Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)[CH2:5]2.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)[CH2:5]2
Reactant: O=C1Nc2ccc(O)cc2CN1C1CCN(Cc2ccccc2)CC1
Reactant: CN(C)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)CN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.1 g (3.26 mmol) of 3,4-dihydro-6-hydroxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone, 50 mL of tetrahydrofuran, 0.30 g (3.366 mmol) of 2-dimethylaminoethanol, 0.94 g (3.584 mmol) of triphenylphosphine, and 0.56 g (3.216 mmol) of azodicarboxylic acid ester was stirred for one hour at ambient temperature, 6 hours at reflux temperature and another 13 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (30-60 μm) using dichloromethane/EE/cyclohexane/methanol/concentrated ammonia 60/16/5/5/0.6 v/v/v/v/v as eluant. Working up the corresponding fractions yielded 0.9 g (69% of theoretical) of a colorless crystalline substance, Rf=0.47 (dichloromethane/EE/cyclohexane/methanol/concentrated ammonia 60/16/5/5/0.6 v/v/v/v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: NCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Product: Cc1ccc(Cl)c(OCC(O)CNCCc2nc3ccc(C4=NNC(=O)CC4)cc3[nH]2)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[C:23]([C:29]#[N:30])[C:22]=4[CH:21]=3)[O:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Si](I)(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[N:19]=[C:18]([C:20]3[O:28][C:27]4[CH:26]=[CH:25][N:24]=[C:23]([C:29]#[N:30])[C:22]=4[CH:21]=3)[O:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2noc(-c3cc4c(C#N)nccc4o3)n2)CC1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1nccc2oc(-c3nc(CC4CCNCC4)no3)cc12
Reaction time: 1 h

Procedure:
A stirred solution 4-[5-(4-cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (Example 82, 134 mg, 328 μmol) in anhydrous CHCl3 (7 mL) was treated with TMS-I (140 μL, 983 μmol). After 1 h, the reaction was treated with MeOH (3.4 mL), then solid Na2S2O3 was added slowly to remove the yellow colour. The reaction mixture was filtered and the excess Na2S2O3 collected was washed with MeOH (3×1 mL). The combined filtrates were allowed to stand for 1 h, before being purified by column chromatography (MeOH—CH2Cl2, 1:9) to yield the title compound: RT=2.44 min; m/z (ES+)=310.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=2[CH2:9][CH:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:31][O:30][C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:12]2[CH2:13][CH2:14][CH:10]([CH2:9][C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[N:1]3[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]3)[C:11]2=[O:15])=[CH:22][CH:23]=1)([CH3:29])[CH3:28]
Reactant: O=C1NCCC1Cc1ccccc1N1CCNCC1
Reactant: COC(C)(C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(C)(C)c1ccc(N2CCC(Cc3ccccc3N3CCNCC3)C2=O)cc1
Yield: 63.6 %

Procedure:
3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one (6) (1.2 grams) was subsequently allowed to react with 1.27 g of 1-bromo-4-(1-methoxy-1-methyl-ethyl)-benzene (11) in the presence of 0.041 grams of N,N′-dimethylethylenediamine, 0.088 g of CuI and 0.96 grams of K2CO3 in toluene (6 mL) at 110° C. for 17 hours to provide 1.2 grams of the racemate 1-[4-(1-methoxy-1-methyl-ethyl)-phenyl]-3-(2-piperazin-1-yl-benzyl)-pyrrolidin-2-one (12) (64% yield) following silica gel chromatography (40:1:0.5 chloroform-methanol-ammonium hydroxide); MS (AP/CI) observed: 408.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:17][C@H:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46]>CN(C)C=O.C(OCC)(=O)C>[CH2:46]([N:22]1[C@@H:19]2[C@H:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C@@:16]1([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:15]([O:14][CH2:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=1)[CH2:21][CH2:20]2)[CH:45]=[CH2:44]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 2.1 g, 4.0 mmol), potassium carbonate (1.7 g, 12.0 mmol) and allyl bromide (0.42 ml, 4.8 mmol) in dimethylformamide (10 ml) were stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate and washed with water. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography, eluting with 10% ethyl acetate/iso-hexane, (1.8 g, 80%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1C(O)=O.[OH-].[Na+].C(=O)=O>O.[Cu-]=O>[F:1][C:2]1[CH:3]=[CH:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1[F:11]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Agent: O=[Cu-]
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(F)c(F)c1F
Reaction time: 4 h

Procedure:
19.4 g (0.1 mol) of 2,3,4,5-tetrafluorobenzoic acid are dissolved in 40 g of water, 20 g of a mixture of trialkylamines having 6 to 14 carbon atoms (Hostarex A 327; a commercial product of Hoechst AG) and 0.2 g of copper(I) oxide are added and the pH is adjusted to 7 by addition of 30% strength aqueous sodium hydroxide solution. The decarboxylation is carried out in an autoclave at 155° C. within a period of 4 hours, the evolved carbon dioxide at a pressure of 12 bar being depressurized via a pressure cooler and the distillate passing overhead in this case being collected (cold trap -78° C.). After termination of the reaction, the autoclave is cooled and the 1,2,3,4-tetrafluorobenzene is distilled off by steam at 100° C. and 1.5 l of distillate are obtained, which distillate is combined with the distillate collected previously. The combined distillates are extracted by means of dichloromethane, the organic phase is separated off, dried over magnesium sulfate, filtered and the solvent is removed in vacuo. 10.5 g of crude, slightly yellowish 1,2,3,4-tetrafluorobenzene are obtained, which can be brought to a very high purity by fractional distillation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:16]=1[CH:17]=[N:18][CH:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21]>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:17]([NH:18][C@@H:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21])[C:16]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:15]=2[F:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)CC(CO)N=Cc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Reaction time: 1 h

Procedure:
To a solution of 1,4-dibromobenzene (24.5 g, 100 mmol, 5 eq) in dry ether (200 mL) under nitrogen atmosphere at −30° C., nBuLi (64.75 mL, 1.6 M solution in hexanes, 5 eq) was added and the reaction mixture was stirred for 1 h. A solution of 2-[(2,4-difluorobenzylidene)-amino]-4-methylpentan-1-ol (5 g, 20 mmol) in dry ether was added slowly at −30° C. After stirring for 4 h, the reaction was quenched with water. The ether layer was washed with saturated solution of NaCl, and dried over MgSO4. The solvent was removed under reduced pressure and the crude was flash chromatographed on 500 cm3 of silica gel using 8:2 hexanes:EtOAc as an eluant to yield (2S)-2-{(S)-[(4-bromophenyl)-(2,4-difluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C@H:19]2[C@H:24]([O:25]CC3C=CC=CC=3)[C@@H:23]([O:33]CC3C=CC=CC=3)[C@H:22]([O:41]CC3C=CC=CC=3)[C@@H:21]([CH2:49][O:50]CC3C=CC=CC=3)[S:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C@H:19]2[C@H:24]([OH:25])[C@@H:23]([OH:33])[C@H:22]([OH:41])[C@@H:21]([CH2:49][OH:50])[S:20]2)=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: Clc1ccc([C@@H]2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: OC[C@H]1S[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
6-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl) tetrahydro-2H-thiopyran-2-yl)benzyl)-2,3-dihydrobenzo[b][1,4]dioxine (126, 204 mg, 0.26 mmol) in dichloromethane (5 mL) reacted with BCl3 (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. After quenching the reaction with methanol, solvent was evaporated under a reduced pressure. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (E047, 13 mg, 12% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:23]=[C:13]3[NH:14][C:15](=[O:22])[C:16]4[C:21]([N:12]3[N:11]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:23]=[C:13]3[NH:14][C:15](=[O:22])[C:16]4[C:21]([N:12]3[N:11]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(-c3cccc([N+](=O)[O-])c3)nn2c2ccccc12
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Yield: 60 %

Procedure:
A mixture of EXAMPLE 8 (1.07 g, 3.5 mmol) and 10% palladium on carbon (0.2 g) in methanol (25 mL) was stirred overnight under 1 atmosphere of hydrogen and filtered. The filtrate was concentrated and the residue crystallized from methanol to provide the title compound (0.58 g, 60%). 1H NMR (DMSO-d6) δ 12.23 (s, 1H), 8.10-8.18 (m, 2H), 7.86-7.95 (m, 1H), 7.49 (t, J=7.0 Hz, 1H), 7.19 (s, 1H), 7.05-7.12 (m, 2H), 6.56-6.63 (m, 1H), 6.20 (s, 1H), 5.19 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[C:16]=1[CH3:28].C(N(CC)CC)C.ClC(OCC)=O.[NH2:42][OH:43]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][C:25]([NH:42][OH:43])=[O:26])=[O:22])[C:16]=1[CH3:28]
Reactant: NO
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
2-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-acetic acid (385 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (140 mg, 35%) as a red solid. LC-MS (m/z) 401 (M+1).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])S(C1C=CC(C)=CC=1)(=O)=O)C.[ClH:32].O>O1CCOCC1>[ClH:32].[CH3:28][O:27][C:19]1[C:20]2[O:26][CH2:25][O:24][C:21]=2[CH:22]=[C:23]2[C:18]=1[CH:17]=[N:6][CH:5]=[CH:4]2
Reactant: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1c2c(cc3ccncc13)OCO2
Temperature: 5 °C
Yield: 61.8 %

Procedure:
N-(2-methoxy-3,4-methylenedioxybenzyl)-N-(p-toluenesulfonyl)aminoacetaldehyde diethylacetal (3) in an amount of 69.89 g (0.155 mol) was dissolved in 0.194 ml of dioxane, to which 14.7 ml (0.169 mol) of concentrated hydrochloric acid and 47.1 ml of water were added and heated under reflux for two hours and 40 minutes. After the mixture were cooled to about 5° C., deposited crystals were collected by filtration, washed with 30 ml of cold dioxcane and then dried to obtain 22.95 g of 8-methoxy-6,7-methylenedioxyisoquinoline hydrochloride (4) as yellow crystals. Yield 61.8%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=3)[CH:10]=[CH:11]4)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: Cc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: Cc1cccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methylbenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:17])C(OCC)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11](=[O:17])[NH:20][CH2:19][CH2:18][N:21]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCN
Solvent: CO
Product: O=C1NCCN=C1c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with ethyl 4-nitrophenylpyruvate (223 mg, 1.00 mmol), 3 pieces of molecular sieves (4-8 mesh, 3A) and anhydrous methanol (10 mL). The resulting solution was cooled to 0° C. with an ice bath and 1,2-ethylenediamine (63 mg, 1.05 mmol) was added dropwise. After addition was complete the reaction was stirred at room temperature for 1 h. After this time the resulting suspension was filtered and the filter cake washed with cold methanol (2×5 mL). The filter cake was dried in an oven at 50° C. overnight under vacuum to afford 31 in 89% yield (196 mg) as a white solid: mp 191-192° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.63 (bs, 1H), 8.26 (d, 2H, J=8.0 Hz), 8.09 (d, 2H, J=8.0 Hz), 3.88 (t, 2H, J=6.5 Hz), 3.37 (m, 2H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:2]#[C:3][CH3:4].Cl.[CH2:21]([O:23][NH2:24])[CH3:22].Cl>N1C=CC=CC=1>[CH2:21]([O:23][N:24]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])[N:11]=[CH:10][N:9]=1)[CH3:22]
Reactant: CCON
Reactant: CC#CCOc1cc(C(=O)c2ccccc2)ncn1
Agent: Cl
Solvent: c1ccncc1
Product: CC#CCOc1cc(C(=NOCC)c2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 3 ml of pyridine were added 0.3 g of 6-(2-butynyloxy)-4-benzoylpyrimidine and 0.17 g of O-ethylhydroxylamine hydrochloride, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into 10% hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give two isomers of (6-(2-butynyloxy)-4-pyrimidyl)phenylketone O-ethyloxime (referred to as isomers A and B).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.[Cu]I>[OH:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:3][CH:4]=2)=[CH:10][C:11]=1[C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[OH:30])=[O:22]
Reactant: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(Cl)nc2)c2ccccc12
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(-n3cccn3)nc2)c2ccccc2c1O
Temperature: 120 °C

Procedure:
To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide (Example 3, 0.050 g, 0.12 mmol) and pyrazole (8.0 mg, 0.12 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added aqueous cesium carbonate (1 N, 0.23 mL, 1 N aqueous, 0.23 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (2.2 mg, 0.015 mmol), and copper(I) iodide (1.4 g, 0.0076 mmol). The mixture was heated at 120° C. for 20 hours, cooled to room temperature, and additional trans-N,N′-dimethylcyclohexane-1,2-diamine (2.16 mg, 0.015 mmol) and copper(I) iodide (1.4 mg, 0.0076 mmol) were added. The reaction was heated at 140° C. for 24 hours, cooled to room temperature, filtered, and purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 442.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.50-8.47 (m, 2H), 8.33 (s, 1H), 7.84-7.81 (m, 1H), 7.76-7.74 (m, 2H), 7.60-7.51 (m, 2H), 7.24-7.20 (m, 2H), 6.48 (br s, 1H), 6.37 (d, J=6.2 Hz, 1H), 4.36 (s, 2H), 3.95-3.92 (m, 1H), 3.58-3.51 (m, 1H), 2.16-2.13 (m, 2H), 1.81-1.78 (m, 2H), 1.46-1.25 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][CH:31]=1)[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-chlorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.4 mg, 35.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.30–7.20 (m, 3H), 7.20 (m, 3H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.71 (apparent d, 1H, J=2.9 Hz), 6.69 (apparent t, 1H, J=2.9 Hz), 6.67 (apparent t, 1H, J=2.9 Hz), 6.65 (apparent d, 1H, J=2.9 Hz), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (apparent sept, partially hidden, 2H, J=7.1 Hz), 2.30–2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 491.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]([OH:17])[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:17][C@H:7]([C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[O:6]1)[CH2:8][NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H](O)[C@H]1COC(C)(C)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](OS(C)(=O)=O)[C@H]1COC(C)(C)O1

Procedure:
Alcohol 24 was dissolved in dichloromethane and cooled to 0°. Triethylamine and methanesulfonyl chloride were added and the solution stirred until the reaction was completed. The solution was extracted and the solvent removed to obtain the mesylate (25) which was purified using silica gel column chromatography. Solvent removal afforded a liquid.