Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: Cc1cc(CC(=O)O)c(C)s1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C)sc1C
Yield: 90 %

Procedure:
A solution of 2,5-dimethyl-3-thiophene acetic acid (34 g, 0.200 mol) and concentrated sulfuric acid (1.0 ml) in MeOH (500 ml) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, diluted to 500 ml with H2O, and neutralized with solid NaHCO3. The product was extracted with Et2O (2×200 ml), the organic layer was washed with H2O (1×100 ml), dried over MgSO4, and treated with activated charcoal. The solvent was removed in vacuo to give the product (33.2 g, 90% yield) as an oil; IR (neat) 1750 cm-1 ; mass spectrum m/z 184 (M+); 1H NMR (CDCl3) δ 2.32 (s, 3H, thiophene-CH3), 2.38 (s, 3H, thiophene-CH3), 3.45 (s, 2H, CH2CO2), 3.67 (s, 3H, CO2CH3), 6.53 (s, 1H, thiophene-H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ccc(Cl)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C=O
Yield: 88.7 %

Procedure:
2-Amino-5-chlorobenzyl alcohol (4.8 g, 30 mmol) and activated manganese (IV) oxide (21 g, 240 mmol) were refluxed in chloroform (100 mL) for 1 hour. The contents were allowed to cool, filtered through diatomaceous earth and concentrated in vacuo to afford the 2-amino-5-chlorobenzaldehyde as a dark solid (4.14 g, 81%): mp 74–76° C. 1H NMR (CDCl3, 300 MHz) 9.80 (s, 1H), 7.42 (s, 1H), 7.23 (d, 1H, J=7.0 Hz), 6.60 (d, 1H, J=7.0 Hz).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[C:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCCCC(=O)O
Product: C=C(C)C(=O)NCCCCCC(=O)O

Procedure:
Methacryloyl chloride was reacted with 6-amino caproic acid to give N-methacryloyl 6-amino caproic acid. This was then esterified with p-nitrophenol using standard synthetic methods to give N-methacryloyl 6-amino caproyl p-nitrophenol. 0.5 gm (0.0018 mol) N-isobutyryl 6-amino osproyl 2-amino pyridine, 0.4 gm N-methacryloyl histidine and 0.1071 gm CoCl2.6H2O were dissolved in 5 ml methanol and stirred for 1 hour. Methanol was then removed under reduced pressure. This was further diluted with 3.5 gm 2-hydroxyethyl methacrylate and 0.5 ml ethylene glycol dimethacrylate, and 100 mg azobisisobutyronitrile.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:15].C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([Cl:25])=[O:7])=[CH:4][C:3]=1[Cl:15]
Reactant: O=S(Cl)Cl
Reactant: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CON=Cc1cc(C(=O)Cl)cc(Cl)c1N
Temperature: 70 °C

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 180 g of the previously prepared 4-amino-3-chloro-5-methoxyiminomethylbenzoic acid, 2 l of toluene, 3 mL of dimethylformamide and 104 g (64 mL) of thionyl chloride. The resulting mixture was heated at 70° C. for 2 hours, filtered while hot and the solvent removed using a rotary evaporator yielding 178.1 g of the expected 4-amino-3-chloro-5-methoxyiminomethylbenzoyl chloride.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(=O)c1ccc(OCC(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(F)F
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (520 mg, clear colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone (750 mg, 3.5 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C([SiH](CC)CC)C.[S:8]1[C:12]([CH2:13][C:14]2[CH:15]=[C:16]([C:24]3(O)[C@H:29]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C@@H:28]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:27]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[O:25]3)[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:10]2[CH:64]=[CH:65][CH:66]=[CH:67][C:9]1=2.O>C(Cl)Cl>[S:8]1[C:12]([CH2:13][C:14]2[CH:15]=[C:16]([C@H:24]3[C@@H:29]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:28]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:27]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[O:25]3)[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:10]2[CH:64]=[CH:65][CH:66]=[CH:67][C:9]1=2
Reactant: OC1(c2cc(Cc3cc4ccccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: c1ccc(COC[C@H]2O[C@@H](c3cc(Cc4cc5ccccc5s4)cc4ccccc34)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
In a nitrogen stream, triethylsilane (0.34 ml, 2.06 mmol) and a boron trifluoride-diethyl ether complex (0.24 ml, 1.89 mmol) were added dropwise to a solution of (3R,4S,5S,6R)-2-[3-(benzo[b]thiophen-2-ylmethyl)naphthalen-1-yl]-3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran-2-ol (1.4 g, 1.72 mmol) in methylene chloride (15 ml) at 0° C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto and extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate n-hexane (1:10)] to obtain the title compound (1.1 g, 80.2%).
Reaction SMILES: [H][H].[OH:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6]>C(O)(C)C.[Rh]>[OH:3][CH:4]([CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)[C:5]([F:6])([F:7])[F:8]
Reactant: Oc1ccc(C(O)C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(C)O
Product: OC1CCC(C(O)C(F)(F)F)CC1

Procedure:
At 50° C. and a hydrogen pressure of 150 bar, 44.1 g of 4-(1-hydroxy-2,2,2-trifluoroethyl)phenol were hydrogenated in the presence of 3 g of rhodium (5% on carbon) in 500 ml of isopropanol. The catalyst was filtered off and the mixture was concentrated, to give the title product as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[Cl:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1Cl
Reaction time: 5 h

Procedure:
To a mixture of 25 g. of 6-methoxy-2-(methoxycarbonylmethyl)-1-tetralone and 150 ml. of benzene, 21 g. of phosphorus pentachloride are slowly added. After the addition, the chlorination mixture is allowed to stand for an additional five hours; then it is added to 500 g. of ice and extracted with xylene. The extracts, containing methyl 1-chloro-6-methoxy-3,4-dihydro-2-naphthylacetate, are combined, washed with water to neutrality and dried over sodium sulfate; then 23 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are added and the resulting mixture is refluxed for five hours. The dehydrogenation mixture is cooled, filtered, and evaporated. The residue is taken up in acetone and chromatographed on alumina and evaporated to yield methyl 1-chloro-6-methoxy-2-naphthylacetate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14]>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:4](=[O:5])[CH2:3][CH2:2][Cl:1]
Reactant: Oc1ccccc1Cl
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)Oc1ccccc1Cl
Temperature: 75 °C

Procedure:
3-chloropropionylchloride (14 ml) was added to 2-chlorophenol (18.18 g) and the mixture was stirred and heated at 60° C. for 1 hour, at 75° C. for 1 hour and left over the weekend at ambient temperature. The compound was purified by destillation in vacuo to give 19,7 g (b.p. 91-94° C. 0.08 mm Hg) of 3-chloro-propanoic acid 2-chlorophenyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:9][C:4]1[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(N)nc(C)n1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)nc(C)n1

Procedure:
To a suspension of 1.2 g of 4-amino-2,6-dimethylpyrimidine in 30 ml of dry acetonitrile with stirring was added 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was stirred for two hours at ambient temperature, allowed to stand for sixteen hours and the desired product, which had precipitated, was removed by filtration and washed with butyl chloride to yield 2.4 g, m.p. 125°-127°. The product showed absorption peaks by Nuclear Magnetic Resource at 4.0, 2.62 and 2.9 ppm; consistent for the product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=[O:21])[C:8]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:9]=2[NH:10][C:11](=[O:15])[C:12]=1[O:13]C>Cl.C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:8]2[C:7](=[O:21])[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[C:12]([OH:13])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: COc1c(-c2cccs2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2cccs2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A solution of 4-(2-thienyl)-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.20 g) in 2.4N HCl/THF (1:1, 200 mL) was allowed to stir at room temperature for 1 hour followed by heating to 50° C. for 1 hour. The reaction mixture was partitioned between ether and water. The organic portion was dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized twice from ethyl acetate/hexanes to afford the title compound (0.048 g); mp 231°-233° C. (dec.); NMR: 11.70 (bs, 1), 7.72 (d, 1, J=8.6), 7.62-7.60 (m,2), 7.40 (d, 1, J=1.9), 7.32 (dd, 1, J=8.6, 2.0), 7.10 (m, 1). Analysis for C14H8O3NClS 0.25 H2O.: Calculated: C, 54.29; H, 2.76; N, 4.51; Found C, 54.38; H, 2.90; N, 4.41.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:22])=[CH:17][C:3]=1[NH:4][C:5](=[O:16])[CH:6](Cl)[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[K].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:22])=[CH:17][C:3]=1[NH:4][C:5](=[O:16])[CH:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:43]1[C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]2[C:39]1=[O:49]
Reactant: CCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Cl)C(=O)c2ccccc2)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(C(=O)c2ccccc2)N2C(=O)c3ccccc3C2=O)c1

Procedure:
A mixture of 16.3 g of 2'-chloro-5'-tetradecyloxycarbonylchloro-benzoylacetanilide and 18.5 g of phthalimide potassium was stirred in 300 ml of dimethylformamide for 3 hours at room temperature. The reaction product thus obtained was treated as in Synthesis example 1. Upon recrystallizing the product from methanol, 12 g of Coupler 6 having a melting point of 81°-82° C. was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:11][CH3:26])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: CCS
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, ethyl mercaptan and DBU in DME. EI-MS m/e (%):46 (M+, 100), 315 (52).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([C@H:12]3[C@H:19]4[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]4)[C:14]([CH2:22][O:23][C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:13]3)=[CH:10][N:11]=2)[CH:6]=[CH:7][N:8]=1>C(O)(C)C>[CH3:21][C:17]1([CH3:20])[O:16][C@@H:15]2[C:14]([CH2:22][O:23][C:24]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:13][C@@H:12]([C:9]3[N:5]4[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]4=[N:11][CH:10]=3)[C@@H:19]2[O:18]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2c1cnc2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@H]2c1cnc2c(N)nccn12
Temperature: 100 °C

Procedure:
Liquid ammonia (10 mL) was added to 8-chloro-3-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazine (1-8) (180 mg, 0.32 mmol, 1 equiv) in isopropanol (10 mL). The resulting solution was placed in a high pressure vessel and heated to 100° C. (pressure did not exceed 600 psi) for 20 h. The resulting amber solution was concentrated, and the residue was purified via reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to afford 3-((3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)imidazo[1,2-a]pyrazin-8-amine (1-9) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.7 (d, 1H, J=5.5 Hz), 7.21-7.50 (m, 17H), 6.06 (s, 1H), 5.19 (d, 1H, J=5.5 Hz), 4.66 (d, 1H, J=5.5 Hz), 4.33 (m, 1H), 3.91 (d, 1H, J=14 Hz), 3.83 (d, 1H, J=14 Hz), 1.43 (s, 3H), 1.33 (s, 3H). LRMS m/z (M+H) 544.9 found, 545.2 required.
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][OH:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl>>[O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccn1
Reactant: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Agent: Cl
Product: c1ccc(Oc2nc3ccccc3c3c2ncn3CCOCc2ccccn2)cc1
Yield: 55.6 %

Procedure:
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.9 g, 2.95 mmol) was reacted with 2-picolyl chloride hydrogen chloride (0.53 g, 3.24 mmol) and the product purified to provide 0.65 g of 4-phenoxy-1-[2-(pyridin-2-ylmethoxy)ethyl]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: Fc1cccnc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc(F)c1Br
Temperature: 50 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A mixture of 2-bromo-3-fluoropyridine (1.0 g, 5.7 mmol) and 3-chloroperbenzoic acid (1.5 g, 7.4 mmol) in chloroform (3.5 mL) was stirred at 50° C. for 18 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 5:95) to give 2-Bromo-3-fluoropyridine 1-oxide as a white solid (878 mg, 80%). 1H NMR (400 MHz, CHCl3-d): δ 8.25 (dt, J=6.6, 1.3 Hz, 1 H); 7.25-7.17 (m, 1 H); 7.06 (ddd, J=8.7, 6.6, 1.3 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)N(C)C)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N,N-dimethylacetamide according to the method of Example 2; m.p. 122°-124°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[S:32][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:30][CH:29]=1)(=[O:27])=[O:26]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:36]1[CH2:35][CH2:34][N:33]([C:31]2[S:32][C:28]([S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)(=[O:27])=[O:26])=[CH:29][N:30]=2)[CH2:38][CH2:37]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=S(=O)(c1ccccn1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccn3)s2)CC1
Yield: 90 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 90%). MS (m/e): 551.2 (M+H+, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=1.[H-].[Na+]>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[N:19]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)c1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)nc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a reaction flask, tert-butyl 4-hydroxypiperidine-1-carboxylate (2.02 g, 10.0 mmol) and 4,6-dichloro-2-(trifluoromethyl)pyrimidine (2.18 g, 10.0 mmol) were dissolved in THF (19.7 mL) and cooled to 0° C. Sodium hydride (0.603 g, 15.1 mmol) was added and then the mixture was stirred for 30 minutes at 0° C. and at 25° C. for another 16 hours. The reaction was quenched with water, and was extracted with ethyl acetate and the organic extracts were washed with water, brine, dried over MgSC4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]=12>>[Cl:15][C:13]1[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]2=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc(Cl)nc3c2cnn3C)CC1

Procedure:
Reaction of N-methylpiperazine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave 6-chloro-1-methyl-4-(4-methyl-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [C:1]([CH:3](OS(C)(=O)=O)[CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[N:8]12[CH2:9][CH2:10][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(C#N)OS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CC2CCN1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a solution of tert-butyl 4-{2-cyano-2-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (80.0 g) in dichloromethane (200 mL) was added a solution of trifluoroacetic acid (137.0 g) in dichloromethane (200 mL), and the reaction system was stirred at room temperature overnight. The reaction system was concentrated, acetonitrile (200 mL) was added to the residue, and triethylamine (98.0 g) was slowly added at 0° C. The mixture was concentrated, the residue was diluted with dichloromethane, and the mixture was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (13.0 g) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH2:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH:13]=[CH2:14]>C(O)C.O>[CH2:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:22][CH:23]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1ccc(C=O)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc(CN2CCC(C(=O)OCC)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
The reaction conditions taught by A. E. Moormann, Syn. Comm., 23(6), 789-795 (1993) were used in the following preparation. To a stirred solution of 4.8 grams (0.030 mole) of ethyl piperidin-4-ylcarboxylate and 4.9 grams (0.030 mole) of 4-(2-propen-1-yloxy)benzaldehyde in 50 mL of ethanol was added 3.8 mL (0.030 mole) of borane-pyridine complex. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was then taken up in water and extracted with methylene chloride. The organic layer was washed with water and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure, yielding 9.0 grams of ethyl N-[4-(2-propen-1-yloxy)phenylmethyl]piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.