Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][C:10]([F:19])([F:18])[S:11]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])=[O:12]>C(Cl)(Cl)(Cl)Cl>[F:9][C:10]([F:19])([F:18])[S:11]([O-:14])(=[O:13])=[O:12].[CH2:17]([N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7])[CH:16]=[CH2:15]
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Reactant: Clc1nsc(Cl)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC[n+]1sc(Cl)c(Cl)c1Cl
Product: O=S(=O)([O-])C(F)(F)F
Yield: 22.9 %

Procedure:
Trichloroisothiazole (5.7 g, 0.03 ml) and a solution of allyl trifluoromethane sulfonate (0.03 mol) in CCl4 were heated and excess CCl4 was removed by distillation until the reacting temperature reached 90° C. After heating at 90° for 30 min, the reaction was cooled and 150 ml of ether added. The solid was collected to yield 2.6 g (30%) of product, mp 103-105. Spectral data (NMR and IR) were consistent with the assigned structure.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([F:8])=[CH:6][N:7]=1.[F:9][C:10]1[CH:11]=[C:12]2[C:18]3([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26](C)(C)C)=[O:24])[CH2:19]3)[CH2:17][NH:16][C:13]2=[CH:14][CH:15]=1.Cl[C:31](OC)=[O:32]>>[F:9][C:10]1[CH:11]=[C:12]2[C:18]3([CH2:22][CH2:21][N:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]3)[CH2:17][N:16]([C:31](=[O:32])[NH:2][C:3]3[S:4][C:5]([F:8])=[CH:6][N:7]=3)[C:13]2=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(F)cc32)C1
Reactant: COC(=O)Cl
Reactant: Nc1ncc(F)s1
Agent: Cl
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(F)s1)c1ccc(F)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that 2-amino-5-fluorothiazole hydrochloride was used instead of 2-amino-5-chlorothiazole hydrochloride, that t-butyl 5-fluorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: N1(C2N=C(CC([O-])=O)NC(=O)C=2)CC[O:4]CC1.[Na+].Cl[C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:45])[N:24]2[C:29](=[O:44])[CH2:30][C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:32]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:4][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:45])[N:24]2[C:29](=[O:44])[CH2:30][C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:32]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2c(Cl)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(O)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 107.5 %

Procedure:
The product is prepared by following the procedure described in example 1c using 1.2 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.82 g of 2-methyl-2,3-dihydro-1H-indol-4-ol [reference example 1c] and 1.17 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 1.1 ml of pyridine and 25 ml of N,N-dimethylformamide. After purification of the residue by chromatography on a 90 g cartridge of 15-40 μm silica, elution being carried out with pure dichloromethane and then with 98/2 then 95/5 v/v dichloromethane/methanol mixtures at a flow rate of 80 ml/min, 0.84 g of 2-[2-(4-hydroxy-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one is obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH:17]1([N:20]2[C:24](S(C)(=O)=O)=[N:23][N:22]=[C:21]2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][O:14][C:24]3[N:20]([CH:17]4[CH2:19][CH2:18]4)[C:21]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)=[N:22][N:23]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1nnn(-c2cccc(Cl)c2)n1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from [2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1ccccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccccc2OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 136.3 %

Procedure:
In methanol (20 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) obtained in Example 1 (2) and 2-benzyloxybenzaldehyde (0.7 g). To the solution were added acetic acid (0.15 g) and cyano sodium borohydride (0.16 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was concentrated, to which were added water (50 ml) and ethyl acetate (60 ml), followed by subjecting the mixture to extraction. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(2-benzyloxybenzylamino)-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (1.05 g) as a colorless oily product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:3])[CH3:2])=[C:15]([CH2:20][C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: Oc1ccc(Br)cc1CC(F)(F)F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Br)cc1CC(F)(F)F
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
Acetyl chloride (0.91 mL, 12.8 mmol) followed by triethylamine (1.8 mL, 12.8 mmol) were added to a stirred solution of 4-bromo-2-(2,2,2-trifluoroethyl)phenol (2.55 g, 10.7 mmol) dissolved in CH2Cl3 (20 mL). The reaction was stirred for 45 mins and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (2.50 g). LCMS: apci 297 MH+
Reaction SMILES: C([CH:8]([CH2:10][NH2:11])O)(OC(C)(C)C)=O.[C:12]([OH:18])([C:14]([F:17])([F:16])[F:15])=[O:13]>C(Cl)Cl>[OH:18][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[C:12]([O:18][CH2:8][CH2:10][NH2:11])(=[O:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)C(O)CN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCN
Reaction time: 1 h

Procedure:
A solution was made containing ethanolamine (36.5 ml, 0.6 mol) in chloroform (1000 ml). The Boc2O (13.1 g, 60 mmol) dissolved in chloroform (600 ml) was slowly added dropwise at 0° C. over a 6-hours period (the temperature was maintained all over this period). The reaction was allowed to reach room temperature and was stirred overnight. The organic layer was washed with water (2×500 ml), brine and dried over magnesium sulfate before being concentrated in vacuo. The desired product (9.5 g,>95%) was isolated as a colourless oil and was used without further purification. A solution was made containing the Boc-ethanolamine (1.92 g, 12 mmol) with potassium carbonate (5 g, 36 mmol) in DCM (40 ml). Acetyl chloride (30 ml, 0.42 mol) was added and the reaction stirred for 6 hours at room temperature. The excess of acetyl chloride was removed in vacuo and the crude dissolved in DCM (100 ml). The organic layer was washed with water (50 ml), brine and dried over magnesium sulfate before being concentrated in vacuo. The desired product (1.86 g, 77%) was isolated as a colourless oil and was used without further purification. A solution was made containing the O-acyl, Boc-ethanolamine (1.65 g, 8.1 mmol) in DCM (20 ml) and TFA (20 ml) was added. After one hour at room temperature, the solvent was removed in vacuo. The crude was concentrated from methanol (2–3 times) and from DCM (2–3 times) to give the expected compound (1.75 g, quant.) as an oil used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[NH:5][C:4]1=[O:24])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:7]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:6]=2[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: CCC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 g (0.092 M) of rac-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 200 ml of absolute acetone, treated with 16 g of powdered potassium carbonate and 8 ml of methyl iodide and the mixture is stirred at room temperature. After 1 hour, a further 4 ml of methyl iodide are added and the mixture is stirred for a further 2.5 hours. The undissolved inorganic salts are filtered off under suction and the solution is concentrated. The residue is treated with water, the mixture is extracted with methylene chloride and the extract is dried with sodium sulphate, filtered and concentrated. After crystallisation from ethyl acetate/petroleum ether, there is obtained rac-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 175°-176° C.
Reaction SMILES: [Cl:1]C(C)C[NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].CC1C=C(C)C=C(C)C=1N>[I-].[K+].C(OCC)C>[ClH:1].[CH3:13][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[NH2:4]
Reactant: Cc1cc(C)c(NCC(C)Cl)c(C)c1
Agent: Cc1cc(C)c(N)c(C)c1
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Product: Cl

Procedure:
32.75 g (0.155 moles) of N-(β-chloropropyl)-2,4,6-trimethyl-aniline, prepared as indicated in point (b) above, are reacted with 41.8 g (0.31 moles) of 2,4,6-trimethyl-aniline in the presence of 1.0 g (6 mmoles) of potassium iodide as described in Example 3, Method (b), point (b). The resulting mixture is admixed with 50 ml of diethyl ether, the separated precipitate is filtered off, washed with diethyl ether and dried. 24.8 g (46.6%) of 2,4,6-trimethylaniline hydrochloride are obtained. The filtrate is acidified with isopropanolic hydrochloric acid (acid content: about 15 g/100 ml), and the resulting mixture is maintained at 0° to +5° for 2 hours. The separated precipitate is filtered off, washed with cold isopropanol, and dried. 50.3 g (84.8%) of 1,2-bis(2',4',6'-trimethylphenyl-amino)-propane dihydrochloride are obtained; m.p.: 172°-173° C. The base is liberated from this salt as described in Example 3, Method (b), point (b), and is separated from the reaction mixture by chloroform extraction.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.Cl.[CH3:20][N:21]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[S:22]([CH3:25])(=[O:24])=[O:23].[C:31](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][N:21]([CH:26]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([CH3:31])=[N:6][C:5]=3[CH:4]=2)[CH2:27]1)[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CN(C1CCNC1)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(N2CCOCC2)c2sc(CN3CCC(N(C)S(C)(=O)=O)C3)cc2n1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (500 mg) and N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide hydrochloride salt (370 mg) in acetonitrile (10 mL) was added potassium carbonate (490 mg). The reaction mixture was heated at 80° C. for 16 h and then allowed to cool to room temperature. The mixture was then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) and the organic layer washed with brine (20 mL), dried (MgSO4), reduced in vacuo and purified on column chromatography to give N-methyl-N-[1-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-pyrrolidin-3-yl]-methanesulfonamide as a pale yellow solid (395 mg).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].[NH2-].[Na+].[C:8]1([CH2:14][O:15][CH2:16][C:17]([O:19]C)=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[C:8]1([CH2:14][O:15][CH2:16][C:17](=[O:19])[CH2:1][C:2](=[O:5])[CH2:3][CH3:4])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCC(C)=O
Reactant: COC(=O)COCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Butanone (47.65 ml) was added dropwise over 10 min to a mechanically stirred suspension of sodium amide (95%; 20.78 g) dry ether (600 ml) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 15 min. A solution of methyl phenylmethoxyacetate (48.0 g) in dry ether (50 ml) was added dropwise over 13 min at room temperature under nitrogen, and the reaction progressed according to the method of Intermediate 16, to give the title compound as a yellow oil (23.35 g)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1c(C(=O)c2cccc(N)c2)[nH]c2cc(Cl)ccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2cccc(NS(C)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-acetylamino-2-(3-aminobenzoyl)-6-chloroindole (Example 135) and methanesulfonyl chloride. m.p.: 133-142° C. (ethyl acetate/hexane)
Reaction SMILES: [CH3:1][N:2](C=O)C.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[CH:11][N:10]=1.IC>C([O-])(O)=O.[Na+].C(OCC)(=O)C.C(Cl)Cl>[NH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:1])[CH3:16])[C:12]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[CH:11][N:10]=1
Reactant: CN(C)C=O
Reactant: CNc1cc(Cl)ncc1-c1cnn(C)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CI
Product: CN(C)c1cc(Cl)ncc1-c1cnn(C)c1
Product: N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 1 %
Yield: 92 %

Procedure:
DMF (2.99 mL) was slowly added to stirred sodium hydride (60% in oil; 51 mg, 1.28 mmol) and 2-chloro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-amine (Intermediate I-15) (104 mg, 0.467 mmol) at room temperature. The mixture was warmed to 80° C. for 10 minutes, followed by addition of iodomethane (0.035 mL, 0.560 mmol). The mixture was stirred at 80° C. for 30 minutes, then cooled and diluted with saturated aqueous NaHCO3 (45 mL) and ethyl acetate (70 mL). After stirring for 10 minutes, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×70 mL). The combined organic layers were evaporated onto silica gel. Gradient chromatography, eluting with 1-10% MeOH: 1% NH3 in CH2Cl2 over 10 column volume, gave 2-chloro-N,N-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-amine (102 mg, 0.431 mmol, 92% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Li+].CO.Cl>CCOCC>[C:23]([O:22][C:20](=[O:21])[N:18]([CH:4]([CH2:3][OH:2])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:19])([CH3:24])([CH3:26])[CH3:25]
Reactant: COC(=O)C(C(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)C(CO)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 32.0 g (86.6 mmol) of 2-(N-tert-butoxycarbonyl-N-methyl-amino)-3,3-diphenyl-propanoic acid methyl ester in 400 ml of ether there are added in succession 3.0 g (130.0 mmol) of lithium borohydride in portions and 5.3 ml (130 mmol) of methanol dropwise (foams!). The reaction mixture is stirred under reflux for 3 hours, then cooled in an ice bath, and 40 ml of 0.5N hydrochloric acid are added (foams!). After further dilution with water, the mixture is extracted twice with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, yielding the title compound in the form of a white foam. TLC: methylene chloride/methanol (95:5) Rf=0.46; FAB-MS (M+H)+=342.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12].[CH:13]#[C:14][CH2:15][CH3:16]>C(NCC)C.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12])#[C:14][CH2:15][CH3:16]
Reactant: COCOc1cc(F)ccc1Br
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOCC
Product: CCC#Cc1ccc(F)cc1OCOC
Temperature: 70 °C
Yield: 91 %

Procedure:
1-Bromo-4-fluoro-2-methoxymethoxy-benzene (7.6 g, 32 mmol) is placed in a pressure flask, dissolved in diethylamine (65 mL) and degassed with nitrogen for 15 min. An excess of butyne is bubbled through the solution, CuI (1.9 g, 10 mmol) and PdCl2(PPh3)2 (2.3 g, 3.3 mmol) are added, and the flask is heated to 70° C. for 44 h. The mixture is diluted with ether, then washed with saturated aqueous NH4Cl and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 3% THF/hexane) to provide 6.12 g (91%) of the title compound as an orange solid. GCMS m/e 208 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]1[C:14]2[C:10](=[N:11][O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[Na].[CH:20]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[O:27])([CH3:22])[CH3:21].Cl>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3](=[O:18])[CH:4]([N+:15]([O-:17])=[O:16])[CH:5]([C:6]1[C:14]2[C:10](=[N:11][O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1)[CH:25]([C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[O:29])[C:26](=[O:27])[CH3:28]
Reactant: COC(=O)C(=Cc1cccc2nonc12)[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OC(C)C
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(C(c1cccc2nonc12)C(C(C)=O)C(=O)OC(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.7 g of 3-(2,1,3-benzoxadiazol-4-yl)-2-nitro-propenoic acid methylester (IV,R1 =CH3) in 120 ml of dioxane is added to 4.2 g of the dry sodium salt of acetoacetic acid isopropylester. The suspension is stirred for 3 hours at room temperature. The mixture is poured into 120 ml of ice water and shaken with ether. The aqueous phase is acidified with hydrochloric acid whilst cooling, and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulphate and the solvent is evaporated under vacuum, after which the substance is obtained.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#N)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:37]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:37])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(O)O
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Temperature: -35 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarbonitrile in 150 ml of methylene chloride was placed at -35° C. in a sulphonation flast while gassing with argon and treated within 8 minutes with 40 ml of an about 1.5N solution of diisobutylaluminium hydride in toluene. After completion of the addition, the mixture was stirred for 2 hours at -35° C. and then for a further 1.5 hours with gradual warming to 0° C., before it was treated cautiously with 100 ml of 1N sulphuric acid and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed with 100 ml of 1N sulphuric acid, twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. There were obtained 9.5 g (95%) of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxaldehyde as a colourless, crystalline mass (m.p. 115°-116° C.) which was used in the following step without further purification. Rf value [toluene/ethyl acetate (19:1)]: educt 0.65, product 0.52.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>C1C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][N:17]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: CN(C)CCCN
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: CN(C)CCCN=Cc1ccc2c(c1)OCO2
Yield: 75.2 %

Procedure:
Interaction of 50 g of piperonal and 34 g of 3-dimethylaminopropylamine in 240 ml. of benzene following the procedure described in Example 1 yields 58.6 g of the product as an oil, boiling point 131°-136° C. at 0.2-0.3 mm. of Hg.