Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17]#[N:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12.C(O)(=O)C.[Cl-].[NH4+:28]>CO>[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][C:8]1[N:9]=[C:10]([C:17](=[NH:28])[NH2:18])[N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12
Reactant: [NH4+]
Reactant: N#Cc1nc(Cc2ccccc2F)c2ncccn12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nc(Cc2ccccc2F)c2ncccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, 6.98 g (32.30 mmol) of sodium methylate (25% solution in methanol) was put in 50 ml methanol and 8.000 g (30.76 mmol) of 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carbonitrile dissolved in 40 ml of absolute methanol was added. The reaction mixture was stirred for 1 h at RT. 7.205 g (119.98 mmol) of acetic acid and 1.975 g (36.92 mmol) of ammonium chloride were added and the mixture was stirred for 2 h at 50° C. The reaction mixture was concentrated by evaporation and the residue was distributed between 150 ml water and 100 ml ethyl acetate. The aqueous phase was made basic (pH=10) with 2N sodium hydroxide solution and the phases were stirred for 1 h at RT. Water was added and it was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, concentrated by evaporation and the residue was dried under high vacuum. 7.53 g (purity 73%, 66% of theor.) of the target compound was obtained.
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][O:8]C.C([Li])(C)(C)C.[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1/[CH:25]=[CH:26]/[C:27]([CH3:29])=O.Cl>CCOCC>[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:23])([CH3:24])[C:18]=1/[CH:25]=[CH:26]/[C:27](/[CH3:29])=[CH:8]/[CH:7]=[CH:6]/[C:5](/[CH3:10])=[CH:4]/[CH:3]=[O:2]
Reactant: COC=CC(C)=CC=CBr
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
6-Bromo-3-methyl-1-methoxy-1,3,5-hexatriene (0.257 g; 1.26 mmol) dissolved in ether (10 cc) is introduced, under an argon atmosphere, into a 25 cc round flask fitted with a thermometer and a magnetic stirrer. The flask is cooled to -70° C. tert-Butyllithium (1.2 cc, 1.8N in pentane; 2.1 mmol, i.e. 1.7 equivalent) is then added over 7 minutes while the temperature is kept below -68° C. The solution becomes slightly coloured from pale yellow to light chestnut-brown. It is stirred for 90 minutes at -70° C. β-Ionone (0.23 g; 1.196 mmol, i.e. 0.85 equivalent) dissolved in ether (3 cc) is then added. The mixture is stirred for 90 minutes at -30° C. 1N hydrochloric acid (4.5 cc) is added at -60° C. and the mixture is then stirred vigorously for 1 hour at 10° C. After phase separation, extraction with ether and evaporation of the solvent, a crude product (0.44 g) is obtained, which is purified by flash chromatography on silica, eluting with a mixture of petroleum ether and diethyl ether (98/2 by volume). Retinal (0.187 g) is obtained in this manner in 55% yield. The structure of the product is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C.[OH-].[Na+]>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH3:28]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1nccs1)C2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCCCC1CCN(c1nccs1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 53 (0.53 g, 1.62 mmol) in DCE (25 mL) were added successively formaldehyde (35% solution in H2O, 0.2 mL, 2.43 mmol), Na(OAc)3BH (1.03 g, 4.86 mmol) and acetic acid (0.2 mL) at 0° C., and the solution was allowed to stir at rt for 16 hours. The reaction mixture was diluted with ethyl acetate and basified with 1N NaOH solution. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by chromatography on neutral alumina eluting 1% methanol-DCM to get compound 54.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH2:30])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH:30][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15]
Reactant: CCn1c2ccccc2c2cc(CN)ccc21
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)NC(=O)OC(C)(C)C)ccc21
Yield: 77.3 %

Procedure:
A solution of 2-((tert-butoxycarbonyl)amino)propanoic acid (200 mg, 1.06 mmol), (9-ethyl-9H-carbazol-3-yl)methanamine (237 mg, 1.06 mmol), HATU (522 mg, 1.37 mmol) and TEA (0.442 mL, 3.17 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 60% ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give tert-butyl (1-(((9-ethyl-9H-carbazol-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (324 mg, 0.819 mmol, 78%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:21]=1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[ClH:15].[CH3:32][O:31][C:29]1[C:28]([O:33][CH3:34])=[CH:27][C:21]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[C:20]([NH:19][CH2:18][CH2:17][CH2:16][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:30]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc(NCCCCl)c(C(=O)N(C)C)cc1OC
Product: COc1cc(NCCCN2CCN(c3ccccc3OC)CC2)c(C(=O)N(C)C)cc1OC
Product: Cl

Procedure:
substituting 1-(2-methoxyphenyl)piperazine and 2-(3-chloropropyl)amino-4,5-dimethoxy-N,N-dimethylbenzamide gave 4,5-dimethoxy-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N,-dimethylbenzamide hydrochloride, m.p. 79°-82° C.; Anal.: Calcd. for C25H36N4O4.HCl.(H2O)0.25 : C, 60.35; H, 7.60; N, 11.26%; Found: C, 60.18H, 7.75; N, 11.35%;
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1=O>[N:17]1[CH:18]=[CH:19][CH:14]=[CH:15][C:16]=1[C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1(c2ccccn2)CCNCC1

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 μL) and the resulting solution heated at 100° for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL) and washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2 Cl2) to afford ethyl 4-(pyridyl)piperidin-4-yl-carboxylate as a crystalline solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[S:11][C:12]1[C:17]([C:18]([NH:20][CH2:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[S:11][C:12]1[C:17]([C:18]([NH:20][CH2:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(OC)c(Sc2ncccc2C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccnc1Sc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of the dimethoxy compound from Example 37 (1.0 g) in dichloromethane (20 ml) at −78° C., was added boron tribromide (5.5 ml of a 1M solution in dichloromethane. The reaction mixture was stirred for 24 hours, warming to ambient temperature. Methanol (5 ml) was added and the solvent was removed under reduced pressure and the residue purified by silica gel chromatography eluting with dichloromethane, ethyl acetate, acetic acid (4:1:0.1). The fractions containing product were combined and the solvent removed under reduced pressure to give the title compound as a white solid (0.40 g).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:26]I>ClCCl.C(Cl)(Cl)Cl>[Br:25][C:21]1[CH:20]=[C:19]([N:18]2[CH:2]([CH2:3][I:26])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])[CH:24]=[CH:23][CH:22]=1
Reactant: II
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.14 g, 0.35 mmol) (from Example 17, Step E, supra) in dichloromethane (20 mL) was added I2 (0.23 g, 1.75 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL) and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired 4-(3-bromo-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a pale yellow foam. (Yield 0.12 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][I:22]>CC#N>[I-:22].[C:1]([O:5][C:6]([NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([N:15]2[CH:19]=[CH:18][N+:17]([CH3:21])=[CH:16]2)=[O:14])[CH2:9]1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)n2ccnc2)C1
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N2CCC(NC(=O)OC(C)(C)C)C2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.9 %

Procedure:
To a suspension of [1-(imidazole-1-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (preparation #2) (5.1 g, 18 mmol) in MeCN (50 mL) was added methyl iodide (4.5 mL, 73 mmol) and the reaction mixture was stirred at ambient temperature for about 1.5 h. Additional methyl iodide (2.0 mL, 32 mol) was added and stirring resumed for about 16 h. The reaction mixture was concentrated in vacuo to afford 3-(3-tert-butoxycarbonylamino-pyrrolidine-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (1.89 g, 100%) as an orange solid which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 1.77 min; m/z: (M+H)+ 295.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=O)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[S:26])[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1
Reactant: O=C1Nc2c(Cl)cc(Cl)cc2C2CCCC12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: S=C1Nc2c(Cl)cc(Cl)cc2C2CCCC12

Procedure:
6,8-Dichloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (100 mg, 0.39 mmol) is heated with Lawesson's reagent (412 mg, 1.02 mmol) for 2 hours in THF (20 ml). The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 100 mg (94%) of product.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH:10]2[Si:16]([CH3:19])([CH3:18])Cl>>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][Si:16]([CH:10]1[CH2:11][CH:12]2[CH2:15][CH:9]1[CH2:14][CH2:13]2)([CH3:19])[CH3:18])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C[Si](C)(Cl)C1CC2CCC1C2
Product: C[Si](C)(OS(=O)(=O)C(F)(F)F)C1CC2CCC1C2
Temperature: 60 °C

Procedure:
At room temperature, trifluoromethanesulfonic acid (7.50 g, 49.0 mmol) is added dropwise to 2-norbornyl-dimethylchlorosilane (9.50 g, 49.3 mmol), whose preparation is described in Example 1. The reaction mixture is heated to 60° C. for 10 h. The crude product is distilled under oil pump vacuum. 12.3 g (83%) of colorless, moisture-sensitive liquid having b.p. 100-105° C. (1 mbar) is obtained. Purity 93% (GC).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][C@H:37]([OH:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NC[C@H](O)c2ccccc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (1R)-2-amino-1-phenylethanol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=494.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.[Br:11][C:12]1[CH:17]=[CH:16][C:15](I)=[C:14]([CH3:19])[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: CC1CCN(CCN)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(Br)ccc1NCCN1CCC(C)CC1

Procedure:
5.00 g (35.00 mmol) of 2-(4-methylpiperidin-1-yl)ethylamine was added under argon to a mixture of 10.39 g (35.00 mmol) of 4-bromo-1-iodo-2-methylbenzene, 0.33 g (1.75 mmol) of CuI, 30.0 g (141.00 mmol) of potassium phosphate, and 4.34 g (70.00 mmol) of ethylene glycol in 35 mL of isopropanol and the mixture was refluxed for 15 hours. The reaction mixture was evaporated down in vacuo and the residue taken up in EtOAc. The organic phase was washed with 5% aqueous ammonia, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, EtOAc). Yield: 1.20 g (11% of theoretical); C15H23BrN2 (M=311.261); calc.: molpeak (M+H)+: 311/313 (Br); found: molpeak (M+H)+: 311/313 (Br); HPLC-MS: 4.24 minutes (method B).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]#N)[CH2:4][CH2:3]1.[Mg].[CH2:16](Br)[CH3:17].Cl.CC[O:22]CC>>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](=[O:22])[CH2:16][CH3:17])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C#N)c2ccccc21
Reactant: CCOCC
Reactant: CCBr
Agent: Cl
Agent: [Mg]
Product: CCC(=O)C1CCC(C)(C)c2ccccc21
Yield: 55 %

Procedure:
61.8 g of 1,1-dimethyl-4-cyano-tetralin in 100 ml of absolute ether are added dropwise while stirring to a Grignard solution prepared from 600 ml of ether, 34.7 g of magnesium shavings and 166 g of ethyl bromide. The mixture is held at reflux temperature for 6 hours, cooled and acidified with 10% hydrochloric acid. The aqueous phase is separated as rapidly as possible and held at reflux temperature for 1 hour. It is cooled, extracted with ether, washed neutral with water, dried over sodium sulphate and evaporated. Distillation in vacuo gives 39.4 g of 1,1-dimethyl-4-propionyl-tetralin of boiling point 75° C./0.05 mmHg; nD20 =1.5263; yield 55%. Odour: rose note, tobacco-like (light), dried fruits, berries, damascone, honey.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:42]([OH:45])(=[S:44])[CH3:43]>CN(C)C=O.ClCCl>[CH3:1][N:2]1[CH2:6][C@@H:5]([S:44][C:42](=[O:45])[CH3:43])[CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9]
Reactant: CC(O)=S
Reactant: CN1C[C@H](O)C[C@H]1C(N)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C(N)=O)N(C)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
(2S,4R)-1-Methyl-2-aminocarbonyl-4-hydroxypyrrolidine (540 mg) was dissolved in dry dimethylformamide (10 ml), and triphenylphosphine (1.78 g) was added thereto. To the resultant mixture, diethyl azodicarboxylate (1.07 ml) was added under nitrogen steam while ice-cooling, and the mixture was stirred for 35 minutes. Thioacetic acid (0.76 ml) was added to the mixture under ice-cooling, and stirring was continued for 30 minutes under ice-cooling and at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2S,4S)-1-methyl-2-aminocarbonyl-4-acetylthiopyrrolidine.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH:9]3[CH2:11][C:5]([OH:12])([CH2:6][CH:7]1[CH2:8]3)[CH2:4]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>CS(C)=O.CCOC(C)=O>[OH:12][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:6]1)[C:3]([NH:2][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22])([CH2:10]3)[CH2:4]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(O)(C3)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a stirred mixture of the compound obtained in step I (280 mg, 1.5 mmol) and K2CO3 (820 mg, 6 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (205 mg, 1.2 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-hydroxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile as a viscous liquid (150 mg) in 35% yield. m/z (M+1) 291; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.0 Hz, 1H), 3.75-3.38 (m, 2H), 3.43 (s, 2H), 2.45-37 (m 1H), 2.35-1.95 (m, 8H), 1.90-1.60 (m, 6H), 1.53-1.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnc(F)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoropyridine-4-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.74 min; Mass spectrum (ESI+): m/z=400 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=O)=[O:6].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:39]1([CH2:44][CH2:45][CH2:46][S:47]([C:50]2[CH:55]=[CH:54][C:53]([NH:56][C:57]3[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][N:58]=3)=[CH:52][CH:51]=2)(=[O:49])=[O:48])[CH2:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CN(C=O)C>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([CH3:1])[CH:3]=2)=[CH:16][C:12]=1[C:13]([NH:63][C:60]1[CH:61]=[N:62][C:57]([NH:56][C:53]2[CH:54]=[CH:55][C:50]([S:47]([CH2:46][CH2:45][CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)(=[O:48])=[O:49])=[CH:51][CH:52]=2)=[N:58][CH:59]=1)=[O:15]
Reactant: Cc1cccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)c1
Reactant: Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)CCCN5CCCC5)cc4)nc3)c2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 44.7 %

Procedure:
To a solution of intermediate 4 (Example 7) (290 mg, 1 mmol) in anhydrous CH2Cl2 (30 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (210 mg, 1.2 mmol) and 4-methylmorpholine (300 mg, 3 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 2 (Example 3) (100 mg, 0.3 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a white solid (85 mg, 13%).