Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CO>[C:12]1([S:18][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1ccccc1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=c1[nH]c(Sc2ccccc2)nc2nc[nH]c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 2-bromohypoxanthine (10.0 g, 46.5 mmol) in methanol (200 mL) was added thiophenol (9.55 mL, 93.0 mmol) and diisopropylethylamine (20.2 mL, 116.3 mmol). The reaction was stirred at 90° C. for overnight. The solvent was removed under reduced pressure and the solid was collected by filtration and washed with hexanes (100 mL×2). The collected solid was further purified by re-crystallization from methanol to afford desired product (10.1 g, 89% yield). 1H NMR (400 MHz, (CD3)2SO) δ 7.50(m, 3H), 7.62 (m, 2H), 7.97 (s, 1H); MS (ES) calc'd for C11H8N4OS [MH+] 245.05, found: 245.05.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:33][C:18]1[C:17]2[N:26]=[C:14]([CH2:13][Cl:12])[N:15]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:16]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: [NH4+]
Reactant: CC(C)(O)Cn1c(CCl)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (77% pure, 36.5 g, 163 mmol) was added over 10 minutes to a stirred suspension of 1-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (23.6 g, 81.4 mmol) in chloroform (500 mL). The resulting solution was stirred at room temperature for 1.5 hours. Concentrated ammonium hydroxide (200 mL) was added. After 5 minutes, p-toluenesulfonyl chloride (18.6 g, 97.7 mmol) was added in portions. The mixture was stirred at room temperature for 2.3 hours, then was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (2×100 mL, then 3×200 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a foam. The crude product was purified in portions by chromatography on a HORIZON HPFC system (silica gel, elution with 5% methanol in chloroform followed by gradient elution with 5-15% methanol in chloroform) to yield 9.42 g of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[CH3:13][O:14][CH:15]([O:21]C)[CH2:16][C:17](OC)=O.C(O)(=O)C.Cl>O>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1/[CH:17]=[CH:16]/[C:15]([O:14][CH3:13])=[O:21]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: COC(=O)CC(OC)OC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C=C/c1c(OC)cc(OC)cc1OC
Reaction time: 1 h
Yield: 96.5 %

Procedure:
1.7 g of 1,3,5-trimethoxybenzene, 1.68 g of methyl 3,3-dimethoxypropionate and 12 mL of glacial acetic acid were mixed, 313 mg of 35 wt % hydrochloric acid was added into the mixture at an inner temperature of 25° C., the added mixture was stirred for 1 hour at the same temperature to cause a reaction. After completion of the reaction, 36 mL of water was added dropwise into the reaction liquid, and the precipitated crystals were filtrated. The crystals were washed with 20 vol % of aqueous methanol, then, dried to obtain 2.46 g of methyl trans-3-(2,4,6-trimethoxyphenyl)acrylate (white solid). Yield: 98%.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[K+].O1CCO[CH2:14][CH2:13]1>>[N:9]1[C:2]2[C:3](=[CH:4][CH:13]=[CH:14][N:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncccc1C=O
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Product: c1cnc2ncccc2c1

Procedure:
0.77 g of diacetyltetraphenylmethane obtained by the method described in Example 7 was reacted with 0.51 g of 2-aminonicotinaldehyde and 0.76 g of potassium hydroxide in dioxane and, by treatment in the normal way, TPM-dNTR (0.82 g) shown below was obtained. 1H-NMR (CDCl3, ppm): 9.12 (d·d, 2H), 8.27−8.16 (m, 8H), 8.00 (d, 2H), 7.49−7.44 (m, 6H), 7.34−7.23 (m, 10H)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12]>C(Cl)Cl>[C:2]1([CH:1]2[S:13][CH2:9][CH2:10][CH2:11][S:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: SCCCS
Solvent: ClCCl
Product: c1ccc(C2SCCCS2)cc1
Reaction time: 8 h
Yield: 89 %

Procedure:
Benzaldehyde (11.5 mL, 112 mmol and 1,3-propanedithiol (120 mL, 92.5 mmol) were stirred in methylene chloride (200 mL) at 0° C. and HCl(g) was bubbled into the solution followed by addition of zinc chloride (9 g). The mixture was stirred overnight after which it was poured onto 10% potassium hydroxide solution. The layers were separated and the organic extract was washed with 10% potassium hydroxide solution, water, brine and dried (MgSO4). Evaporation of solvent at reduced pressure afforded an oil which crystallized upon standing and was recrystallized from diethyl ehter to give 16.2 g (89%) of product. 1H NMR (CDCl3) δ: (m, 2H), 5.16 (s, 1H), 7.25-7.36 (m, 3H), 7.45-7.48 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[CH2:10][CH:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:5]2[CH2:10][CH:9]([CH3:11])[CH2:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: CC1Cc2nc(N)[nH]c(=O)c2C1
Reactant: O=P(Cl)(Cl)Cl
Product: CC1Cc2nc(N)nc(Cl)c2C1
Yield: 34 %

Procedure:
Compound 2 (297 mg, 1.8 mmol) and phosphorus oxychloride (15 mL) were heated to reflux for 3 h. The reaction mixture was cooled and evaporated at reduced pressure, and the residue was diluted with chloroform (50 mL) and neutralized with ammonium hydroxide slowly in an ice bath. The organic portion was washed with water (3×30 mL). Solvents were evaporated at reduced pressure, and the residue was purified by column chromatography using chloroform/hexane (4/1) as eluent to afford 112 mg (34%) of 3 as a white-off solid TLC Rf0.48 (CHCl3/CH3OH, 10:1); mp: 181.5-182.9° C., 1H NMR (DMSO-6): δ 1.16-1.18 (d, 3 H, CH3), δ 1.55-1.65, 2.15-2.38, 2.49-2.62, 2.83-2.92 (m, 5 H, CH2CHCH2), δ 6.83 (br, 2H, NH2, exch). Anal. (C8H10ClN3) C, H, N, Cl: calcd, 52.32, 5.49, 22.88, 19.31; found, 52.33, 5.62, 22.63, 19.09.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][CH:11]([O:15][CH2:16][CH3:17])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:14]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccccc1F)OCC
Temperature: 110 °C
Yield: 81 %

Procedure:
A stirred mixture of 2-fluorophenol (1.00 g, 8.92 mmol), 2-bromo-1,1-diethoxyethane (1.75 g, 8.92 mmol), and K2CO3 (1.47 g, 10.7 mmol) in anhydrous DMF (10 mL) was heated at 110° C. overnight. The reaction mixture was poured into ice cold water (15 mL) and extracted with EtOAc (2×100 mL). The EtOAc solution was washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(2,2-diethoxyethoxy)-2-fluorobenzene (1.65 g, 81%) as a viscous liquid. 1H NMR (400 MHz, CDCl3): δ 7.09-6.96 (m, 3H), 6.93-6.87 (m, 1H), 4.85 (t, 1H, J=5.2 Hz), 4.07 (d, 2H, J=5.2 Hz), 3.82-3.74 (m, 2H), 3.69-3.61 (m, 2H), 1.24 (t, 6H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].C[O:22][C:23](=[O:35])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[O:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:33][CH2:32][O:31][C:25]3[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=3[C:23]([OH:35])=[O:22])[CH2:19][CH2:20]2)=[CH:7]1)[CH3:2]
Reactant: COC(=O)c1cc(C)ccc1OCCCl
Reactant: CCOCCn1cc(C2CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOCCn1cc(C2CCN(CCOc3ccc(C)cc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 152 (parts D and E) starting with 0.85 g (3.1 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole, 0.97 g (4.0 mmol) of 2-(2-chloroethoxy)-5-methyl-benzoic acid methyl ester, 0.65 g (4.7 mmol) of potassium carbonate and 0.38 g (2.3 mmol) of potassium iodide. After the saponication and purification through silica gel 0.52 g (36%) of the corresponding carboxylic acid were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCOCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K62) (286 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (393 mg, 88%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10]COC.C(O)(=O)C.S(=O)(=O)(O)O>O>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:5][C:4]=1[CH2:3][CH2:2][OH:1]
Reactant: COCOc1ccc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(CCO)c3)nc2c1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.25 g, 1.27 mmol), 3-(2-hydroxy-ethyl)-4-methoxymethoxy-benzaldehyde (0.268 g, 1.27 mmol), sodium hydrogensulfite (0.146 g, 1:4 mmol) and p-toluenesulfonic acid (0.025 g, 0.127 mmol) in N,N-dimethyl acetamide (8 mL) was stirred at 150° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure. Water (70 mL) was added to obtain a solid. The yellow solid was filtered off, washed with water and dried under vacuum to provide crude 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.182 g, 36.7%) which was used as such in the next step. A solution of 2-[3-(2-hydroxy-ethyl)-4-methoxymethoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.18 g), 50% acetic acid solution (4 mL) and catalytic amount of concentrated sulfuric acid (0.02 mL) was heated at 70° C. for 2.5 h. After cooling to room temperature the reaction mixture was diluted with water (30 mL) to obtain a solid. The solid was filtered off, washed with water and dried under high vacuum to provide crude solid (0.135 g, 85%). The crude was purified by flash column chromatography to give pure 2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.035 g. 8% over 2 steps). Selected data: MS (ES) m/z: 343.0; MP 249-250.3° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[N:24]=[C:25]=[O:26])[CH3:15].N1C=CC=CC=1.Cl>ClCCl>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:17]=1[NH:24][C:25]([NH:13][CH:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:26])[CH3:15]
Reactant: CCc1cccc(CC)c1N=C=O
Reactant: NC1CCC(c2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)NC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-phenylcyclohexylamine in 10 ml of dichloromethane was added 2,6-diethylphenylisocyanate dropwise in the presence of pyridine and the mixture was stirred for 2 hours at room temperature. To the resultant mixture was added 30 ml of diluted hydrochloric acid and the solution was extracted with chloroform. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, and then dried over magnesium sulfate. The solvent was distilled away and the residue was crystallized from methanol to give 0.4 g of N-(2,6-diethylphenyl)-N'-(4-phenylcyclohexyl)urea, melting at 247°-249° C.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:11]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:11]2[CH:10]=[N:9][NH:8][C:13](=[O:14])[C:12]=2[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:26][CH:25]=1
Reactant: O=c1c(-c2ccncc2)c(-c2ccc(F)cc2)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]ncc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of 2-benzyl-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (1.04 g, 2.91 mmol) in toluene (15 mL) was added aluminum chloride (970 mg, 7.28 mmol). The reaction was stirred at 90° C. for 30 min. After cooling to RT, the reaction mixture was poured into water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated aqueous NaHCO3, saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 5-(4-fluorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one as an off-white solid (560 mg, 70%). LC/MS (method A): RT=1.25 min, (M+H)+=268.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]1[CH2:20][CH2:19]1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+]>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH:18]1[CH2:20][CH2:19]1)[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Yield: 58.5 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-2-cyclopropyl-4-hydroxy-1H-indole (367 mg, 1.1 mmol) was alkylated by treating with 0.1 mL (1.1 mmol) of methyl bromoacetate and 43 mg(1.1 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane to give 265 mg(59% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1.CCOCC>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=2)(=[O:21])=[O:22])=[CH:24][CH:25]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (200 mg, 0.80 mmol) in anhydrous pyridine (4 mL) was added dropwise methyl 3-(4-chlorosulfonylphenyl)propionate (251 mg, 0.96 mmol) at rt. After 60 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 200 mg) was added and the resulting mixture was stirred for 1 hr at rt. After filtration and rinsing the resin, water (100 mL) was added into the filtrate. Extraction with EtOAc (100 mL), washing with HCl (1N, 60 mL) and an aqueous saturated solution of NaHCO3 (50 mL), drying over MgSO4 and evaporation under vacuo gave a yellow oil. The residue was taken up in Et2O and a white solid precipitated out. Filtration and washing with Et2O gave the title compound (214 mg) was obtained as a white solid (56%) in 99.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][CH2:2][P:3]([CH2:10][CH:11]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[C:6]([O:5][P:3]([CH2:10][CH:11]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])([CH2:2][NH:1][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:35])=[O:4])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CN)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(CP(=O)(CNC(=O)c1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of di-tert-butyl 2-{[(aminomethyl)-(tert-butoxy)phosphoryl]methyl}pentane-1,5-dioate (1.222 g, 3.0 mmol) and benzoyl chloride (0.46 mL, 4.0 mmol) in dichloromethane (10 mL) was added triethylamine (0.56 mL, 4.0 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (15 mL), washed with 1 N HCl (25 mL), dried over Na2SO4, and concentrated. The crude material was purified by silica gel chromatography (ethyl acetate/hexanes=2/1) to give 1.259 g of colorless oil (74% yield).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]#[CH:18].[CH:23](=[O:25])[CH3:24]>C1COCC1.CCCCCC>[OH:25][CH:23]([CH3:24])[CH:18]=[CH:17][C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C#CC(=O)OCC
Reactant: CC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=CC(C)O
Temperature: -10 °C
Reaction time: 1.17 h

Procedure:
2,2,6,6-Tetramethylpiperidine (74.16 g, 0.525 mot) is dissolved in THF (600 ml) and cooled to −45° C. nBuLi is added (0.022 mol g−1 in hexane, 228.3 g, 0.500 mol) and is allowed to warm to −10° C. The reaction mixture is cooled to −70° C. Then ethyl propiolate (49.05 g, 0.500 mol) is added dropwise over 25 min at ≦−66° C. After additional stirring for 70 min at −72° C., acetaldehyde (23.35 g, 0.530 mol) in cold THF (30 ml) is added dropwise in 30 min at ≦−67° C. After stirring at −72° C. for 1 hour the reaction mixture is quenched with 2 M HCl (700 ml) and extracted with tBuOMe (650 and 400 ml). The organic phases are washed with saturated NaHCO3 (200 ml) and brine (3×125 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. Filtration over SO2 (150 g) with tBuOMe:heptane fraction (0.5 l) and tBuOMe (0.2 l) yields crude 20 (rac-Ethyl 4-hydroxypent-2-enoate) (6744 g, 90%, HPLC: ˜90 area %) as a brown oil. The crude product is used in the next step without further purification. 1H-NMR- and GC-analysis corresponded to an analogous synthesis of 20 (rac-Ethyl 4-hydroxypent-2-inoate) with LDA as base.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].F[B-](F)(F)F.[CH3:14][O+](C)C>C(Cl)Cl>[CH3:14][O:8][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:1]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCCN1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCCCC1

Procedure:
A solution of azepan-2-one (5.0 g, 44 mmol) and trimethyloxonium tetrafluoroborate (7.8 g, 53 mmol) in DCM (30 mL) was stirred at room temperature for 12 h. Then the reaction mixture was quenched with saturated sodium carbonate (50 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired product. MS (ESI): 128 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[NH4+]>O>[C:10]1([CH2:9][CH2:8][NH:16][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1ccccc1
Reactant: Clc1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CCNc2ccncc2)cc1
Yield: 16 %

Procedure:
A mixture composed of 2.0 g (0.0176 m) of 4-chloropyridine and 4.3 g (0.0352 m) of phenethylamine was heated under nitrogen to 160°-165° C for one hour. The mixture was then cooled and 200 mL of a 50/50 mixture of ammonium hydroxide in water was added. The product was extracted into CH2Cl2, which was then concentrated to dryness. The resulting material was purified by HPLC on silica gel, eluting with ethyl acetate to provide 0.560 g of the title product.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:8]([CH2:9]Br)=[C:7]([F:17])[CH:6]=1.O>CN(C=O)C>[Cl:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([F:17])[CH:6]=1
Reactant: CC(C)Oc1cc(CBr)c(F)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(CC#N)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
26 g (0.53 mol) of sodium cyanide was dissolved in 700 ml of DMF, and 143 g (0.50 mol) of 4-chloro-2-fluoro-5-isopropoxybenzyl bromide was dropwise added thereto at room temperature. After stirring at room temperature for 8 hours, the reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 107 g (yield: 92%) of the desired product.