Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1>CCOCC>[CH2:1]([NH:8][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([OH:19])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC(Br)c2ccccc21
Solvent: CCOCC
Product: OC1CC(NCc2ccccc2)c2ccccc21

Procedure:
Cool a solution of benzylamine (3.22 g.) in dry ether (25 ml.) to below 0° C. With stirring under nitrogen add a cooled (below 0° C.) solution of 3-bromo-1-indanone (3.17 g.) in ether (25 ml.) dropwise over 1.5 hours. Store the reaction under nitrogen at -10° C. for one day. Quickly filter the cold solution and add it cold to a stirring solution of one molar borane in tetrahydrofuran (60 ml.) below 0° C. and under nitrogen. Stir the solution for 18 hours at room temperature. Carefully add a solution of water (3.24 ml.) in tetrahydrofuran (20 ml.) dropwise, followed by 8.0 ml. of 5M isopropanolic --HCl, and continue stirring overnight. Store the reaction at -10° C. overnight, then filter the precipitate through filter-aid. Extract the dry solid mixture with methanol-methylene chloride, filter and evaporate the solvents in vacuo. Triturate the resulting solid with cold ethyl acetate, filter and dry to obtain 2.36 g. of the title product as the hydrochloride salt, m.p. 233-235°. λmaxKBr 3.0 μ (OH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Br[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23]>C(#N)C>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)NCCBr
Reactant: OCC1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCN1CCC(CO)CC1
Yield: 54.8 %

Procedure:
4-Piperidine methanol (1.60 g) was dissolved in dry acetonitrile (40 ml), N,N-diisopropylethylamine (5 ml) was added, followed by N-(2-bromoethyl)methanesulphonamide (2.95 g) in acetonitrile (10 ml), and the resulting mixture heated at reflux for 2 h. The solvent was removed in vacuo to leave a gum. This was purified by FCC eluting with System A (75:8:1) to give the title compound (1.80 g) as a solid, m.p. 81°-82°.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=4)[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccc(C(F)(F)F)c3)CC12
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 3-(trifluoromethyl)phenylacetic acid (1.43 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (30 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(3-(trifluoromethyl)phenyl)acetyl]-4-perhydroisoindolone (2 g) is obtained in the form of white crystals melting at 184° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:20][CH2:21][CH2:22][CH3:23])=[N:15][CH:16]=[C:17](I)[CH:18]=3)=[N:8][C:7]=12)[CH3:2].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].C(#N)C>C(N(CC)CC)C.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>[CH2:1]([C:3]1[N:4]([CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:20][CH2:21][CH2:22][CH3:23])=[N:15][CH:16]=[C:17]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[CH:18]=3)=[N:8][C:7]=12)[CH3:2]
Reactant: CCCOc1ncc(I)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Reaction time: 2 h

Procedure:
The product from stage e) (0.25 mmol) was suspended in triethylamine (2 ml) and trimethylsilylacetylene (0.39 mmol) and acetonitrile (2 ml to try and solubilise reactants). Pd(PPh3)2Cl2 (0.006 mmol) and cuprous iodide (0.006 mmol) were added and the reaction mixture stirred. After 1 h a further portion of trimethylsilylacetylene (0.19 mmol) was added and stirring continued for 2 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organics were washed with brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 99% dichloromethane/methanol) gave the title compound; 1H NMR (400MHz, MeOD): δ=0.25 (s, 9H), 1.05 (t, 3H), 1.31 (t, 3H), 1.44 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q, 2H), 4.33 (t, 2H), 4.52 (t, 2H), 4.54-4.80 (m, 2H), 5.18-5.25 (m, 1H), 8.32 (d, 1H), 8.74 (d, 1H); LRMS (TSP—positive ion) 569 (MNH4+), 452.0 (MH+); Anal. Found C, 60.82;H, 6.90; N, 15.15 Calcd for C28H38O4N6Si: C, 61.07;H, 6.95; N, 15.26.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.[C-:13]#[N:14].[Na+].[Cl-].[NH4+]>CN1CCCC1=O.O>[C:13]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2)#[N:14]
Reactant: [C-]#N
Reactant: Oc1ccc2ncc(Br)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cnc2ccc(O)cc2c1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
3-Bromo-6-hydroxyquinoline (1.12 g) in dry N-methylpyrrolidin-2-one (10 ml) was treated with cuprous cyanide (0.55 g) and stirred at 150° C. for 7 hours under an atmosphere of nitrogen then stored at ambient temperature for 18 hours. The mixture was treated with sodium cyanide (1.5 g) in water (5 ml) and heated at 75° C. for 15 minutes. 10% Aqueous ammonium chloride solution (25 ml) was added and the mixture cooled to ambient temperature. The reaction mixture was extracted with ethyl acetate and the organic phase separated, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a yellow brown solid. The solid was fractionated by chromatography to give the required product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:26][C:27]5[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
To a stirred solution of 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.29 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.05 g, 1.25 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then 2-(bromomethyl)-5-(trifluoromethyl)furan (0.25 mL, 1.80 mmol) was added. The mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 40% gradient) to afford 3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.35 g, 80%): mp 111-112° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.46 (d, J=9.0 Hz, 1H), 7.33-7.27 (m, 1H), 7.15-7.12 (m, 1H), 7.06-7.01 (m, 3H), 6.77-6.76 (m, 1H), 6.55-6.52 (m, 1H), 5.20-4.85 (m, 4H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ175.7, 163.9, 158.1, 154.9, 151.6, 141.4, 130.2, 129.5, 123.9, 123.1, 120.7, 117.9, 117.1, 112.9, 109.3, 108.9, 108.8, 107.9, 81.2, 56.2, 37.5, 9.8; MS (ES+) m/z 462.9 (M+23).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: NCCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCO)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.7 %

Procedure:
Triethylamine (18.9 g, 136 mmol) was added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25 g, 113 mmol) in N,N-dimethylformamide (100 mL). 4-Aminobutan-1-ol (11.1 g, 124. mmol) was added with a syringe and the reaction mixture was allowed to stir under a nitrogen atmosphere at ambient temperature for 17 hours. A portion (85 mL) of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with water (2×50 mL) then with brine (75 mL), dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide a solid. This material was recrystallized from ethyl acetate/hexanes to provide 15.07 g of 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butan-1-ol as yellow powder. An additional 5.70 g was isolated from the mother liquor.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][C:7](=[N:12][OH:13])[C:8]([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7](=[N:12][OH:13])[CH2:6][N+:1]([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)C(CBr)=NO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(C[N+](=O)[O-])=NO
Reaction time: 20 h
Yield: 29.2 %

Procedure:
To a stirred solution of 18.2 g (0.26 m) of sodium nitrite in 130 ml of dimethyl sulfoxide is added, in portions, 29.0 g (0.15 m) of 1-bromo-3,3-dimethyl-2-butanone oxime. A mild exotherm results and external cooling is used to keep the temperature below 27° C. Additional solvent is added to maintain stirrability. After 20 hours stirring, the mixture is poured onto ice and water to give a solid which is collected on a filter. The 10 g of solid, m. 115°-120° C, thus obtained is recrystallized from a hot benzene-petroleum ether mixture to give 7 g of white crystals, m. 124°-125° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[O:13])=[C:4]([OH:14])[CH:3]=1.[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21](O)[C:17]=1[C:18]([OH:20])=[O:19].S(=O)(=O)(O)O>>[OH:15][C:16]1[CH:24]=[CH:23][C:22]2[N+:12]([O-:13])=[C:5]3[C:4](=[CH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=43)[O:14][C:21]=2[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1c(O)cccc1O
Reactant: O=Nc1c(O)cc(O)c2ccccc12
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(O)ccc2c1oc1cc(=O)c3ccccc3c-1[n+]2[O-]

Procedure:
2.84 g. 1,3-dihydroxy-4-nitrosonaphthalene, 2.31 g. 2,6-dihydroxybenzoic acid, 1.29 g, pyrolusite and 1.6 ml. concentrated sulphuric acid are reacted analogously to Example 1(a). Yield 2.8 g.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH:22]=O)=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[C:4]([C:15]2[S:25][C:18]3[N:19]([CH3:24])[C:20]([CH2:22][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][C:17]=3[CH:16]=2)=[N:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(C=O)n(C)c2s1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1cc2cc(CN3CCCC3)n(C)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To solution of methyl 5-ethyl-6-(5-formyl-6-methyl-6H-thieno[2,3-b]pyrrol-2-yl)-2-methoxynicotinate (49.4 mg, 0.14 mmol) in dichloroethane (1.5 mL) was added pyrrolidine (20 μL, 0.24 mmol) followed by AcOH (15 μL, 0.25 mmol). After stirring at room temperature for 10 min NaBH(OAc)3 (60 mg, 0.28 mmol) was added. Reaction was stirred at room temperature overnight and then quenched with NaHCO3 solution (aqueous saturated, 5 mL). Product was extracted with DCM (3×7 mL). Organic phase was dried over Na2SO4 and solvent was concentrated. Product was purified by column chromatography (MeOH/DCM, 0-5% gradient). Methyl 5-ethyl-2-methoxy-6-(6-methyl-5-(pyrrolidin-1-ylmethyl)-6H-thieno[2,3-b]pyrrol-2-yl)nicotinate (49.7 mg) was obtained in 86% yield. LC-MS 343.1 [M-71+H]+, RT 1.00 min.
Reaction SMILES: C(C1C=CC(OCC2N=C(CC3C=CC(C(O)=O)=CC=3)ON=2)=C(Cl)C=1O)(=O)C.C([O:31][C:32](=[O:58])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][C:40]2[O:44][N:43]=[C:42]([CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([C:53](=[O:55])[CH3:54])=[C:49]([OH:56])[C:48]=3[Cl:57])[N:41]=2)[CH:34]=1)C>>[C:53]([C:50]1[CH:51]=[CH:52][C:47]([O:46][CH2:45][C:42]2[N:41]=[C:40]([CH2:39][C:35]3[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=3)[C:32]([OH:58])=[O:31])[O:44][N:43]=2)=[C:48]([Cl:57])[C:49]=1[OH:56])(=[O:55])[CH3:54]
Reactant: CCOC(=O)c1cccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)c1
Agent: CC(=O)c1ccc(OCc2noc(Cc3ccc(C(=O)O)cc3)n2)c(Cl)c1O
Product: CC(=O)c1ccc(OCc2noc(Cc3cccc(C(=O)O)c3)n2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid, employing 3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[ 1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester. 1H NMR (DMSO-d6) δ 13.06 (s, 1H), 12.99 (s, 1H), 7.91 (m, 2H), 7.83 (m, 1H), 7.58 (m, 1H), 7.46 (dd, 1H), 6.89 (d, 1H), 5.49 (s, 2H), 4.48 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.C([N+](CC)(CC)CC)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=S)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:43][N:44]([CH3:51])[CH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH2:48]>O1CCCC1>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:48][CH2:47][C:46]([CH3:50])([CH3:49])[CH2:45][N:44]([CH3:51])[CH3:43])=[N:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)CCNC(=S)Nc1ccc(OCc2ccccc2)cc1
Reactant: CN(C)CC(C)(C)CN
Agent: O=[Mn](=O)(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)CCN=C(NCC(C)(C)CN(C)C)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.9 %

Procedure:
Benzyltriethylammonium permanganate (0.281 g; 1.5 eq.) is added, at 5° C. and portionwise, to a solution of N-(4-benzyloxyphenyl)-N′-(3-methylbutyl)thiourea (0.200 g) and 3-dimethylamino-2,2-dimethylpropylamine (0.156 g; 2 eq.) in tetrahydrofuran (THF; 2.2 ml). The reaction medium is stirred for three days at room temperature. After filtration and concentration, the product is purified by chromatography on silica (eluent: methanol +0.1% acetic acid). The product, dissolved in dichloromethane, is washed with 1N sodium hydroxide. After drying and concentration, 0.067 g of N-(4-benzyloxyphenyl)-N′-(3-dimethylamino-2,2-dimethylpropyl)-N″-(3-methylbutyl)guanidine is obtained.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]1)#[N:20]
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Reactant: O=C(O)c1cc2ccccc2s1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCN(CCO)CC1
Yield: 40.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1 g) and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (1.2 g), the title compound (0.8 g) was obtained. melting point: 238-239° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[Mg].C(O[C:14]1(OCC)[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])C.[Cl-].[NH4+]>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19]
Reactant: Cc1cccc(CCl)c1
Reactant: CCOC1(OCC)CCCN1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cccc(CC2CCCN2C)c1

Procedure:
Prepare a Grignard solution from 103 g of 3-methylbenzyl chloride and 8 g of magnesium in 400 ml of diethyl ether. With stirring and boiling under reflux, add a solution of 126.9 g of 2,2-diethoxy-1-methylpyrrolidine dropwise to the Grignard solution. Keep the thus-prepared mixture at the boil for a further 1 hour before adding 130 ml of saturated ammonium chloride solution dropwise thereto. Then filter off the magnesium salts and dry the filtrate over sodium sulfate. Free the residue (31 g) from ether and then hydrogenate it with Raney nickel/hydrogen. Distil the hydrogenated product twice under a vacuum to obtain 16.2 g (13% of theory) of the title compound (b.p. 56° to 0.001 mm of Hg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27])[CH2:22][OH:23].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:24]=[C:25]([Cl:28])[C:26]=1[O:27][CH:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1)[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccccc1
Yield: 20.4 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 4, 0.400 g (2.07 mmol) of the product of Step C was alkylated with 0.522 g (2.28 mmol) of methyl 2-bromophenylacetate to afford 0.144 g (20%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 2-(4-chloro-phenyl)-pyrimidin-5-ol (Preparation 27) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (110 mg, 45.2%)
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
25.0 mg (1.00 mmol) 95% sodium hydride were given to a solution of 217 mg (1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 3.0 ml DMF and stirred for 30 min. 346 mg (1.00 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. for 24 h. After cautious addition of 10 ml water the mixture was diluted to 60 ml by further addition of water and stirred for 30 min. The resulting precipitate was washed with 3×10 ml water, 2×10 ml methanol/water, diethyl ether and dried to yield 440 mg (84%) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CSc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(NCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To 5.0 mL (40.19 mmol) of 4-(methylthio)aniline and 8.4 mL (60.28 mmol) triethylamine dissloved in 30 mL dichloromethane was added 5.0 mL (40.19 mmol) 4-fluorobenzyl bromide. The mixture was stirred at room temperature for 12 h, partitioned between dichloromethane and sat. aqueous ammonium chloride, dried over MgSO4 and concentrated. Purification by column chromatography, eluting with ethyl acetate/hexane, provided 3.10 g of 4-[(4-fluorobenzyl)amino]thioanisole, along with recovered starting material.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14](Cl)=[O:15]>C(OCC)(=O)C.O>[CH2:1]([NH:7][C:14](=[O:15])[C:13]1[CH:12]=[C:11]([Cl:10])[CH:19]=[C:18]([Cl:20])[CH:17]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccco1)c1cc(Cl)cc(Cl)c1
Yield: 85.4 %

Procedure:
To a vigorously stirred solution of furfurylamine (2.78 g) in ethyl acetate (40 ml) was added sodium hydroxide (1.15 g) in water (45 ml), followed immediately by the addition of a solution of 3,5-dichlorobenzoyl chloride (6.0 g) in ethyl acetate (20 ml). Following the mild exothermic reaction the ethyl acetate layer was removed, dried (MgSO4), and evaporated. Crystallisation of the residue from cyclohexane gave the product (6.6 g) as colourless needles.