Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1
Reactant: Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cn1nnnc1[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2N
Yield: 79.1 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-1-phenyl-6-(1-methyl-1H-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Description 33a; 57 mg, 0.12 mmol) was dissolved in ethanol (5 mL) and treated with 1,4-cyclohexadiene (5 mL), followed by 10% palladium on activated charcoal (50 mg). The suspension formed was heated at reflux for 72 hours, then cooled and filtered. The filtrate was concentrated, and the residue taken up in ethyl acetate (2 mL) and treated with ethereal hydrogen chloride (2 mL, 1M). The solid formed was removed by filtration, washed with diethyl ether and dried to give the crude title compound as a solid (27 mg). MS (ES+) 285 (M+H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:18]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Anisole (2.16 g, 20 mmol) was dissolved in toluene (20 ml). The mixture was cooled to −10° C. and aluminum chloride (2.67 g, 20 mmol) was added. 4-Chlorobutyryl chloride (2.47 ml, 22 mmol) was added dropwise at −10° C. and stirred for 0.5 hour at −10° C. The reaction mixture was poured into iced water (40 ml). After separation, the organic layer was washed with 20%citric acid (10 ml) twice, 1N-sodium hydroxide (10 ml) and 20% brine (10 ml) twice, and was concentrated under reduced pressure to give 4-chloro-1-(4-methoxyphenyl)-1-butanone (4.21 g, yield 99%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][O:18]1)(=O)=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][C:33]([NH2:36])([CH3:35])[CH3:34].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:22].[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[CH:31][CH:30]=2)[C:26]([CH2:32][C:33]([NH:36][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)([CH3:34])[CH3:35])=[CH:27]1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CS(=O)(=O)OCCOc1ccccc1OCC1CCCO1
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)(Cc1c[nH]c2ccccc12)NCCOc1ccccc1OCC1CCCO1
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(tetrahydrofur-2-ylmethyloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{2-[2-(tetrahydrofur-2-ylmethyloxy)phenoxy]ethyl}amine hydrochloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>ClCCl>[Cl:13][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc(CCl)cc1
Temperature: 25 °C

Procedure:
4-Methylsulfanylbenzyl alcohol (30.5 g; 0.2 mol) was dissolved in dichloromethane (180 ml). A solution of thionyl chloride (23.8 g; 0.2 mol) in dichloromethane (120 ml) was added dropwise to the initial charge, which was kept under reflux. The reaction mixture was stirred under reflux for a further 2 h. The solution was cooled to room temperature, washed with H2O (2×250 ml), dried over Na2SO4 and concentrated. The oily residue (6) was purified by column chromatography (Al2O3, CH2Cl2).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5](=O)[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>CO>[CH2:1]=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5](=[N:24][OH:25])[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: NO
Reactant: C=C1c2cnccc2CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C1c2cnccc2CC(=NO)c2ccccc21

Procedure:
A mixture of the ketone from Step E (6.2 g.), anhydrous sodium acetate (3.1 g.), hydroxylamine hydrochloride (2.48 g.) and CH3OH (130 ml.) is heated under reflux for 24 hours. The solvent is removed in vacuo, water (100 ml.) is added to the residue and the resulting yellow-orange solid is collected and dried, 6.4 g., m.p. 183°-205° C. Recrystallization from toluene provides material with m.p. 218.5°-221° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:35][CH2:34][C:28]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=3[F:26])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Reactant: OCCc1cc(F)ccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cc(F)ccc3F)c2)Cc2ccccc2C1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
300.1 mg (0.88 mmol) of 2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl ester, 208.6 mg (1.32 mmol) of 2-(2,5-difluoro-phenyl)-ethanol and 346 mg (1.32 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The mixture was cooled in an ice bath, and 355.5 mg (1.76 mmol) of DIAD were added. After stirring overnight, the mixture was evaporated to dryness and the residue was purified by preparative RP HPLC (water/ACN gradient). 340 mg of the title compound were obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:8]([C:7]3[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[O:10])[CH2:24][CH2:25]2)=[N:27]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3nsc4ccccc34)CC2)c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example 2.6) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[C:29]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:28]=3)[CH2:12]1)[C:8](=[O:45])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[C:39]1([C:29]2[N:28]=[C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:45])[CH2:23]5)[CH2:12]3)[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Yield: 76.7 %

Procedure:
A solution of the ethyl ester 17e (0.67 g, 1.1 mmol) in THF/MeOH 1:1 (30 ml) was treated with a 1M solution of LiOH (15 ml) as described in Example 13 step d which gave the title compound, (0.49 g, 76%), (M+H)+581.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[NH2:2].[CH3:10][CH2:11][CH2:12][C:13](=O)[CH2:14][CH2:15][CH3:16]>>[CH3:10][CH2:11][CH2:12][C:13](=[N:2][NH:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NNc1cc(O)ncn1
Reactant: CCCC(=O)CCC
Product: CCCC(CCC)=NNc1cc(O)ncn1

Procedure:
10.0 g (79.3 mmol) 6-hydrazinopyrimidin-4-ol (CAS-No: 29939-37-5) were transformed in analogy to intermediate example 1c using heptan-4-one to give after working up and purification 13.5 g (77%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][S:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:10]1[CH:11]=[N:12][C:8]([S:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3])=[N:9]1)=[O:24])[CH3:21]
Reactant: C=CCOCCSc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOCCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A solution of 7.4 g. 3-(2-allyloxyethylthio)-1,2,4-triazole, 8ml. triethylamine 6.0 g. diethylcarbamoyl chloride in 40 ml. of tetrahydrofuran was heated under reflux for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated under vacuum to remove the solvent. Further precipitation of amine hydrochloride was filtered off. The filtrate was dissolved in 50 ml. methylene chloride and washed with ice-cold N/10 sodium hydroxide, with N/10 hydrochloric acid and finally with ice-cold water. The solvent was removed by vacuum distillation to give a liquid product, 1-diethylcarbamoyl-3-(2-allyloxyethylthio)-1,2,4-triazole, b.p. 148° - 153°C./0.05 mm. GLC assay showed that the 1-isomer was present to the extent of 98.33%. Elemental analysis was satisfactory.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC([O-])=O.[Na+].[N:30]#[C:31]Br>CO.C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:31]#[N:30])[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: N#CBr
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine (346 mg, 1 mmol) in MeOH (20 mL) was treated with NaOAc (574 mg, 7 mmol) then was warmed and stirred for 30 min. The suspension was then treated with a solution of cyanogen bromide (318 mg, 3 mmol) in CH2Cl2 (1.5 mL) at 0° C. The mixture was stirred and allowed to warm to room temperature overnight. The mixture was filtered, washed with MeOH and CH2Cl2, and the material was purified by chromatography on a silica gel column using 0 to 100% CH2Cl2/EtOAc, then 2.5% MeOH/CH2Cl2 to afford (4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbonitrile (250 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:22])[N:18]([CH3:21])[CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[F:29][C:30]([F:42])([F:41])[C@@:31]([O:36][Si](C)(C)C)([CH3:35])[C:32](Cl)=[O:33].NC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:8]([F:9])=[C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:22])[N:18]([CH3:21])[CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32](=[O:33])[C@:31]([OH:36])([CH3:35])[C:30]([F:42])([F:41])[F:29]
Reactant: CCN(C)C(=O)c1ccc(Sc2ccc(N)c(Cl)c2F)cc1
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Solvent: c1ccncc1
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: CCN(C)C(=O)c1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2F)cc1
Reaction time: 4 h
Yield: 47.9 %

Procedure:
2-Chloro3-fluoro-4-[4-(N-methyl-N-ethylcarbamoyl)phenylsulphanyl]aniline (Method 83; 580 mg, 1.7 mmol) was dissolved in DCM (6 ml) and pyridine (0.28 ml) was added. (S)-3,3,3-Trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (508 mg) was dissolved in DCM (1 ml) and added to the aniline. The solution was stirred for 4 hours and then washed with HCl (2 M) to remove excess pyridine. The organic layer was evaporated to dryness, dissolved in MeOH (17 ml) and HCl (2M, 1.7 ml) was added. The solution was left to stir overnight at room temp. The MeOH was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, the organic layers were combined, washed with water, brine and dried by pouring down a Chem Elut column and eluting with EtOAc. The resulting solution was evaporated to dryness and purified by chromatography on a Bond Elut column, eluting with 5-65% EtOAc/hexane to yield the title compound (390 mg) as a white solid. NMR: 1.0 (s, 3H), 1.6 (3, 3H), 2.8 (s, 3H), 3.2 (d, 2H), 7.2 (d, 2H), 7.3 (d, 2H), 7.6 (t, 1H), 7.9 (s, 1H), 9.9 (s, 1H); m/z 477.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:38][O:39][C:40]1[CH:46]=[C:45]([CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]2)[CH:44]=[CH:43][C:41]=1[NH2:42]>>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([CH2:47][CH2:48][N:49]4[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]4)=[CH:46][C:40]=3[O:39][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Product: COc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 51 %

Procedure:
The title compound (0.092 g, 0.12 mmol, 51%) was prepared from 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) and 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 131, step D) in an analogous manner to that described for Example 26, step E. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=5.9 Hz, 6H), 2.13 (s, 3H), 2.26-2.35 (m, 3H), 2.38-2.45 (m, 3H), 2.52 (d, J=8.8 Hz, 4H), 2.66-2.75 (m, 2H), 3.82 (s, 3H), 4.82-4.91 (m, 1H), 6.63 (d, J=5.1 Hz, 1H), 6.76 (dd, J=8.3, 1.7 Hz, 1H), 6.92-7.03 (m, 2H), 7.19 (t, J=7.9 Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 7.34-7.40 (m, 1H), 7.44 (dd, J=8.4, 6.2 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.67-7.77 (m, 2H), 8.07 (d, J=2.2 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 9.36 (d, J=6.2 Hz, 1H), 9.70 (s, 1H). MS (M+H, ES+) 733.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC1N=C(OC)N=C(OC)[N:32]=1.CN1CCOCC1.[NH4+].[OH-]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:32])=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic acid (12.0 g, 28.58 mmol) was suspended in tetrahydrofuran (100 mL). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (6.02 g, 34.3 mmol) was added followed by 4-methylmorpholine (9.43 mL, 85.74 mmol). The resulting mixture was stirred at room temperature for 1.5 hours at which time NH4OH (50.0 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then partially concentrated. The precipitate was collected by filtration washing with H2O and diethyl ether to provide an off-white solid (12.11 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 7.91 (br s, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.63 (app q, J=7.9 Hz, 1H), 7.31 (dt, J=2.6, 10.5 Hz, 1H), 7.17-7.12 (m, 1H), 7.13 (app d, J=8.3 Hz, 2H), 6.59 (s, 1H), 5.32 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 419.0968 (M+H calcd for C21H18ClF2N2O3 requires 419.0969).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:16][NH-:17].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:17][OH:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [NH-]O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCN(Cc2ccccc2)CC1

Procedure:
18.9 g of 1-benzyl-4-oxopiperidine, 26.8 g of hydroxylamide hydrochloride, and 24.8 g of sodium acetate in 200 ml of ethanol are stirred for 8 hours.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])#[CH:2].Br[CH2:20][CH2:21]CCCC.BrCC(CC)CCCC>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH:14]([CH2:20][CH3:21])[CH2:15][CH2:16][CH2:17][CH3:18])#[CH:2]
Reactant: CCCCCCBr
Reactant: C#Cc1c(CCCCCC)ccc2ccccc12
Agent: CCCCC(CC)CBr
Product: C#Cc1c(CC(CC)CCCC)ccc2ccccc12

Procedure:
1-Ethynyl-2-(2-ethylhexyl)naphthalene was prepared in a similar manner to 1-ethynyl-2-hexylnaphthalene, except that bromohexane was replaced by 1-bromo-2-ethylhexane.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)=[CH:15][CH:14]=2)=[N:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.F[B-](F)(F)F.C1CCN2C(=NCCC2)CC1>CC1C=CC=CC=1C.CN(C)C(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=3)[NH:12][C:3]=2[N:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(Cl)c(Nc2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Oc1ncc2c(n1)[nH]c1ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc12
Temperature: 155 °C

Procedure:
(S)-tert-Butyl 2-(4-(5-chloro-2-isopropoxypyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (55 mg, 0.12 mmol), palladium-(II) acetate (2.8 mg, 0.012 mmol), tricyclohexylphopsphine tetrafluoroborate (9 mg, 0.024 mmol) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene; 37 mg, 0.245 mmol) were dissolved in a mixture of o-xylene (0.5 ml) and N,N-dimethylacetamide (0.5 ml). The mixture was degassed with Ar for 5 min, the vessel closed and heated at 155° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The residue was purified by column chromatography (SiO2, 5 to 20% EtOAc in heptane, 2 g ISCO column). White solid (11 mg, 22%). MS (ISP): 413.3 ([M+H]+).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ClCl.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[C:15]([Cl:1])[C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CN(Cc1ccc(O)c(Br)c1)C1CCCCC1
Reactant: Cl
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(Cc1cc(Cl)c(O)c(Br)c1)C1CCCCC1
Temperature: 0 °C

Procedure:
3.6 gm of N-methyl-N-cyclohexyl-3-bromo-4-hydroxy-benzylamine hydrochloride were dissolved in 50 ml of 90% acetic acid and admixed with a solution of 0.75 gm of chlorine in 15 ml of glacial acetic acid while cooling with ice water. After stirring for a short time, the solution was poured into a mixture of ice and 10 N sodium hydroxide solution and extracted three times with methylene chloride. The organic phase was evaporated to dryness. The residue was purified by means of column chromatography over silicagel with ethyl acetate as the eluant, yielding N-methyl-N-cyclohexyl-3-bromo-5-chloro-4-hydroxy-benzylamine, m.p. 136°-138° C, of the formula ##STR29## after recrystallization from ethanol/ether.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[SH:10].[H-].[Na+].[N+]([C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1)([O-])=O>O1CCCC1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[S:10][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1
Reactant: Sc1nc2ccncc2[nH]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3ccncc3[nH]2)o1
Temperature: 25 °C
Yield: 11 %

Procedure:
3H-Imidazo[4,5-c]pyridine-2-thiol (1.51 g, 10.0 mmol) is suspended into 80 mL of tetrahydrofuran under argon. Then, 0.72 g (15.0 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (1.41 g, 10.0 mmol) is then added and the reaction mixture is stirred at room temperature for 16 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined and filtered. The filtrate is washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 70 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/acetonitrile/methanol from 75/20/5 to 90/0/10 v/v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is triturated in diethyl ether, filtered and dried under reduced pressure. 270 mg of 5-(3H-imidazo[4,5-c]pyridin-2-ylsulfanyl)-furan-2-carbaldehyde are obtained as a crystalline yellow powder. LCMS: m/z 246: [M+H]+ (base peak); m/z 244: [M−H]− (base peak).