Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23.[CH3:28][N:29](C=O)C>CO.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:22]1[C:21]([C:4]2[C:5]3[O:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]4[C:17](=[O:20])[NH:18][C:19]([C:6]=34)=[C:2]([C:28]#[N:29])[CH:3]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: CN(C)C=O
Reactant: Cc1noc(C)c1-c1cc(Br)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CO
Product: Cc1noc(C)c1-c1cc(C#N)c2[nH]c(=O)n3c2c1OCC3c1ccccc1
Temperature: 150 °C

Procedure:
9-Bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (6.9 mg, 0.016 mmol), zinc cyanide (19 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.8 mg, 0.0024 mmol) were dissolved in DMF (1.6 mL) and the solution was deoxygenated. The stirred reaction mixture was heated at 150° C. in a microwave for 5 min. The mixture was diluted with MeOH and purified by preparative LCMS using pH 10 buffer to give the title compound. LCMS calc. for C21H17N4O3 (M+H)+: m/z=373.1. found: 373.2.
Reaction SMILES: Cl.[N:2](C(OC(C)(C)C)=O)([CH3:21])[C@@H:3]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[NH:2]([CH3:21])[C@@H:3]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The title compound was synthesized as hydrochloride from Boc-N-Me-D-Phe-ProOH (Bajusz et al., J. Med. Chem. 1990, 33, 1729-1735) and 3-(2-amino-ethyl)-2,5-dihydropyrrole-1-(N,N'-di-tert.-butoxycarbonyl) carboxamidine (example 3 k) by the same method as described in example 31). FAB-MS: m/z 412 MH+.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=2[I:15])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=2[I:15])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(C2CCC2)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2CCC2)c(I)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of methyl 4-cyclobutyl-3-iodobenzoate (compound 9.2, 11.0 g, 34.8 mmol) and sodium hydroxide (4.00 g, 100 mmol) in methanol (100 mL) and water (50 mL) was stirred at 50° C. overnight. After cooling to ambient temperature, the volatile solvent was removed under reduced pressure. The residual aqueous material was washed with ethyl acetate (20 mL). The pH of the aqueous was then adjusted to 3-4 with aqueous hydrogen chloride (6 M). The resulting precipitate was collected by filtration and dried to yield the title compound as a white solid (8.60 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: NCCCn1ccnc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1

Procedure:
When 5-chloroisatoic anhydride was reacted with 1H-imidazole-1-propanamine by the procedure of Example 11, the above compound, mp 155°-157° C., was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[CH:8][C:7]([CH2:10][N:11]3C(=O)C4C(=CC=CC=4)C3=O)=[N:6]2)[CH2:3][CH2:2]1.O.NN>C1COCC1.C(O)C.C(OC)(C)(C)C>[CH:1]1([CH2:4][N:5]2[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[N:6]2)[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccn(CC2CC2)n1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: COC(C)(C)C
Product: NCc1ccn(CC2CC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
To a colorless solution of 2-((1-(cyclopropylmethyl)-1H-pyrazol-3-yl)methyl)isoindoline-1,3-dione (example BV; 400 mg, 1.42 mmol) in THF (10 mL) and ethanol (5 mL) was added hydrazine hydrate (0.62 g, 0.60 mL, 12.3 mmol). The white suspension was stirred for 20 h at room temperature, diluted with t-butylmethyl ether (50 mL) and phtalyl hydrazide was removed by filtration. The filtrate was concentrated in vacuo and the crude material was purified by flash chromatography (amino phase, 12 g, 0% to 100% ethyl acetate in heptane) to yield 197 mg (92%) of the title compound as a light yellow oil; MS (EI): 152.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:26]([C:22]3[N:23]=[CH:24][O:25][C:21]=3[CH3:20])=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Cc1ocnc1C(=O)O
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Product: Cc1ocnc1C(=O)Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 5-methyl-4-oxazolecarboxylic acid (CAN 103879-58-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 384.1102 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17]C1C=CC(C)=C(C=1)N.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:17])[CH:12]=[CH:11][C:10]=1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(Cl)cc1N
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: Cc1ccc(Cl)cc1NC(=O)OC(C)(C)C
Yield: 77 %

Procedure:
N-tert-Butoxycarbonyl-4-chloro-2-methylaniline. By the procedure in Example 1, Part C, 28.3 g (0.2 mole) of 5-chloro-2-methylaniline was reacted with 48.1 g (0.22 mol) of di-tert-butyl dicarbonate to give 37.1 g (77% yield) of N-tert-butoxycarbonyl-5-chloro-2-methylaniline melting at 100°-102° C., after crystallizing from hexane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-bromoiodobenzene (10.0 g, 35.3 mmol) in triethylamine (Et3N, 100 mL) was added propargyl alcohol (2.7 mL, 2.57 g, 45.9 mmol), Cul (0.81 g, 4.24 mmol), and Pd(PPh3)4 (1.63 g, 1.41 mmol). The mixture was stirred overnight, then the reaction mixture was concentrated. Column chromatography (20-35% EtOAc/hexanes) provided 1-(4-bromophenyl)-1-propyne-3-ol B (6.58 g, 88%) as a yellow/orange solid. 1H NMR (300 MHz, CDCl3) 1.77 (t, 1H), 4.48 (d, 2H), 7.29 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[CH:15][C:12]=1[C:13]#[N:14].C(OCC)(=O)C.[ClH:28]>C(O)(=O)C>[Cl:28][C:11]1[C:18]([CH3:19])=[C:17]([F:20])[C:16]([F:21])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cl
Reactant: Cc1c(N)c(C#N)cc(F)c1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc(C#N)c1Cl
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Sodium nitrite (5.6 g) is added to conc. sulfuric acid (59 ml) at below 70° C. The mixture is heated at 70° C. for 10 minutes and then cooled, and thereto is added dropwise a solution of 2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) in acetic acid (123 ml) at below 40° C. The mixture is stirred at the same temperature for 30 minutes and then added in portions to a solution of cuprous chloride (20 g) in conc. hydrochloric acid (200 ml), and thereafter is heated at 80° C. for 30 minutes. After cooling, to the reaction mixture is added ice water, and ethyl acetate is distilled off. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane =1:1) to give 2-chloro-4,5-difluoro-3-methylbenzonitrile (8.0 g), as a white crystal, m.p. 59°-61° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[CH:3]=1.[N:22]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:7]([C:8]([N:30]2[CH2:31][CH2:32][CH:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH2:29]2)=[O:10])=[C:6]([CH3:11])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[CH:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(-c2cncc(C(F)(F)F)c2)nc(C)c1C(=O)O
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine (intermediate 6) to give 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid ethyl ester; ii) 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid ethyl ester has been saponified to give 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid; iii) 4,6-dimethyl-5′-trifluoromethyl-[2,3′]bipyridinyl-5-carboxylic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless amorphous solid. MS: 433.3 (MH+).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:9][C:10]([Si:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:12])[CH3:11]>O>[Si:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:10]([CH3:12])([CH3:11])[CH3:9])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-butanediol was added sodium hydride (1.0 g of a 60% dispersion in mineral oil). This mixture was allowed to stir at an ambient temperature for 1 h, before TBDPSCl (5.0 mL, 18.2 mmol) was added. The mixture was stirred overnight at an ambient temperature. The reaction mixture was poured into water and extracted with ether (3×100 mL). The combined extract was washed with water and brine and dried over sodium sulfate. Filtration and concentration gave an oily residue, which was purified via radial chromatography on a 4 mm plate eluting with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexane. This gave 3.36 g (56%) of desired product as clear oil. 1H NMR (CDCl3); δ1.24 (s, 9H), 1.65 (m, 4 h), 3.65 (m, 4H), 7.40 (m, 6H), 7.64 (d, 2H, J=1.5 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Cl:10])[N:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Cl:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1cccc(CCl)n1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 2,6-bis(chloromethyl)pyridine (20 g, 113.6 mmol, 1 eq.) in 250 ml of DMF was added potassium phthalimide (21.04 g, 113.6 mmol, 1 eq.). The reaction was stirred at r.t. overnight then the solvent was evaporated and the residue taken in EtOAc. The insolubles were removed by filtration and the filtrate washed with H2O. The organic layer was separated, dried over MgSO4 and concentrated. The resulting white solid was recrystallised from IPE/EtOAc (1/1) to give 2-{[6-(chloromethyl)pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (22.34 g, 68% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[CH:14]([Li])(CC)[CH3:15].C(I)C>C1COCC1>[CH2:1]([C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7])[CH2:14][CH3:15]
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCI
Product: CCCc1cccc2c1C(=O)NS2(=O)=O
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 28A 10 g (0.051 mol) of 4-methylsaccharin was reacted with 86 ml (0.10 mol) of a 1.18M solution of s-butyl lithium in THF and the resulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide to give 10.15 g (89%) of 4-propylsaccharin, which on reaction with 5.32 ml (0.056 mol) of chloromethyl phenyl sulfide in toluene in the presence of tetrabutylammonium bromide afforded a 65% yield of 2-phenyl-thiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) of which, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDC afforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.N.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC#N)C[C@H]1OC
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Yield: 13 %

Procedure:
A mixture of 3 parts of cis-4-amino-5-chloro-N[1-(2-cyanoethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide and 200 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at 20° C. with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 0.4 parts (13%) of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4piperidinyl]-5-chloro-2-methoxybenzamide; mp. 174.8 (interm. 3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.[NH2:22][C:23]1([C:26]#[N:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:13][C@H:14]([C:15]([NH:22][C:23]2([C:26]#[N:27])[CH2:25][CH2:24]2)=[O:17])[CH2:18][CH2:19][CH3:20])[C:9]([F:10])([F:11])[F:12])=[CH:6][CH:7]=1
Reactant: N#CC1(N)CC1
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentanoic acid (19.0 g, 53.6 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (12.71 g, 107 mmol, synthesized according to O'Donnell, M. J. et al., Synthesis, 1984, 127-128), and HATU (22.42 g, 59.0 mmol) was dissolved in DMF (200 mL) and cooled to −78° C. Diisopropylethylamine (37.35 mL, 214 mmol) was added and after stirring for 1 hour, the cooling bath was removed. The reaction mixture was allowed to stir for an additional 1 hour, whereupon saturated NaHCO3 (300 mL) was added. The product was extracted with ethyl acetate (500 mL), washed with brine (100 mL), 0.25 M citric acid (200 mL), saturated NaHCO3 (200 mL), brine (200 mL), dried over MgSO4/DARCO, filtered through silica, and evaporated to dryness. After eluting the residue through another short plug of silica with 10% ethyl acetate/dichloromethane as mobile phase, the product was concentrated and recrystallized from ether/hexanes to yield N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH2:21][CH2:22][NH2:23])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+].[Cl-].[Na+]>C1(C)C=CC=CC=1.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH2:21][CH2:22][NH:23][CH:2]2[CH2:11][CH2:10][CH2:9][C:8]3[N:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]2=3)[CH:20]=1
Reactant: COc1ccc(F)cc1CCN
Reactant: N#Cc1ccc2c(n1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)cc1CCNC1CCCc2nc(C#N)ccc21

Procedure:
21.98 g (127.66 mmol) of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile, 21.6 g (127.66 mmol) of 2-(5-fluoro-2-methoxyphenyl)ethanamine [CAS Reg.-No. 1000533-03-8] and 3.64 g (19.15 mmol) of p-toluenesulphonic acid monohydrate were dissolved in 511 ml of toluene, and the solution was stirred under reflux overnight using a water separator. 200 ml of toluene were then distilled off and, after cooling, replaced by fresh toluene. The reaction solution was then evaporated to dryness and the resulting residue was taken up in 511 ml of anhydrous ethanol and 511 ml of anhydrous THF. With stirring at a temperature of from 15° to 20° C., 9.66 g (255.32 mmol) of sodium borohydride were added a little at a time to the solution (careful: reaction mixture foams). The reaction solution was then stirred at the same temperature overnight. 10% strength aqueous sodium chloride solution was then added carefully, and the reaction mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and then concentrated to dryness. The residue obtained in this manner was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). This gave 19.5 g (59.93 mmol, 46% of theory) of the target compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[O:22][C:16]=3[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCCC1.[OH-].[Na+]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][C:17]3[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[O:22][C:16]=3[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 0.147 g (0.414 mmol) of methyl 6-(6-phenylhexanoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate in 10 ml of tetrahydrofuran, 1 ml of 1 N aqueous sodium hydroxide was added, followed by stirring at room temperature for 1 day. The reaction mixture was acidified with 10 ml of 1 N hydrochloric acid and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure to yield the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of 1-benzylpyrrolidin-3-one (9.98 g, 57.0 mmol) in THF (57.0 mL) at −20° C. was added to 1.4M MeMgBr (85.4 mL, 120 mmol). When addition was complete, the ice bath was removed and the reaction was allowed to warm to ambient temperature and then quenched with water (200 mL). The mixture was diluted with saturated NH4Cl (200 mL) and ethyl acetate (300 mL) and stirred vigorously for 5 minutes. An inseparable emulsion formed with fine particulates. The reaction mixture was filtered under vacuum and the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL) and the organic layer was washed with brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to an oil which was purified by flash chromatography (0-5% Methanol/DCM) to give (+/−)1-benzyl-3-methylpyrrolidin-3-ol (6.10 g, 31.9 mmol, 56.0% yield).
Reaction SMILES: C[O:2]/[CH:3]=[C:4]1\[CH2:5][CH2:6][C:7]2[C:8]([C:13]#[N:14])=[CH:9][CH:10]=[CH:11][C:12]\1=2.B(Br)(Br)Br>C(Cl)Cl>[CH:3]([CH:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:7]=2[CH2:6][CH2:5]1)=[O:2]
Reactant: CO/C=C1\CCc2c(C#N)cccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc2c1CCC2C=O
Reaction time: 3 h

Procedure:
A solution of (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile (250 mg, 1.05 mmol) in DCM (5 mL) was added BBr3 dropwise at −78° C. under N2. Then the mixture was stirred at this temperature for 3 h. It was poured into ice-saturated NaHCO3 solution, and extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo to give crude 1-formyl-2,3-dihydro-1H-indene-4-carbonitrile, which is used for next step directly. 1H-NMR (400 MHz, CDCl3) δ ppm 9.72 (s, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.34 (t, J=7.6 Hz, 1H), 3.76 (s, 1H), 3.18-3.24 (m, 2H), 2.42-2.58 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30]#[N:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[C:29](=[CH:15]/[C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:13]=2)/[C:30]#[N:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=Cc1ccc(OCCCCCCCCO)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(OCCCCCCCCO)cc2)cc1OC
Yield: 46 %

Procedure:
(2Z)-2-(3,4-dimethoxyphenyl)-3-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 4-[(8-hydroxyoctyl)oxy]benzaldehyde and the commercial (3,4-dimethoxyphenyl)acetonitrile according the same procedure following for example 1 in 46% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.