Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:23])[CH3:2].[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>>[CH2:1]([C:3]1[C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=[CH:5][C:4]=1[O:23]/[C:25](=[CH:24]\[C:30]([O:32][CH3:33])=[O:31])/[C:26]([O:28][CH3:29])=[O:27])[CH3:2]
Reactant: CCCc1ccccc1OCCCOc1cccc(O)c1CC
Reactant: COC(=O)C#CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)OC)C(=O)OC)c1CC

Procedure:
A mixture of 73.9 parts of 2-ethyl-3-(3-[2-propylphenoxy] propoxy)phenol, 35.0 parts of acetylene dicarboxylic acid, dimethyl ester and 4 parts of benzyl trimethyl ammonium hydroxide was warmed, with stirring, to 70° when an exothermic reaction occurred. The reaction mixture was maintained at 100°-120° for a further fifteen minutes, cooled, and 1000 parts of 1N sodium hydroxide solution was added. The mixture was extracted with chloroform and the chloroform extract washed with water and saturated sodium chloride solution and dried. Evaporation of the chloroform gave an oil which on trituration with 40/60 petrol gave a solid that crystallised from methanol to give 43.4 parts of dimethyl 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxy fumarate, m.pt. 63.5°-66° (raised to 71°-72.5° by recrystallisation).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=2)[N:13]=1
Reactant: Cc1ccc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 46.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-93, 0.350 g, 1.00 mmol), pivaloyl chloride (0.128 g, 1.0 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.200 g of the desired product. 1H NMR (300 MHz, DMSO c/6): δ 1.13 (s, 9H), 2.34 (s, 3H), 4.29 (d, J=6.3 Hz, 2H), 7.39-7.47 (m, 2H), 7.58-7.61 (m, 2H), 7.82 (d, J=8.7 Hz, 1H), 8.01 (s, 1H), 8.18 (t, 1H), 12.58 (s, 1H); MS (m/z): 433.19 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:18][C:19]1[N:20]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1>>[CH3:18][C:19]1[N:20]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]3[CH:3]=[C:4]([C:8]4([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[CH:5]=[CH:6][CH:7]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: NC(=O)C1(c2cccc(O)c2)CCOCC1
Agent: Cl
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCOCC3)c2)cc1

Procedure:
4-(3-Hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide was reacted with 4-(2-methylimidazol-1-yl)benzyl chloride hydrochloride according to the procedure described in Example 2H to give the titled compound.
Reaction SMILES: C([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:10]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:9]1[C:40]([O:42][CH2:43][CH3:44])=[O:41])C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)(=O)C>[CH2:30]([O:29][C:10]1[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8][C:9]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1c(OCCCCCCCCCC)c(C(=O)OCC)n(Cc2ccccc2)c1C(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCOc1c(C(=O)OCC)[nH]c(C(=O)OCC)c1OCCCCCCCCCC
Reaction time: 84 h
Yield: 75.9 %

Procedure:
Into a 1-L autoclave, 121.1 g (0.197 mole) of the diethyl N-benzyl-3,4-didecyloxypyrrole-2, 5-dicarboxylate, 600 ml of acetic acid and 12.0 g of 10% palladium-carbon were put, and the reaction was carried out for 84 hours at 30° C. and a hydrogen pressure of 1.8×106 Pa. After the reaction was completed, the 10% palladium-carbon was removed by filtration, and the filtrate formed was evaporated to dryness. The residue formed was purified by silica gel column chromatography (eluent: toluene/acetic acid=5/1) to obtain 78.3 g of diethyl 3,4-didecyloxypyrrole-2,5-dicarboxylate (yield: 75.8%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH:24]([CH3:26])C)[NH:13][C:12](=[O:27])[CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:29][NH2:30]>C(O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH2:24][CH3:26])[NH:13][C:12](=[O:27])[CH:11]=3)[CH:6]=2)[NH:30][N:29]=1
Reactant: NN
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)cc(=O)[nH]1
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)cc(=O)[nH]1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoro-5-(6-{2-[(2-methylpropyl)oxy]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile (50 mg), and hydrazine hydrate (2 mL) in ethanol (10 mL)was heated to 100° C. for 3 h. The reaction mixture was concentrated and the product was purified by preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate) to afford 4-(3-amino-1H-indazol-5-yl)-6-[2-(propyloxy)phenyl]pyridin-2(1H)-one (20 mg). 1H NMR (400 MHz, d4-CD3OD): δ 8.18 (s, 1H), 7.72 (d, 1H), 7.57 (d, 1H), 7.46 (t, 1H), 7.39 (d, 1H), 7.16-7.08 (m, 2H), 6.92 (d, 1H), 6.76 (s, 1H), 3.88 (d, 2H), 2.12-2.05 (m, 1H), 1.00 (d, 6H). MS (EI) for C22H22N4O2: 375 (MH±).
Reaction SMILES: S([O-])(O)(=O)=O.[K+].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:25][CH:26]([F:28])[F:27])[C:16]([C:18]2[C:19](=[O:24])[O:20][CH2:21]C=2O)=O)=[CH:10][CH:9]=1>C(#N)CCC>[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:25][CH:26]([F:27])[F:28])[C:16]2[CH2:21][O:20][C:19](=[O:24])[CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C1OCC(O)=C1C(=O)N(Cc1ccc(Cl)nc1)CC(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 25 °C
Yield: 77 %

Procedure:
At room temperature, 0.5 g of potassium hydrogensulphate are added to a suspension of 1.7 g of N-[(6-chloropyridin-3-yl)methyl]-N-(2,2-difluoroethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxamide in 50 ml of butyronitrile. The mixture is heated at reflux for 5 hours. It is then cooled to room temperature and washed with 30 ml of water. The solvent is removed in vacuo. This gives 1 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (this corresponds to 77% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[C:8]([C@H:17]([NH:27][C:28](=[O:43])[CH2:29][N:30]2[C:38]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=3[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31]2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[N:9][C:10](S(C)(=O)=O)=[N:11][CH:12]=1>ClCCl>[Br:6][C:7]1[C:8]([C@H:17]([NH:27][C:28](=[O:43])[CH2:29][N:30]2[C:38]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=3[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31]2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[N:9][C:10]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: COCCN
Solvent: ClCCl
Product: COCCNc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reaction time: 8 h

Procedure:
2-Methoxyethylamine (0.086 ml, 1 mmol) was added at room temperature to a solution of compound 11H (62 mg, 0.1 mmol) in dichloromethane (5 mL). Stirring was continued at 45° C. for overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography using an ethyl acetate/hexanes eluent to yield the title compound. MS (m/z) 618.00 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[CH2:10]([S:14]CCCC)[CH2:11][CH2:12][CH3:13]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:14][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: CCCCSCCCC
Product: CCCCSc1ccc(OC)cc1

Procedure:
The general procedure was used to convert 4-methoxy iodobenzene and n-butyl sulfide to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (370 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.26–7.23 (d, J=9.0. 2H; Hb, Hb′), 6.76–6.73 (d, J=8.8, 2H; Hc, Hc′), 3.69 (s, 3H; Hg), 2.75–2.70 (t, 2H; Hd), 1.50–1.43 (m, 2H; He), 1.36–1.28 (m, 2H; Hf), 0.83–0.78 (t, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 158.62 (C4), 132.81 (C1), 126.85 (C2, C2), 114.39 (C3, C3), 55.21 (C9), 35.04 (C5), 31.63 (C6), 21.75 (C7), 13.59 (C8). Anal. Calcd. for C11H16SO: C, 67.30; H, 8.22; S, 16.33; Found C, 66.87; H, 8.28; S, 16.21.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=O.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][NH2:26])[CH:20]=1>CN1CCCC1=O>[I:16][C:13]1[CH:12]=[C:9]2[C:8](=[CH:15][CH:14]=1)[N:25]([C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[N:26]=[CH:10]2
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1ccc2c(cnn2-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of 2-fluoro-5-iodobenzaldehyde (6.87 g, 27.46 mmol) and 3-pyridylhydrazine dihydrochloride (5 g, 27.46 mmol) in 136 mL N-methylpyrrolidon. The reaction mixture is stirred overnight at r.t. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for 4 h at 160° C. The reaction mixture is allowed to cool down and the dark brown suspension is poured on 1000 mL ice water. After vigorously stirring at r.t. for 45 min, the precipitated product is sucked off via a glass microfibre filter, washed with water and dried at the evaporator at 45° C. 8.28 g (93.9%) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][S:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]([CH2:32][CH3:33])[C:9](=[O:31])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][S:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1ccccc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 83.4 %

Procedure:
Methyl 2-{[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (0.137 g, 0.296 mmol) was dissolved in a mixture of acetonitrile/water (1/1, 4 ml), lithium hydroxide (0.014 g, 0.591 mmol) was added. The reaction was performed in an single node microwave oven (5 min, 150 deg). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The waterphase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation and gave 0.111 g of 2-{[2-(4-{2[-benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]-thio}benzoic acid (yield 83.5%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[CH3:12][CH:13](O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:13]([CH3:14])[CH3:12]
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: CC(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
A solution of 6-chloro-2-fluoro-9H-purine (616 mg, 3.57 mmol) in THF (18 mL) was cooled in an ice water bath under nitrogen and iPrOH (858 mg, 14.3 mmol), triphenylphosphine, polymer-bound (2.38 g, 7.14 mmol, ˜3 mmol/g), and di-tert-butyl azodicarboxylate (1.730 g, 7.14 mmol) were added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hr. The solid resin was removed and washed well with ethyl acetate (50 mL). The filtrate was concentrated down in vacuo to give a light yellow solid residue. This was then loaded onto silica and purified via flash chromatography (eluting with 30-50% ethyl acetate in heptanes) to give the title product as a white solid (445 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (s, 1 H) 4.72-4.92 (m, 1 H) 1.57 (d, J=6.85 Hz, 6 H). m/z (APCI+) for C8H8FN4Cl 217.10, 215.10 (M+H)+.
Reaction SMILES: CC(C)(O[C:5]([NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:9]1=[O:24])=[O:6])C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:50][C:51]1[CH:60]=[C:59]2[C:54]([C:55]([N:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)=[CH:56][C:57]([NH2:61])=[N:58]2)=[CH:53][CH:52]=1>>[C:18]1([O:17][C:15]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:8]([NH:7][C:5]([N:65]3[CH2:66][CH2:67][N:62]([C:55]4[C:54]5[C:59](=[CH:60][C:51]([Cl:50])=[CH:52][CH:53]=5)[N:58]=[C:57]([NH2:61])[CH:56]=4)[CH2:63][CH2:64]3)=[O:6])[C:9]2=[O:24])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)Oc2ccccc2)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)Oc4ccccc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid, phenyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 537 (M++1). 1H NMR (CDCl3,) δ 1.56˜2.08 (m, 5H), 2.16–2.24 (m, 1H), 3.14 (m, 4H), 3.54 (dd, 1H), 3.68 (m, 4H), 4.54 (br.dd, 1H), 4.84 (br.s, 2H), 4.90 (ddd, 1H), 5.80 (d, 1H), 6.15 (s, 1H), 7.16˜7.22 (m, 3H), 7.27 (m, 1H), 7.41 (m, 2H), 7.62 (d, 1H), 7.72 (d, 1H).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1)(=O)C.Cl>>[NH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1
Reactant: CC(=O)NCCc1ccc(C(CCCCC(=O)O)c2cccnc2)cc1
Agent: Cl
Product: NCCc1ccc(C(CCCCC(=O)O)c2cccnc2)cc1

Procedure:
4.0 g of 6-(4-(2-acetylaminoethyl)phenyl)-6-(3-pyridyl)hexanoic acid are refluxed for 18 hours with 50 ml of half concentrated hydrochloric acid. The mixture is then rotary evaporated and the residue is purified by chromatography over a column of silica gel using methanol.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][OH:5].CC(O)(CCCCCC)C=C.S(=O)(=O)(O)O.[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][OH:5]
Reactant: CCCCCCC(C)=CCO
Agent: C=CC(C)(O)CCCCCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCC(C)CCO

Procedure:
The 3-methyl-2-nonen-1-ol employed in the perfume compositions of this invention and as a reactant in the production of monocarboxylic acid esters of that alcohol is produced by employing 3-methyl-1-nonen-3-ol as the starting material. The starting alcohol is reacted in the absence of solvents with a monocarboxylic acid such as acetic acid together with sulfuric acid and maintained at a temperature of about 50° to 80° C. The progress of the reaction is followed by I.R. spectroscopy. Under these conditions there is dehydration of the tertiary alcohol, 3-methyl-1-nonen-3-ol to a hydrocarbon, allylic rearrangement of the tertiary alcohol to the primary alcohol, 3-methyl-2-nonen-1-ol and partial esterification with formation of a monocarboxylic acid ester of 3-methyl-2-nonen-1-ol. A solution of an alkali metal hydroxide, such as sodium hydroxide and a suitable solvent such as methanol is added to the reaction product and the solution refluxed for three to six hours to saponify the esters. The solvent is removed by distillation under a slight vacuum. The remaining reaction product is then washed successively with water, an alkali metal bicarbonate solution and water. Fractional distillation under vacuum is conducted to obtain a fraction containing the 3-methyl-2-nonen-1-ol. The fraction distilling at 10 mm and a temperature of 110°-111° C. is recovered and contains primarily the 3-methyl-2-nonen-1-ol. The corresponding saturated alcohol, 3-methylnonan-1-ol is produced by hydrogenation of the unsaturated alcohol 3-methyl-2-nonen-1-ol in the presence of Raney nickel or other suitable catalyst.
Reaction SMILES: OC1C=CC(CC(C2C=NC=CC=2)C[NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=CC=1.C(N(CC)CC)C.C(Cl)(=O)OCC.O>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH2:11])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: O=S(=O)(NCC(Cc1ccc(O)cc1)c1cccnc1)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
N-[3-(4-hydroxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide (54.5 mg) and 15.1 mg of triethylamine were dissolved in 3 ml of methylene chloride, followed by addition of 16.2 mg of ethyl chlorocarbonate dissolved in 1 ml of methylene chloride, and stirred at room temperature for 15 hours. To the reaction mixture was added water, and the organic phase was separated which was then extracted with methylene chloride. The organic phases were combined and washed in water, followed by drying over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 47.4 mg of N-[3-(4-ethoxycarbonylphenyl)-2-(3-pyridyl)}propyl]-4-chlorobenzene sulfonamide. The spectrometric data supports the structure of [35] as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:20])[C:5]2[C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]([NH:22][C:23]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:24]=3[CH:25]=[N:26][NH:27]4)[C:6]=2[CH:7]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2cc(Cl)cc(O)c21
Yield: 18.2 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 410 mg of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 168 mg of 4-aminoindazole. 98 mg of the title compound is obtained by reaction of 200 mg of imine with 6.7 ml of BBr3 (1N in dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][C:14]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33].FC(F)(F)C(O)=O>C(#N)C>[Cl:1][C:2]1[C:3]([NH:31][S:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:33])=[O:34])=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11](=[CH:10][CH:9]=2)[N:12]=[CH:13][C:14]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[N:15]3)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(-c2ccc3ncc(N4CCNCC4)nc3c2)cnc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(7-{6-chloro-5-[(phenylsulfonyl)amino]-3-pyridinyl}-2-quinoxalinyl)-1-piperazinecarboxylate (0.83 mmol) in acetonitrile (6 ml) was added concentrated trifluoroacetic acid (3 ml). The reaction stirred at ambient temperature for 3 hours and was then concentrated to an orange oil. The residue was neutralized with saturated sodium bicarbonate solution upon which a precipitate was formed. The product was filtered and dried to give the title compound (260 mg, 65%) as an off-white solid. MS(ES)+ m/e 481.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17](=[S:26])[NH:16][CH:15]=2)([CH3:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[CH2:41]Cl>CC(C)=O>[Cl:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[CH2:41][S:26][C:17]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:14]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:13])[CH3:12])=[CH:15][N:16]=1
Reactant: Fc1ccc(CCl)c(Cl)c1
Reactant: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)c2cnc(SCc3ccc(F)cc3Cl)n2-c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A mixture of 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (170 mg, 0.46 mmol) and K2CO3 (95 mg, 0.69 mmol) in acetone (5 mL) was stirred for 30 min at room temperature. The resulting mixture was charged with 2-chloro-1-(chloromethyl)-4-fluorobenzene (98 mg, 0.55 mmol) and then heated at reflux overnight. The reaction mixture was cooled to room temperature and filtered through a Celite™ pad. The filtrate was evaporated in vacuo to give a crude product, which was purified by flash chromatography to afford the title product (208 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 1H), 7.20 (s, 1H), 7.04 (dd, 1H), 6.86 (td, 1H), 6.74 (m, 2H), 6.64 (d, 1H), 6.45-6.43 (m, 2H), 6.21 (m, 2H), 4.25 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H), 1.47 (s, 6H); MS (EI) m/z 515 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2N3N=CC=[C:13]3[N:12]=[CH:11][C:10]=2[C:18](OCC)=O)=[C:4](C)[CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][C:10]3([CH2:11][NH:12][CH2:13]3)[CH2:18]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(F)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(N2CC3(CNC3)C2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
tert-Butyl 6-(4-fluorophenyl)-2,6-diazaspiro[3,3]heptane-2-carboxylate (0.029 g, 0.098 mmol) obtained in step 1 was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (0.11 mL, 1.467 mmol) was added. The mixture was stirred at room temperature for 5 hr, and saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.013 g, 68%).