Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][CH:15]([CH2:25][N:26]1[C:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:31]=[CH:30][C:29]=2[N:28]=[C:27]1[CH2:39]Cl)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>O1CCCC1>[Si:7]([O:14][CH:15]1[CH2:25][N:26]2[C:38]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][C:29]=3[N:28]=[C:27]2[CH2:39][N:17]([C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC(Cn1c(CCl)nc2cnc3ccccc3c21)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2nc3cnc4ccccc4c3n2CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Potassium tert-butoxide (116.1 mL of a 1M solution in tetrahydrofuran) was added to a solution of tert-butyl 2-{[tert-butyl(dimethyl)silyl]oxy}-3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (42.72 g, 84.57 mmol) in anhydrous tetrahydrofuran (THF) (50 mL), and the reaction was stirred overnight at ambient temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 99:1 to 95:5) to provide 20.23 g of tert-butyl 11-{[tert-butyl(dimethyl)silyl]oxy}-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.Br[CH2:30][C:31]1[CH:35]=[C:34]([CH3:36])[O:33][N:32]=1.C(OC([N:44]1[CH2:49][CH2:48][O:47][C@H:46]([CH2:50][C:51]2[CH:56]=[C:55]([F:57])[C:54]([OH:58])=[CH:53][C:52]=2[F:59])[CH2:45]1)=O)(C)(C)C>>[F:59][C:52]1[CH:53]=[C:54]([O:58][CH2:30][C:31]2[CH:35]=[C:34]([CH3:36])[O:33][N:32]=2)[C:55]([F:57])=[CH:56][C:51]=1[CH2:50][C@H:46]1[O:47][CH2:48][CH2:49][NH:44][CH2:45]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(F)c(O)cc2F)C1
Reactant: Cc1cc(CBr)no1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: Cc1cc(COc2cc(F)c(C[C@@H]3CNCCO3)cc2F)no1

Procedure:
The title compound was synthesized in analogy to Example 78, intermediate (a), using 3-(bromomethyl)-5-methylisoxazol and (R)-2-(2,5-difluoro-4-hydroxy-benzyl)-morpholine-4-carboxylic acid tert-butyl ester as starting materials.
Reaction SMILES: [C:1]([NH:18][C:19]1[C:20]([CH3:28])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC(C)([O-])C.[K+]>>[CH2:2]([C:1]1[NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]=2[CH:28]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)O)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCc1cc2c(C(=O)O)cccc2[nH]1
Yield: 54.2 %

Procedure:
A mixture of 3-(n-hexadecanamido)-2-methylbenzoic acid (6.0 g) and potassium tert-butoxide (23 g) was treated in a similar manner to that described hereinbefore in Example 1 to give 2-(n-pentadecyl)indole-4-carboxylic acid (3.1 g), in the form of a cream solid, m.p. 114°-117° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:22][CH:23](O)[CH3:24])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]([CH2:22][CH:23]([Cl:3])[CH3:24])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(C)c1N(CC(C)O)C(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(C)c1N(CC(C)Cl)C(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
4.65 ml (7.7 g, 65 mmoles) of thionyl chloride are added dropwise, at room temperature, to a solution of 14.2 g (50 mmoles) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-propanol in 100 ml of dry benzene, and the mixture is boiled then for 45 minutes. The solvent is evaporated under reduced pressure, and 30 ml of benzene is distilled off from the residue in order to remove the traces of thionyl chloride. This latter operation is repeated. The solid residue is triturated with n-hexane, the crystalline product is filtered off, washed with n-hexane and dried. 14.3 g (95%) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-chloro-propane are obtained as a white, crystalline substance; m.p.: 106°-109° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:21][N:17]1[CH2:18][CH2:19][O:20][CH:15]([CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:16]1
Reactant: CN1CCOC(CN2CCN(Cc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCOC(CN2CCNCC2)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
2-((4-benzylpiperazin-1-yl)methyl)-4-methylmorpholine (346 mg) is dissolved in ethanol (10 ml). Palladium on carbon (100 mg) is added and the mixture is stirred for 5 hours at 50° C. under an atmosphere of hydrogen (50 psi). The catalyst is removed by filtration and the filtrate concentrated under reduced pressure to give 4-methyl-2-(piperazin-1-ylmethyl)morpholine (234 mg). m/z(+) 200 (M+H+).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=C[C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.CC1[O:34]C(CS)=CC=1>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[O:34][C:6]([CH3:5])=[CH:7][CH:2]=2)[N:22]=1)[CH3:27]
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: Cc1ccc(CS)o1
Product: Cc1ccc(CSc2nc(N[C@H](C)CO)c3ncc(=O)[nH]c3n2)o1
Yield: 34.3 %

Procedure:
The titled compound (0.058 g) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 5-methyl-2-furanylmethylmercaptan (0.15 g of 80% pure).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)N2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)N2CCCCC2)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(piperidin-1-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (210 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 145 mg, 80%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[N:9]O)[CH3:2].[Na].Cl>C(O)C.O>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9])[CH3:2]
Reactant: CCC1CCCCC1=NO
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCC1CCCCC1N
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To the solution of 2-ethyl-1-(hydroxyimino)cyclohexane (6.8 g, 48.5 mmol) in ethanol (75 mL) were added sodium pieces (about 8.0 g) in portions, and the reaction was heated to reflux at 110° C. overnight. More sodium pieces were added, and the reaction was stirred for another 6 hours. The reaction was treated with concentrated HCl (12 M, 4.0 mL) in water (25 mL). Ethanol was removed in vacuo. The aqueous layer was washed with ether (10 mL), and treated with aqueous KOH (25 mL) and extracted with ether (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give 2-ethylcyclohexylamine as an off-white oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a suspension of (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (2.01 g, 3.78 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (TFA) (3 mL) dropwise. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with CH2Cl2 (30 mL) and aqueous saturated sodium bicarbonate. Phases were separated and the aqueous layer was extracted with CH2Cl2 (30 mL). Organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (1.648 g, 101%)as a yellow oil.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>O.O1CCCC1>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(O)nc(SCc2cccc(F)c2F)n1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 94.4 %

Procedure:
To a stirred suspension of 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (67.7 g) in a mixture of water (920 ml) and tetrahydrofuran (300 ml) was added aqueous sodium hydroxide solution (46-48% w/w; 24 ml) followed by water (40 ml). The resulting hazy, pale yellow solution was cooled to 20° C. before adding 2,3-difluorobenzyl bromide (83.0 g) uniformly over 25 minutes, to yield a white precipitate. The mixture was stirred at ambient temperature for 3.5 hours, the product collected and washed twice with a mixture of water (68 ml) and tetrahydrofuran (24 ml), to afford the title compound as a white solid (101.89 g).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[C:3](C)[CH3:4].C/C=C\C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[CH2:1]([NH:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH3:4]
Reactant: CC(C)=CCNCC(=O)O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: C/C=C\C
Solvent: ClCCl
Product: CC=CCNCC(=O)O
Yield: 84 %

Procedure:
The prenylglycine derivative 19 was subjected to the conventional cross metathesis procedure (Section 7.5.4) with cis-2-butene under the following conditions: (2S)-Methyl 2-N-acetylamino-5-methylhex-4-enoate 19 (16.2 mg, 81.4 μmol), DCM (5 mL), 2nd generation Grubbs' catalyst (3.5 mg, 4.1 μmol, 5 mol %), cis-2-butene (5 psi), 50° C., 14 h, 100% conversion into 81. Purification by flash chromatography (SiO2, light petroleum:DCM:EtOAc:MeOH, 1:2:1:0.2) gave (2S)-methyl 2-N-acetylaminohex-4-enoate 81 as a brown oil (12.6 mg, 84%). GC: tR (E/Z)=4.2 min, 4.4 min (GC column 30QC5/BPX5, 150° C. for 1 min, 10° C. min−1 to 280° C. for 6 min). νmax (neat): 3284s, 2966w, 2954m, 2856w, 1747s, 1658s, 1547s, 1437s, 1375s, 1217m, 1142m, 1072w, 1016w, 968m, 848m cm−1. 1H n.m.r. (300 MHz, CDCl3): δ 1.60 (dd, J=6.3, 1.2 Hz, 3H, H6), 1.95 (s, 3H, CH3CO), 2.36-2.44 (m, 2H, H3), 3.67 (s, 3H, OCH3), 4.55 (dt, J=7.8 Hz, 5.9 Hz, 1H, H2), 5.24 (m, 1H, H5), 5.49 (m, 1H, H4), 6.17 (bd, J=6.4 Hz, 1H, NH). 13C n.m.r. (100 MHz, CDCl3): δ 18.1 (C6), 23.3 (CH3CO), 35.4 (C3), 52.1, 52.4 (C2, OCH3), 124.6, 130.2 (C4, 5), 169.7, 172.6 (C1, CONH). Mass Spectrum (ESI+, MeOH): m/z 208.1 (M+Na)+, C9H15NNaO3 requires 208.1. Spectroscopic data were in agreement with those reported in the literature.117,119
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.[CH3:22][CH:23]([CH3:27])[CH2:24][CH2:25]Br>CN(C)C=O.O>[O:3]=[C:4]1[N:10]([CH2:25][CH2:24][CH:23]([CH3:27])[CH3:22])[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6](=[O:21])[CH2:5]1
Reactant: CC(C)CCBr
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride 80% dispersion in oil (0.057 g) was added portionwise to a solution of 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.40 g) in dry dimethylformamide (15 ml). The reaction mixture was cooled to 0° and stirred for 30 min, then a solution of 3-methyl-1-bromobutane (0.23 ml) in dry dimethylformamide (4 ml) was added and stirring continued for 2 h. The reaction mixture was then diluted with water (100 ml), extracted with ethyl acetate (3×100 ml), washed with brine (2×50 ml), dried and concentrated in vacuo to give an oil which was purified by flash -chromatography (eluting with CH-EA 60:40) to give the title compound as a white solid (0.44 g). T.l.c. CH-EA (1:1), Rf=0.36.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](=N)[O:12][CH3:13])[CH:6]=[C:7]([Cl:9])[CH:8]=1.C1(C)C=CC=CC=1.[OH2:22]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:12][CH3:13])=[O:22])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: COC(=N)Cc1cc(Cl)cc(Cl)c1
Reactant: O
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(Cl)cc(Cl)c1
Yield: 91 %

Procedure:
To methyl 3,5-dichlorobenzeneethanimidate hydrochloride (1:1) (i.e. the product from Step A1a) (50 g, 0.107 mol) was added to a mixture of toluene (167 mL) and water (167 mL). After 60 min the organic phase was removed, dried (MgSO4), and evaporated to give the title compound as an oil (39 g, 91%).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28](ON3C(=O)CCC3=O)=[O:29])=[C:26]([CH2:38][OH:39])[N:25]=[C:24]2[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.C(Cl)Cl.CO>[CH3:1][NH:2][C:28]([C:27]1[N:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])=[CH:21][CH:20]=2)[C:24]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:25][C:26]=1[CH2:38][OH:39])=[O:29]
Reactant: CN
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc(CO)c(C(=O)NC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 16 h

Procedure:
0.4 ml of a 40% by volume solution of methylamine in water was added at room temperature to a solution of 0.278 g of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in Example 52(a)] in a mixture of 3 ml of methylene chloride and 2 ml of methanol, and the resulting mixture was allowed to stand for 16 hours at room temperature. At the end of this time, the solution was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate. The resulting solution was washed with an aqueous solution of potassium bisulfate and with an aqueous solution of sodium hydrogencarbonate, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 176 mg of the title compound as a glass.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][CH:4]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(#N)C>[CH3:16][C:12]1([CH3:17])[C:11](=[O:18])[O:10][C:9]2[CH:8]=[CH:7][C:6]3[C:14]([C:13]1=2)=[CH:15][C:3]([CH2:2][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=[CH:4][CH:5]=3
Reactant: CC1(C)C(=O)Oc2ccc3ccc(CBr)cc3c21
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CC1(C)C(=O)Oc2ccc3ccc(Cn4cncn4)cc3c21

Procedure:
A solution of 8-bromomethyl-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone in acetonitrile (5 ml), was treated with 1,2,4-triazole (1.4 g) and the mixture was heated under reflux for 18 h. The solution was evaporated to dryness under reduced pressure and the residue was partitioned between 1N aqueous sodium hydrogen carbonate and ethyl acetate. The ethyl acetate extract was separated, dried and evaporated to dryness, and the residue was purified by flash chromatography. Elution with methanol:chloroform, 1:49 v/v, gave 1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2-(1H)-naphtho[2,1-b]furanone, m.p. 136°-137° after recrystallisation from a mixture of ethyl acetate and cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[N:14].C(N(CC)CC)C.[CH2:22]1[CH2:27][C@@H:26]([NH2:28])[C@H:25]([NH2:29])[CH2:24][CH2:23]1.O>CC#N>[NH2:28][C@@H:26]1[CH2:27][CH2:22][CH2:23][CH2:24][C@H:25]1[NH:29][C:6]1[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]([C:13]#[N:14])=[C:2]([Cl:1])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(C#N)c1Cl
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1c(Cl)c(Cl)c(N[C@@H]2CCCC[C@H]2N)c(C#N)c1Cl
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To the suspension of 2,4,5,6-tetrachloro-1,3-dicyanobenzene (2.0 g, 7.52 mmol) and triethylamine (5 ml) in methyl cyanide (40 ml) is added a solution of (1R,2R)-diaminocyclohexane (0.85 g, 7.52 mmol) in methyl cyanide (10 ml). The mixture is mixed for 60 min. at 120° C., then cooled to room temperature and the water (10 ml) is slowly added. After cooling in a refrigerator the solid is recovered on a G4 filter and washed with water-methyl cyanide (1:1) and with methyl cyanide. Finally, the product is vacuum-dried on KOH tablets. 2.32 g (89%) of pale yellow powder are obtained, dec. at a temp. greater than 190° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]1[C:14]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[N:11]1.O>CS(C)=O>[CH3:9][N:10]1[C:14]([N:15]2[CH2:16][CH2:17][C:18]3([O:21][CH2:4]3)[CH2:19][CH2:20]2)=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[N:11]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (60% in mineral oil, 200 mg, 4.9 mmol) was added portionwise to DMSO (15 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 15 min before trimethyl sulfoxonium iodide (1.0 g, 4.6 mmol) was added. After stirring for 90 min at room temperature, a solution of 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one (1.0 g, 4.45 mmol) in DMSO (15 mL) was added. The mixture was heated at 55° C. for 3 hr, then poured into water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give 6-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1-oxa-6-azaspiro[2.5]octane as an orange liquid. To a solution of this liquid (0.4 g, 1.67 mmol) in a reaction tube was added a 7 M solution of NH3 in MeOH (20 mL) and the mixture stirred in a sealed tube at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure and the residue purified via silica gel chromatography (1-10% 7 M NH3 in MeOH/DCM) to give 4-(aminomethyl)-1-(2-methyl-4-nitro-pyrazol-3-yl)piperidin-4-ol as a yellow solid, (350 mg, 60% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 3.76 (s, 3H), 3.64-3.54 (m, 2H), 3.09-3.03 (m, 2H), 2.72 (s, 2H), 1.73-1.62 (m, 4H). Exchangeables not observed.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([SH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:35]=[CH:34][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=2)=[CH:22][CH:21]=1>>[F:18][C:19]([F:36])([F:37])[C:20]1[CH:35]=[CH:34][C:23]([CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[CH2:32][S:16][C:13]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:17])=[C:7]3[C:12]=2[O:11][CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester and 79B. MS m/z 519 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH:10]([C:22]([OH:24])=[O:23])[NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.[CH3:25]O>>[CH3:25][N:11]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:10]([C:4]1[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])[C:22]([OH:24])=[O:23]
Reactant: O=C(O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Reactant: CO
Agent: Cl
Product: CN(c1ccc2ccccc2c1)C(C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Gaseous hydrogen chloride is introduced for 11 hours through a stirred and refluxing solution of 17.3 parts of (±)-2-(2,6-dichlorophenyl)-N-(2-naphthyl)glycine in 96 parts of methanol. The reaction mixture is allowed to cool overnight to room temperature. The precipitated product is filtered off and crystallized from methanol, yielding 6.4 parts of (±)-methyl 2-(2,6-dichlorophenyl)-N-(2-naphthyl) glycine; mp. 143.5° C.
Reaction SMILES: [NH2:1][C:2]1([C:30]([NH2:32])=[O:31])[CH2:7][CH2:6][N:5]([S:8](/[CH:11]=[CH:12]/[C:13]2[C:18]([CH3:19])=[CH:17][C:16]([N:20]3[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[NH:22][C:21]3=[O:28])=[CH:15][C:14]=2[CH3:29])(=[O:10])=[O:9])[CH2:4][CH2:3]1>CO.CN(C)C=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1([C:30]([NH2:32])=[O:31])[CH2:7][CH2:6][N:5]([S:8]([CH2:11][CH2:12][C:13]2[C:14]([CH3:29])=[CH:15][C:16]([N:20]3[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[NH:22][C:21]3=[O:28])=[CH:17][C:18]=2[CH3:19])(=[O:9])=[O:10])[CH2:4][CH2:3]1
Reactant: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC(N)(C(N)=O)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1CCS(=O)(=O)N1CCC(N)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
A mixture of (E)-4-amino-1-((4-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)-2,6-dimethylstyryl)sulfonyl)piperidine-4-carboxamide (1.3 g, 2.8 mmol) and palladium hydroxide on carbon (20% Pd) (wetted with approximately 50% water) (1.3 g) in methanol (21 mL) and dimethylformamide (7 mL) was stirred under hydrogen atmosphere at room temperature for four hours. The reaction mixture was filtered and washed, and then the filtrate was concentrated under reduced pressure to afford 4-amino-1-((4-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2,6-dimethylphenethyl)sulfonyl)piperidin-4-carboxamide (998 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][F:19])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Br)cc1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(Br)cc1
Yield: 48.8 %

Procedure:
Using 0.47 g of (4-bromobenzyl)malononitrile, 5 ml of N,N-di-methylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.27 g of 2-(4-bromobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (51)).