Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)(=O)C>C(O)C>[CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH2:14][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1nc(C=O)cc(C(F)(F)F)n1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCSc1nc(CN2CCOCC2)cc(C(F)(F)F)n1

Procedure:
2-Hexylsulfanyl-6-trifluoromethyl-pyrimidine-4-carbaldehyde (0.5 g, 1.7 mmol) and morpholine (0.16 mL, 1.9 mmol) were dissolved in ethanol (5 mL) and acetic acid (0.5 mL) and treated with borane-pyridine complex (0.19 mL, 1.9 mmol) for 4 h at 20° C. The reaction mixture was evaporated to dryness. Extraction: 2×AcOEt, 1×10% aqueous Na2CO3. One obtained a mixture of the expected product and the reduced aldehyde which was more polar. This mixture was separated by chromatography on Si-amine from Silicycle with a gradient of heptane/ethyl acetate from 10:1 up to 1:1. Gave 220 mg (35%) of a colorless oil. MS: m/z=364 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29].[I-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][CH2:24][NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])=[CH:8][CH:7]=1
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(Oc2cccc(Cl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)NCCOc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
To a solution of 13.2 g of 4-(3-chlorophenoxy)phenol (m.p. 53°-54° C.) are added 16.6 g of finely powdered potassium carbonate, 13.6 g of ethyl 2-chloroethylcarbamate and 1 g of powdered potassium iodide. With stirring, the reaction mixture is heated to +95° C. over 15 hours and then filtered. The filtrate is taken up in ice-water and extracted three times with ether. The organic extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by chromatography over silica gel with a 1:3 mixture of ether/hexane to give the pure ethyl 2-[4-(3-chlorophenoxy)phenoxy]ethylcarbamate of m.p. 45°-46° C. The 1H-NMR spectrum is in conformity with the indicated structure.
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH3:11]OC(OC)OC>CO>[CH3:11][O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)CCCC(=O)O
Reactant: COC(OC)OC
Solvent: CO
Product: COC(=O)CCCS(N)(=O)=O
Temperature: 60 °C
Reaction time: 19 h
Yield: 99 %

Procedure:
A mixture of 4-sulfamoylbutyric acid (2.53 g, 15.1 mmol), methanol (25 ml), trimethylorthoformate (10 ml, approx 5 eq) and polystyrene-bound toluenesulfonic acid (0.58 g) was stirred at 60° C. After 19 h the mixture was decantated from the catalyst and concentrated to yield 2.70 g (99%) of the title ester as an oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14]I)[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][N:25]=[N+:26]=[N-:27])[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CI)O2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 90 %

Procedure:
To a stirred solution of the 3'-O-t-butyldimethylsilyl-5'-iodo-5'-deoxythymidine (10.8 g, 20 mmol) prepared according to the method of Example 25 in dry DMF (50 ml) was added sodium azide (3.9 g, 60 mmol) and the mixture heated at 0° C. for 12 hours. Then the reaction mixture was diluted with ethyl acetate (200 ml) washed with water (2×50 ml) and brine (50 ml) and then dried with sodium sulfate. The title compound was purified by flash chromatography using 50% ethyl acetate in hexance in 90% yield.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:37][CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41].C[O-].[Na+]>CCO>[F:29][C:27]1[CH:28]=[C:23]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:9]=3)[C:14]([OH:15])=[C:5]([C:3]([NH:37][CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41])=[O:4])[N:6]=2)[CH:24]=[N:25][CH:26]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A mixture of 1-(5-fluoro-pyridin-3-yl)-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (51 mg, 0.13 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (121 mg, 0.52 mmol) and NaOMe (56 mg, 1.05 mmol) in EtOH (3 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (20 mL) and EtOAc (20 mL). 1 M HCl was added with vigorous stirring until pH was ˜3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-35% EtOAc/hexanes+2% AcOH) to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 476.14 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11](=O)[N:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11](=[S:29])[N:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1nc(=O)c2ccccc2n1-c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCc1nc(=S)c2ccccc2n1-c1ccccc1
Reaction time: 1 h

Procedure:
1.50 g (5.99 mmol) 2-ethyl-1-phenyl-1H-quinazolin-4-one and 2.42 g (5.99 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were suspended in 40 ml toluene and boiled for 1 h. After evaporation the crude mixture was purified by column chromatography on silica gel, eluent dichloromethane/acetone 95/5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[O:23])=[C:3]([OH:13])[C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 44.3 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40mg, 0.18mmol) and 2-chlorophenylisocyanate (33 mg, 0.22 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), followed by recrystallization from acetone and hexane, gave the desired product (30 mg, 44%). EI-MS (m/z) 374.3, 376.1 (M−).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])/[CH:10]=[C:11](\[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)/[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](#[N:25])[CH2:23][CH3:24]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:8][C:9]([C:10]1[C:22]([CH2:23][CH3:24])=[N:25][N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C(=C/C(=O)OCc1ccccc1)Nc1ccc(F)cc1
Reactant: CCC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccc(F)cc2)c(C)c1C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
According to AVV A, (Z-3-(4-fluorophenylamino)-but-2-enoic acid benzylester (285.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. After purification by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→70:30→0:100), the product was obtained in the form of a yellow oil (283.0 mg, 0.84 mmol, 84%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]>[Pd]>[C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)C=Cc1ccccc1CC#N
Agent: [Pd]
Product: CCOC(=O)CCc1ccccc1CC#N

Procedure:
Reagent XV is prepared from ethyl o-bromomethylcinnamate by the following series of reactions. (1) The starting ester is heated with a solution of sodium cyanide in ethanol to yield ethyl o-cyanomethylcinnamate. (2) This ester is hydrogenated over a Pt or Pd catalyst to afford ethyl o-cyanomethylhydrocinnamate. (3) This ester is reduced with sodium bis(2-methoxyethoxy)aluminum hydride in benzene to yield [2-(3-hydroxypropyl)phenyl]acetonitrile. (4) The nitrile is hydrolyzed by being heated with aqueous-ethanolic sodium hydroxide solution, and the acid is esterified (ethanol and mineral acid catalyst) to give ethyl [2-(3-hydroxypropyl)phenyl]acetate. (5) This hydroxyester is treated with phosphorous tribromide in ether to afford reagent XV.
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.Cl.[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.CCOC(C)=O>[C:14]([C:18]1[O:22][N:21]=[C:20]([NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:11][CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)=[O:25])[CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=CC1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2CC2CCOCC2)no1
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (0.19 g, 3.02 mmol) and tetrahydro-pyran-4-carbaldehyde (0.26 g, 2.26 mmol) is added to a solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.4 g, 1.51 mmol) in DMF (5.0 mL). After stirring for four hours, the reaction mixture is diluted with EtOAc and washed twice with water. The organic phase is dried over anhydrous Na2SO4 and after removal of the solvent under reduced pressure, the crude is purified by prep TLC to afford the title compound; m/z 364 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[C:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)#[C:26][CH3:27]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)c(-c3ccccc3)coc2c1

Procedure:
A mixture of 7-hydroxyisoflavone (2.38 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.1 g of a product with the following characteristics: m.p. 130-131° C.; 1H NMR (CDCl3) δ: 2.6 (m, 1H), 4.8 (s, 2H), 6.99-8.28 (m, 7H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][C:18](OCC)=[O:19]>C(O)C>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[S:14][CH:17]=[C:18]([OH:19])[N:15]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=S)Nc1ccn(-c2ccccc2)n1
Reactant: CCOC(=O)CCl
Solvent: CCO
Product: Oc1csc(Nc2ccn(-c3ccccc3)n2)n1

Procedure:
A solution of N-(1-phenyl-1H-pyrazol-3-yl)thiourea (4.2 g) and ethyl 2-chloroethanoate (3.0 g) in ethyl alcohol (50 ml) was heated under reflux for 2 hours. The mixture was cooled and the title compound collected by filtration as a yellow solid 4.0 g, mp >230°.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[CH:15](=O)[CH:16]([CH3:18])[CH3:17].[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:15]([NH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1)[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)[C@H](NCC(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (5.23 mmol, 1 eq) in MeOH (50 ml) there were added first acetic acid (2 drops) and then, at 0° C., isobutyraldehyde (0.47 ml, 5.23 mmol, 1 eq), and stirring was carried out for 1 h at RT. The reaction mixture was cooled to 0° C. again, NaCNBH3 (821 mg, 13.07 mmol, 2.5 eq) was added, and stirring was carried out for a further 30 min at RT. After monitoring by thin-layer chromatography, the reaction mixture was concentrated, and the residue was taken up in water (50 ml) and extracted with dichloromethane (2×75 ml). The combined organic phases were washed with sat. NaCl solution (2×60 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (Alox neutral, 3% MeOH in dichloromethane), the desired product was obtained. Yield: 65% (0.850 g, 33.44 mmol).
Reaction SMILES: [C:1]([N:11]([CH3:38])[CH2:12][CH2:13][C:14]([O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:19]([C:20](=O)[CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C:26]2=[O:36])[CH2:18]1)=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:40][OH:41]>>[C:1]([N:11]([CH2:12][CH2:13][C:14]([O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:19](/[C:20](=[N:40]/[OH:41])/[CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C:26]2=[O:36])[CH2:18]1)=[O:15])[CH3:38])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CN(CCC(=O)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)C(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Product: CN(CCC(=O)O[C@H]1CC[C@@]2(C)C(C1)/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)C(=O)OCc1ccccc1
Yield: 60 %

Procedure:
The procedure described in Prepn. 20 was followed starting from 3β-(N-carbobenzyloxy-N-methyl-3-aminopropionyloxy)androstane-6,17-dione (0.70 g) and hydroxylamine hydrochloride. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 60/40) to give the title compound (0.43 g, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.31 (1H, s), 7.30 (5H, m), 5.05 (2H, s), 4.56 (1H, m), 3.50-0.87 (27H, m), 0.78 (3H, s), 0.68 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CN(C=O)C.C(OCC)(=O)C>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:10][CH:9]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Potassium carbonate (1.45 g, 10.47 mmol) and 4-chlorobenzyl chloride (1.82 g, 8.86 mmol) were added to a solution of tert-butyl piperazine-1-carboxylate (1.5 g, 8.05 mmol) in DMF (10 ml), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford tert-butyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (2.50 g, quantitative) as a colorless oil.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)=O>O>[C:7]1([C:13]#[C:14][C:1]([OH:2])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cs+]
Solvent: O
Product: O=C(O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4,7-Diphenyl-1,10-phenanthroline)bis[tris(p-fluorophenyl)phosphine]copper(I) nitrate (10.9 mg, 0.01 mmol) and cesium carbonate (391 mg, 1.20 mmol) were placed in a flask. The reaction vessel was then flushed with nitrogen and closed by means of a septum. Degassed DMF (3.00 ml) was subsequently added and the resulting mixture was stirred for 5 minutes at room temperature. After repeated evacuation and admission of CO2 into the reaction vessel, phenylacetylene (110 μL, 1.00 mmol) was injected. The reaction mixture was stirred at 35° C. and 5 bar of CO2 pressure in a steel autoclave for 12 hours. After the reaction time had expired, the reaction mixture was cooled to room temperature, diluted with water and extracted three times with 100 ml each time of n-hexane. The aqueous fraction was admixed with dilute HCl (1N, 10.0 ml), forming a colorless solid which was filtered off and purified further by recrystallization from water and ethanol. The purified colorless solid (143 mg, 98%) having a melting point of 133-134° C. could be identified as the desired reaction product.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][PH2:9]=[O:10])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][PH2:9]=[O:10])=[CH:6][CH:5]=1
Reactant: O=[PH2]Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C[PH2]=O)cc1
Reaction time: 24 h
Yield: 59.7 %

Procedure:
A mixture of 1-(4-nitrobenzyl)phosphorane-1-oxide (1.80 g) and 10% Pd—C (0.2 g) in ethanol (30 ml) was vigorously stirred under hydrogen atmosphere for 24 hours, and the catalyst was filtered off. The filtrate was concentrated and purified with column chromatography (ethanol/ethyl acetate=1:2) and recrystallized from ethanol-diethylether to give 1-(4-aminobenzyl)phosphorane-1-oxide (0.90 g) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. LC-MS: 720.3 [(M+H)+]
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([O-:12])(=[O:11])=[O:10])[CH:4]=1.[Na+].[CH:14](OC)(OC)OC>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([O:12][CH3:14])(=[O:11])=[O:10])[CH:4]=1
Reactant: C=Cc1cccc(S(=O)(=O)[O-])c1
Reactant: COC(OC)OC
Agent: [Na+]
Product: C=Cc1cccc(S(=O)(=O)OC)c1

Procedure:
Next, the desalted product of sodium m-styrenesulfonate was subjected to methyl esterification with trimethyl orthoformate by following the same procedure as in Example Y-1, whereby methyl m-styrenesulfonate was obtained.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4]>O.CO>[CH2:3]([O:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A solution of potassium hydroxide (1.3 g, 22.2 mol) in water (20 ml) was added to a stirred solution of ethyl 2-ethoxy-3-(3-nitrophenyl)acrylate (5.6 g, 21.1 mmol) in methanol (100 ml) and the resulting mixture heated to reflux overnight. The methanol was then evaporated in vacuo and the residue diluted with water (150 ml). The solution was washed with dichloromethane (2×80 ml), filtered through a pad of celite and then acidified by the addition of 3M HCl to pH 3. The mixture was refrigerated for 18 h then the precipitated solid was collected by filtration, washed with water (3×30 ml) and dried in vacuo at 40° C. The resulting solid was recrystallized from ethyl acetate and heptane to give 2-ethoxy-3-(3-nitrophenyl)acrylic acid as a yellow solid (3.06 g, 61%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
5.00 g of diethyl aminomalonate hydrochloride and 4.78 g of triethylamine were added to 100 ml of chloroform, and the resulting solution was stirred at the room temperature for 30 minutes. After cooling down the solution to 10° C., 4.13 g of 4-chlorobenzoylchloride was slowly added to the solution and the resulting solution was stirred at the room temperature for 2 hours. Upon the completion of the reaction, the solution was washed with 20 ml of water and 20 ml of 5% sodium bicarbonate and the organic layer was subjected to dry filtration to yield 6.70 g (90.4%) of diethyl 4-chlorobenzamidomalonate.