Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[C:14]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])[CH:15]=[CH2:16].Cl>C(O)(C)C.O>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[C:14]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])[CH:15]=[CH2:16]
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: C=CC(=O)OC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: C=Cc1ccc(O)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Next, 130.5 g of poly(p-tert-butoxystyrene/cyclohexyl acrylate) was suspended in isopropanol. Subsequently, 30 ml of concentrated hydrochloric acid was added to the suspension, and agitated at 70 to 80° C. for four hours. The reaction liquid was cooled, and poured in 1500 ml of water, thereby precipitating a reaction product. The precipitated solid was collected by filtration, washed with water, and dried in vacuum. Thus, 85.5 g of poly(p-hydroxystyrene/cyclohexyl acrylate) was obtained as a white powdery crystal.
Reaction SMILES: [C:1]([C:3]1([C:14]([O:16]CC)=[O:15])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]1([CH3:13])[CH3:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[C:1]([C:3]1([C:14]([OH:16])=[O:15])[CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4]1([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)C(c2ccccc2)C1(C#N)C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 147 mg (0.60 mmole) of cyclopropanoid cyanoester 10 (produced in accordance with Example VIII), 88 mg (0.64 mmole) of anhydrous potassium carbonate, 0.50 mL of water, and 2.0 mL of methyl alcohol was heated at reflux for 20 minutes. The product was isolated by cooling the mixture to room temperature, cautiously acidifying it by addition of 2 mL of 2M aqueous HCl, subsequent dilution with 20 mL of saturated brine, and extraction with ether. The ether extracts were washed with saturated brine, then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the ether by evaporation at reduced pressure afforded 110 mg (85% yield) of cyanoacid 18, which was immediately decarboxylated in accordance with Example XVI.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:19][C:17]1[CH:18]=[C:2]([CH3:1])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=2)=[C:15]([CH3:22])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-nitro-phenoxy)-2-isopropyl-phenol (478 mg, 1.59 mmol) in a mixture of ethanol (10 mL) and EtOAc (30 mL) was added catalyst (10% Pd/C, 100 mg). The mixture was hydrogenated under 50 psi at RT for 2 h. The mixture was filtered through Celite® and concentrated to give the title compound of Step C (458 mg) as a brown solid. The title product of Step C was used without further purification in the next step. MS (APCI−) Calc.: 271.2, Found: 270.2 (M−1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:32]1(O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Reactant: Oc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccccc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol: ESMS m/e: 497.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.C[Si]([C:18]#[N:19])(C)C>[Zn+2].[I-].[I-].CC#N>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:18]#[N:19])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Product: COc1ccc2c(c1)OCC=C2C#N

Procedure:
7-Methoxy-4-chromanone (7 g) was added to trimethylsilyl cyanide (TMSCN) (7 ml), CH3CN (10 ml) and a catalytic amount of ZnI2 and refluxed for 2 hrs. The reaction was cooled, evaporated to dryness, then isopropyl alcohol saturated with HCl(g) (100 ml) was added and this solution refluxed 2 hrs. The reaction was cooled, evaporated to dryness, and saturated aqueous NaCl added. This was then extracted with CH2Cl2, the organic layer separated, dried (Na2SO4), filtered and evaporated affording 7.1 of product. IR(CHCl3): 2218 cm-1.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)[CH2:7][CH2:8]2)=[CH:31][CH:32]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCCCC[C@H]2CC[C@H](N(C)C(=O)Oc3ccc(Cl)cc3)CC2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-chlorophenyl chloroformate were reacted, followed by treatment with N-methyl-piperazine to give trans-Methyl-{4-[5-(4-methyl-piperazin-1-yl)-pentyl]-cyclohexyl}-carbamic acid 4-chloro-phenyl ester, MS: 436 (MH+, 1Cl).
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:36]([C:38]1[CH:43]=[CH:42][C:41]([CH:44]=[CH:45][C:46]([O:48][CH3:49])=[O:47])=[CH:40][CH:39]=1)=O>CN(C=O)C>[CH3:2][N:3]([CH3:25])[CH2:4][CH:5]=[CH:36][C:38]1[CH:43]=[CH:42][C:41](/[CH:44]=[CH:45]/[C:46]([O:48][CH3:49])=[O:47])=[CH:40][CH:39]=1.[CH3:2][N:3]([CH3:25])[CH2:4][CH:5]=[CH:36][C:38]1[CH:43]=[CH:42][C:41](/[CH:44]=[CH:45]/[C:46]([OH:48])=[O:47])=[CH:40][CH:39]=1
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC=Cc1ccc(/C=C/C(=O)O)cc1
Product: COC(=O)/C=C/c1ccc(C=CCN(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34 %

Procedure:
(E)-3-[4-(3-Dimethylaminopropenyl)phenyl]acrylic acid, methyl ester was prepared by the following way: (2-dimethylaminoethyl)triphenylphosphonium bromide (7.2 g, 17.4 mmol) in 30 mL of DMF was treated with KHMDS (27 mL, 1.01 equiv., 0.5 M in toluene) at -78° C. for one hour. At -40° C., 3-(4-formylphenyl)acrylic acid, methyl ester (2.54 g, 13.3 mmol, prepared according to the procedure of Syper et al., Synthesis, 1984, 9, 747-752) was added dropwise. The resulting mixture was stirred for 12 hours at rt and quenched with water. Extraction with EtOAc, drying over MgSO4 and evaporation in vacuo gave a residue that was purified via flash chromatography with DCM:MeOH (90:10) as eluting solvent. The title compound (1.1 g, 34%) was obtained as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](I)[CH3:24]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:23][CH3:24])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCl)c1
Reactant: CCI
Product: CCOc1cc(CC)cc(OCCCCl)c1OCc1ccccc1
Yield: 77 %

Procedure:
1-Benzyloxy-2-[3-chloropropoxy]-4-ethyl-6-ethoxy benzene was prepared in 77% yield as a white solid from 1-Benzyloxy-2-[3-chloropropoxy]-4-ethyl-6-hydroxy benzene and ethyliodide.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][CH2:20][C:21]1[C:22]2[C:27]([CH:28]=[C:29]3[C:34]=1[CH:33]=[CH:32][CH:31]=[CH:30]3)=[CH:26][CH:25]=[CH:24][CH:23]=2>CCO>[ClH:19].[CH:23]1[C:22]2[C:27](=[CH:28][C:29]3[C:34]([C:21]=2[CH2:20][S:18][C:9]2[NH:8][C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C@H:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:10]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: c1ccc([C@H]2NC(SCc3c4ccccc4cc4ccccc34)=N[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 9-chloromethylanthracene (256 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 179 mg of the product 232. 1H NMR (DMSO-d6) δ 11.35 (s, 2H), 8.80 (s, 1H), 8.64 (d, 2H), 7.85-7.50 (m, 4H), 7.38 (d, 1H), 7.30-6.80 (m, 10H), 6.80-6.65 (m, 4H), 5.92 (s, 4H); MS: m/z 445 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([O:1][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:11]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1cc(O)nc2ccccc12
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(C)c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
A mixture of 2-hydroxy-4-methylquinoline (0.48 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 4 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.24 g, 27% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[N:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]3[O:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23][C:11]=23)=[CH:4][CH:3]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>>[CH2:26]([N:8]([CH2:9][C:10]1[CH:15]=[N:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]2[O:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23][C:11]=12)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ncc(CNc2ccc(F)cc2)c2c1OC(C)(C)OC2
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)c1ncc(CN(Cc2ccccc2)c2ccc(F)cc2)c2c1OC(C)(C)OC2

Procedure:
Methyl 5-((benzyl(4-fluorophenyl)amino)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate 25a was prepared from methyl 5-((4-fluorophenylamino)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (21a) (120 mg, 0.3 mmol), benzaldehyde (100 uL, 1.0 mmol) and sodium cyanoborohydride (28 mg, 0.45 mmol) according to the procedure described in Example 24. MS-ESI m/z 437 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH:11](OC)[O:12]C)[CH:5]=1>CCO.C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH:11]=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C(OC)OC)c1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N)c(C=O)c1
Reaction time: 0.08 h

Procedure:
Compound 6 (0.95 g, 4.2 mmol) was dissolved at room temperature in 15 mL of a solvent mixture composed of EtOH-acetic acid-water 2:2:1. The strongly colored yellow solution became pale yellow in 5 minutes. The mixture was let stand for an additional 15 minutes before it was evaporated to dryness and further dried in high vacuum overnight to get Compound 7 as a yellow powder.
Reaction SMILES: I[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([NH:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.[C:15]([O-:18])(=[O:17])C.[K+].[CH3:20]O>[Pd]>[C:12]([NH:11][C:5]1[C:6]2[O:10][CH2:9][O:8][C:7]=2[C:2]([C:15]([O:18][CH3:20])=[O:17])=[CH:3][CH:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(I)c2c1OCO2
Reactant: CC(=O)[O-]
Reactant: CO
Agent: [Pd]
Agent: [K+]
Product: COC(=O)c1ccc(NC(C)=O)c2c1OCO2
Temperature: 150 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
A mixture of intermediate (2-b) (38.8 g), potassium acetate (20 g) and Pd/C (10%; 2 g) in CH3OH (500 ml) was stirred at 150° C. under 4.9×106 Pa (50 kg) pressure of CO, during 16 hours. The reaction mixture was cooled, filtered over dicalite, and the filtrate was evaporated. The residue was diluted with water, then extracted three times with DCM. The combined organic layers were dried, filtered and the solvent evaporated. The residue was dissolved in acetic acid (250 ml) and acetic anhydride (6 ml) was added dropwise. The mixture was stirred for 30 minutes at room temperature, then diluted with water (250 ml) and the resulting precipitate was filtered off, washed with water, then dried, yielding 19.4 g (64.7%) of methyl 7-(acetylamino)-1,3-benzodioxole-4-carboxylate (intermediate 2-c).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5](NC)=[CH:4][CH:3]=1.C([N:12]([CH2:15]C)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:15][NH:12][S:18]([CH2:17][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][CH:8]=1)(=[O:20])=[O:19]
Reactant: CCN(CC)CC
Reactant: CNc1ccc(C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNS(=O)(=O)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A solution of p-methyl-N-methylaniline (5.00 g) and triethylamine (5.05 g) in dichloromethane (140 ml) was cooled to 0° C. and methanesulphonyl chloride (4.73 g) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and quenched with water (100 ml). The organic phase was washed with 2N aqueous hydrochloric acid solution (75 ml) and 2N aqueous sodium hydroxide solution (75 ml), dried (MgSO4) and the solvent removed by evaporation. Thus was obtained N-methyl-(4-tolyl)methanesulphonamide (5.3 g, 65%), m.p. 49°-52° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].C1(C2CC(O)C3C(=CC=C(O)C=3)[O:34]2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH:14]3[OH:34])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2)O3)nc1

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) starting from 1.5 g of 2-phenylchroman-4,6-diol. The product was passed through a silica gel column using toluene-ethyl acetate (4:1) as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.7 Hz), 8.61 (dd, 1H, J 9.1, 2.7 Hz), 7.50-7.36 (m, 5H), 7.25 (d, 1H, J 2.7 Hz), 7.22 (d, 1H, 9.1 Hz), 7.00 (dd, 1H, J 8.7, 2.7 Hz), 6.88 (d, 1H, J 8.7 Hz), 5.65 (d, 1H, J 6.3 Hz), 5.30 (dd, 1H, J 11.9, 1.3 Hz), 4.99 (m, 1H), 2.33 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[N:10]([C:35]([C@H:32]1[CH2:33][CH2:34][C@H:29]([CH3:28])[CH2:30][CH2:31]1)=[O:36])[CH:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2ccnn2)CC1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2ccnn2)CC1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,3]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (0.20 g, 0.50 mmol) in toluene (1 ml) is added a solution of trans-4-methylcyclohexyl carboxylic acid chloride 1 M (1.0 ml, 1.0 mmol) and pyridine (0.046 ml, 0.58 mmol). The mixture is stirred overnight at 105° C. and diluted with ethyl acetate. The organic layer is washed with NaHCO3 sat (2×) and brine. The organic layer is dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue is purified by silica gel column chromatography (20% ethyl acetate/hexane to 100% ethyl acetate followed by 10% MeOH/ethyl acetate) to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: O.O[N:3]1[C:7]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[O:33]=[C:34]([NH:43][C@H:44]([C:49]([NH:51][CH:52]([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[CH:53]([P:55](CC)([O:57][CH3:58])=[O:56])[OH:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH:62]1([CH2:61][C@H:52]([NH:51][C:49](=[O:50])[C@H:44]([CH2:45][CH:46]([CH3:47])[CH3:48])[NH:43][C:34](=[O:33])[CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:53]([P:55]([NH:3][CH3:7])(=[O:56])[O:57][CH3:58])[OH:54])[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1
Reactant: CCP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNP(=O)(OC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
1-Hydroxybenzotriazole hydrate (225 mg, 1.47 mmol), N,N-diisopropylethylamine (237.8 μl, 1.365 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (281.8 mg, 1.47 mmol) were sequentially added to a solution of the title B compound obtained from the previous reaction and the title B compound from Example 17 (276 mg, 1.26 mmol) in 5 ml dimethylformamide of 0°. The reaction mixture was warmed and stirred at room temperature for 24 hours after which it was concentrated, then treated with 30 ml pH=4.01 buffer and extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed sequentially with saturated NaHCO3 (2×20 ml). Saturated NaCl (1×15 ml), dried and concentrated to give 398 mg crude product. Chromatographic purification (40 g silica gel, 1:1 hexane/ethyl acetate followed by 30:1 CHCl3 /MeOH) yielded 320 mg (60%) pure title compound. It was crystallized from ethyl acetate, m.p.=175°-177° C., [α[D =-74° (c=0.64, CH3OH) and characterized by MS, IR, 1H NMR, 13C NMR and 31P NMR [30.8 and 30.65 ppm (1.5:1.0) w.r.t. H3PO4 as external reference, CDCl3, 36.5 MHz].
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])O.P(Br)(Br)[Br:13]>>[Br:13][CH2:1][CH:2]=[C:3]([CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(C)C
Product: CC(C)=CCCC(C)=CCBr

Procedure:
Following the procedure of Example 9, linalool and phosphorus tribromide are reacted to form 1-bromo-3,7-dimethyl-2,6-octadiene.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH2:3][CH2:2]1.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:1]1[C:9]2[C:4](=[C:5]([CH:10]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc2c1CCC2
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc3c2CCC3)c2c[nH]nc2N1

Procedure:
The title compound was prepared from indan-4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[C:28]([CH3:29])=[C:27]([C:30](O)=[O:31])[C:26](=[O:33])[N:25]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[OH:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:27]4[C:26](=[O:33])[N:25]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:24]([CH3:23])[C:28]=4[CH3:29])=[O:31])=[CH:22][CH:21]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCO)ccc34)cc2)c(=O)n(-c2ccccc2)n1C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 2-((4-(4-aminophenoxy)quinolin-7-yl)oxy)ethanol (0.14 g, 0.5 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxylic acid (0.11 g, 0.51 mmol) in DCM (1.5 mL) was added HOAT (0.014 g, 0.1 mmol), and EDCI (0.11 g, 0.6 mmol). The reaction was refluxed for 3 hours. The cooled mixture was diluted with water (30 mL) and filtered. The solid was collected and stirred in a mixture of EtOAc (3 mL) and water (3 mL) overnight. The solid was collected by filtration and dried in vacuo at 50° C. for 9 hours to afford the title compound as a gray-white solid (180 mg, 74.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ncccn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ncccn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 50.8 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-2-ylcarbamate (200 mg, 0.739 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (182 mg, 0.739 mmol), diisopropylethylamine (0.258 ml, 1.48 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (138 mg, 51.1%) as a solid.