isopropanol and dried in vacuo to afford the desired product. MS: (M+H)+=449.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:9]([O:11]CC)=[O:10])=[C:4]([CH3:20])[CH:3]=1.Cl>CO.C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:14]([CH3:19])[C:15]([F:16])([F:17])[F:18])[C:9]([OH:11])=[O:10])=[C:4]([CH3:20])[CH:3]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1C)[C@@H](C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)ccc1C(C(=O)O)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.10 g (crude, about 10.04 mmol) of ethyl (3R)-2-(4-chloro-2-methylphenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in a mixture of 10 ml of methanol, 10 ml of THF and 5 ml of water, and 8.03 g of 50% strength aqueous sodium hydroxide solution were added at 0° C. The reaction mixture was stirred at RT overnight. The mixture was then acidified with 1 N hydrochloric acid (pH about 2) and extracted three times with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1 to 4:1). This gave 1.46 g (51.8% of theory) of the target product as a mixture of diastereomers (about 5:1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13](=[O:15])[CH3:14])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.[Br:22]Br.O>CO>[Br:22][CH2:14][C:13]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][CH2:12]1)=[O:15]
Reactant: CC(=O)C1(c2ccc(C(F)(F)F)cc2)CCC1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(CBr)C1(c2ccc(C(F)(F)F)cc2)CCC1
Temperature: 0 °C
Yield: 80 %

Procedure:
1-[1-(4-Trifluoromethyl-phenyl)-cyclobutyl]-ethanone (1.06 g) in methanol (8 mL) was cooled to 0° C. Acetic acid containing 30% HBr (0.35 mL) was added, and then precisely 1 molar equivalent of bromine was added dropwise. The reaction mixture was maintained at 0° C. overnight, poured into 20 mL of water, and extracted with ether. The extracts were dried, filtered, concentrated, and purified on silica gel to give pure 2-bromo-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanone (1.12 g, 80%). Data for this bromoketone: MS 321 (M); 1H NMR (300 MHz, CDCl3) δ 7.82 (d, 8 Hz, 2H), 7.39 (d, 8 Hz, 2H), 3.82 (s, 2H), 2.80-2.95 (m, 2H), 2.45-2.60 (m, 2H), 1.90-2.10 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17].C(=O)([O-])[O-].[K+].[K+].P(OCC)(OCC)(O[CH2:31][CH3:32])=O>O>[CH2:31]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([O:18][CH3:19])=[C:3]([O:20][CH3:21])[C:2]=2[F:1])[C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]1)[CH3:32]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(OC)c(OC)cc2c1=O
Reactant: CCOP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC)c2c(F)c(OC)c(OC)cc2c1=O
Temperature: 120 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
A mixture of ethyl 8-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (41 g, 139 mmol) and potassium carbonate (28.8 g, 208 mmol) in triethyl phosphate (118 ml, 694 mmol) was stirred at 120° C. for 5 h. LCMS indicated completion of the reaction. Then the reaction mixture was cooled down and diluted with water, extracted with DCM, dried over sodium sulfate and evaporated in vacuo. The crude material was purified by reverse phase automatic C-18 column chromatography (Combiflash RF, 130 g column), eluting with Acetonitrile/Water (10-80%) to afford ethyl 1-ethyl-8-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (26 g, 80 mmol, 57.9% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[NH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]#[N:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:36]([CH2:35][CH2:34][O:33][CH2:32][CH2:31][NH:30][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])#[N:37]
Reactant: N#CCCOCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCC#N)ccc21
Yield: 53.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-cyano-ethoxy)-ethyl]-amide (54 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (82 mg), 3-(2-amino-ethoxy)-propionitrile hydrochloride (60 mg), HBTU (91 mg), and DIEA (52 uL). LC/MS: m/z 506.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])[CH3:2].[C-:23]1([NH2:28])[CH:27]=[CH:26][CH:25]=[CH:24]1.[CH-:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1.[Fe+2:34]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:28][C-:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH3:21])[N:15]=1)[CH3:13])[CH3:2].[CH-:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1.[Fe+2:34]
Reactant: N[c-]1cccc1
Reactant: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=O)n1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=N[c-]2cccc2)n1
Reaction time: 40 h

Procedure:
In an inert atmosphere, monoimine 2-[1-(2,6-diethylphenylimino)ethyl]-6-acetylpyridine (8, 368 mg, 1.25 mmol) and ferrocenylamine (268 mg, 1.33 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 40 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 160 mg (27%) red crystals of mixed diimine 9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][C:12]=2[CH2:20][CH:21]=[CH2:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:47][C@@H:48]([NH2:58])[CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:58][C@H:48]([CH3:47])[CH2:49][CH2:50][CH2:51][C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)=[O:19])=[CH:13][C:12]=2[CH2:20][CH:21]=[CH2:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[C@@H](N)CCCc1cccnc1
Reactant: C=CCc1cc(C(=O)O)ccc1-c1ccc(OC)c(OC)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)N[C@H](C)CCCc2cccnc2)ccc1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A solution of 379 mg of 3',4'-dimethoxy-2-(2-propenyl)[1,1'-biphenyl]-4-carboxylic acid in 8 mL of dimethylformamide was cooled in an ice bath and 0.19 mL of triethylamine and 0.30 mL of diphenylphosphorylazide were added. After 1 hour. 0.223 g of (R)-alpha-methyl-3-pyridinebutanamine was added and the reaction mixture was allowed to warm to room temperature over 48 hours. The mixture was diluted with ethyl acetate and washed with water and saturated potassium carbonate, dried. and concentrated. The residue was chromatographed over 50 g of silica gel, eluting with ethyl acetate to afford 527 mg of (R)-3',4'-dimethoxy-2-(2-propenyl)-N-[1-methyl-4-(3-pyridinyl)butyl][1,1'-biphenyl]-4-carboxamide as a water white oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:37])[CH:25]=[CH:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH3:22][O:23][C:24](=[O:37])/[CH:25]=[CH:26]/[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:21][C:16]3[CH:15]=[C:14]([C:12]4[O:13][C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][N:11]=4)[CH:19]=[CH:18][C:17]=3[N:20]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)C=Cc1cc(C)c(C=O)c(C)c1
Reactant: COc1ccc(-c2nnc(-c3ccc(N)c(N)c3)o2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine (564 mg, 2.0 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-acrylic acid methyl ester (436 mg, 2.0 mmol) (Example 1-60, step C) in 10 mL of DMF and 1 mL of water was added oxone (824 mg, 1.34 mmol) and the mixture was stirred at RT for 20 min. Ethyl acetate was added and stirred for a while then water was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure to give the title compound. MS: m/z 481 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([F:22])[CH:3]=1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:3][C:4]=2[F:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2F)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 140 °C
Yield: 62.3 %

Procedure:
A mixture of 77 (312 mg, 0.864 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (62%) of compound 78. 1H NMR (400 MHz, CDCl3): δ1.52 (s, 9H), 1.58 (m, 6H), 2.07 (br s, 2H), 2.25 (br s, 2H), 4.78 (s, 1H), 6.30 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.08 (t, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.49 (d, J=16.0 Hz, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15](O)=[O:16])=[CH:12][C:11]=2[CH:18]=1)#[N:6]>>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]([Cl:3])=[O:16])=[CH:12][C:11]=2[CH:18]=1)#[N:6]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Product: N#Cc1ccc2oc(C(=O)Cl)cc2c1

Procedure:
Thionyl chloride (8 ml, 110 mmol) was added to 5-cyano-2-benzofurancarboxylic acid (1.00 g, 5.34 mmol) and the mixture was refluxed under heating for 30 minutes. Thionyl chloride was distilled away under reduced pressure and toluene (3 ml) was added which was again distilled away under reduced pressure to give 5-cyano-2-benzofurancarbonyl chloride. This was dissolved in toluene (20 ml) and pyridine (0.86 ml, 10.7 mmol), 4-dimethylaminopyridine (131 mg, 1.07 mmol) and t-butyl 4-hydroxycyclohexylacetate (1.35 g, 5.88 mmol) were added. The mixture was refluxed under heating for one hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1-5/1) to give 1.12 g of t-butyl [4-[(5-cyano-2-benzofuranyl)carbonyloxy]cyclohexyloxy]acetate as a colorless solid (52%).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[CH3:10][C:11]([CH3:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:10][C:11]1([CH3:13])[O:7][CH2:6][C:3]([CH2:1][CH3:2])([CH2:8][OH:9])[CH2:4][O:5]1
Reactant: CCC(CO)(CO)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1(CO)COC(C)(C)OC1

Procedure:
2-Ethyl-2-hydroxymethyl-propan-1,3-diol (34 g.), acetone (37 ml.) and p-toluenesulphonic acid (0.5 g.) were refluxed in benzene (140 ml.) and water was removed using Dean and Stark apparatus. After ten hours refluxing the mixture was cooled and washed with saturated aqueous sodium hydrogen carbonate solution. The benzene solution was dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. Distillation gave 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane (35 g.), a colourless oil (bpt) 80°-2° 0.9 mm)2.