Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]=[CH:10][N:9]([C:12]3[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:17]=3)[C:6]2=[N:7][CH:8]=1)#[CH:2].[N:30]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[N+:31]=[N-:32]>CN(C=O)C.[Cu](I)I>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:16]1[CH:17]=[C:12]([N:9]2[C:6]3=[N:7][CH:8]=[C:3]([C:1]4[N:32]=[N:31][N:30]([CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH:2]=4)[CH:4]=[C:5]3[N:11]=[CH:10]2)[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=1
Reactant: C#Cc1cnc2c(c1)ncn2-c1cc(NC(C)=O)cc(-c2ccc(F)cc2F)c1
Reactant: [N-]=[N+]=NC1CCOCC1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)cnc32)c1
Yield: 45 %

Procedure:
A mixture N-(5-(6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (250 mg, 0.644 mmol), 4-azidotetrahydro-2H-pyran (90 mg, 0.77 mmol, 1.2 eq.), copper iodide (12 mg, 0.06 mmol, 0.1 eq.) in DMF was stirred at 90° C. for 16 h. The mixture was quenched with water and the precipitate formed was filtered and dried to give the crude product which was purified by preparative HPLC to give the product in 45% yield (150 mg). 1H NMR (300 MHz, DMSO): δ 10.4 (s, 1H), 8.99-8.97 (m, 2H), 8.88 (s, 1H), 8.61-8.60 (m, 1H), 8.32-8.29 (m, 1H), 7.91 (d, 1H), 7.76-7.68 (m, 2H), 7.48-7.41 (m, 1H), 7.3-7.24 (m, 1H), 4.80 (m, 1H), 4.02 (m, 2H), 3.50-3.60 (m, 2H), 2.10 (s, 3H), 2.0-2.12 (m, 4H); LC-MS (ESI): Calculated mass: 515.5; Observed mass: 516.5 [M+H]+ (rt: 1.37 min).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:31]=[C:30]([OH:32])[C:24]3[CH2:25][C:26]([CH3:29])([CH3:28])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([O:32][C:30]2[C:24]3[CH2:25][C:26]([CH3:28])([CH3:29])[O:27][C:23]=3[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C:15]3[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=3)[CH:31]=2)=[CH:7][N:6]=1)=[O:9]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Temperature: 160 °C
Yield: 48.2 %

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (60.1 mg, 0.348 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (100 mg, 0.348 mmol) and Cs2CO3 (227 mg, 0.696 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluting with 45% to 70% EtOAc in hexanes to give a colorless thick oil (71 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1 H) 8.85 (d, J=1.01 Hz, 1 H) 8.52 (d, J=1.26 Hz, 1 H) 7.27 (d, J=2.27 Hz, 1 H) 7.21 (s, 1 H) 7.15 (s, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 4.03 (s, 3 H) 3.74 (s, 3 H) 2.86 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H21N5O5 m/z 424.20 (M+H+).
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=CC=1)CCC.C[N:34](C=O)C>C1COCC1.S(Cl)(Cl)=O>[CH2:25]([N:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:32][C:19]=2[CH:20]=[C:21]([C:29]([NH2:34])=[O:30])[CH2:22][CH2:23]1)[CH:26]([CH3:28])[CH3:27]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)CN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy) phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml), thionyl chloride (0.25 ml) and DMF (1 droplet) were added at room temperature, and the mixture was stirred for 1.5 hours at room temperature. The solvent was concentrated under reduced pressure, and a solution of the residue in THF (25 ml) was added dropwise to a solution of 4-[[(1-trityl-1H-imidazol-1-yl)methyl]thio]aniline (1.13 g) in pyridine (10 ml) at 0° C. The mixture was stirred at room temperature for 20 hours, and water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give 7-[4-(2-butoxyethoxy) phenyl]-N-[4-[(1-trityl-1H-imidazol-4-yl) methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.43 g) as yellow crystals.
Reaction SMILES: I[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:14]#[CH:15])[CH3:12].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:14]([Si:13]([C:11]#[C:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][CH:3]=[CH:4]2)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:15]
Reactant: C#C[Si](CC)(CC)CC
Reactant: In1ccc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc2[nH]ccc2c1)(CC)CC
Temperature: 60 °C

Procedure:
To a scintillation vial was added -iodo-1H-indole (1.1 eq.), triethyl(ethynyl)silane (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.1 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.1 eq) were added. The vial was sealed and heated at 60° C. overnight. Upon completion of the reaction as monitored by TLC, the content of the vial was loaded onto a silica gel column pretreated with hexanes. Column was washed with hexanes and diethylether until all eluents containing product were collected. Carefully distill off hexanes and ether using rotary evaporator with minim heating afforded product 5-((triethylsilyl)ethynyl)-1H-indole as colorless oil, which was carried directly on to the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: Cc1cccc(C(O)CN)c1
Solvent: Cc1ccccc1C
Product: Cc1cccc(C(O)CNC2=NCCN2)c1

Procedure:
A mixture of 8.2 parts of α-(aminomethyl)-m-methylbenzyl alcohol, 6.1 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred in an oil-bath at 150°-160°C, while almost all xylene is distilled off. The residue is diluted with a few parts of acetone and allowed to crystallize. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding α-(2-imidazolin-2-ylaminomethyl)-m-methylbenzyl alcohol; m.p. 121°C.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][C:45]23[CH2:54][CH:49]4[CH2:50][CH:51]([CH2:53][CH:47]([C:48]4([F:56])[F:55])[CH2:46]2)[CH2:52]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][C:45]34[CH2:46][CH:47]5[CH2:53][CH:51]([CH2:50][CH:49]([C:48]5([F:55])[F:56])[CH2:54]3)[CH2:52]4)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variation as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.32 g, 86%): 1H NMR (300 MHz, CDCl3) δ 8.69 (br s, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.53 (d, J=14.1 Hz, 1H), 3.59 (s, 2H), 3.39 (s, 3H), 2.28 (br s, 2H), 2.08-1.92 (m, 6H), 1.53-1.51 (m, 6H), 0.97-0.89 (m, 2H), 0.66-0.60 (m, 2H); MS (ES−) m/z: 456.2 (M−1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCCCCCC[N+](CCCCCCCCCC)(CCCCCCCCCC)C.CCCCCCCCC[N+](CCCCCCCCC)(CCCCCCCCC)C.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[Cl-].[Cl-]>[CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([O:7][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: CC1CC1C(=O)O
Agent: CCCCCCCCCC[N+](C)(CCCCCCCCCC)CCCCCCCCCC
Agent: CCCCCCCCC[N+](C)(CCCCCCCCC)CCCCCCCCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Product: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Temperature: 45 °C
Yield: 93 %

Procedure:
A mixture of 2-methylcyclopropanecarboxylic acid (commercial product which is a cis-trans mixture, 75.0 g, 0.75 mol) and 1 N NaOH (900 mL, 0.90 mol) is warmed and stirred at 45° C. To the stirring solution is added benzyl bromide (131.0 mL, 1.10 mol) and methyltrialkyl(C8-C10)ammonium chloride (Adogen™ 464, 37.5 g). The mixture is stirred at 40-45° C. for 4 h, cooled to room temperature, and extracted with ethyl ether (800 mL). The organic layer is dried (MgSO4) and evaporated to a liquid. Chromatography over silica gel, eluting with hexanes gradually increasing to 5% ethyl acetate in hexanes, provides the racemic benzyl trans-2-methylcyclopropanecarboxylate as a liquid (132.2 g, 93%); 1H NMR (DMSO-d6) δ 7.40 (m, 5H), 5.05 (s, 2H), 1.43 (m, 1H), 1.30 (m, 1H), 1.06 (d, J=6.0 Hz, 3H), 1.02 (m, 2H), 0.74 (m, 1H). [Note: If NMR reveals the presence of a minor amount of cis isomer, it is removable by the chiral HPLC separation which may be carried out as described above.]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:15])([CH2:13][OH:14])[CH2:11][OH:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:15])([CH2:13][OH:14])[CH2:11][OH:12])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(C(O)(CO)CO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(O)(CO)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of 2-(4-nitrophenyl)propane-1,2,3-triol (1.1 g, 5.164 mmol, 1.0 eq) in ethanol (25 mL) was added 10% Pd/C (200 mg) and the mixture was stirred under a H2 gas balloon at RT for 1 h. The reaction mixture was passed through a celite bed and the solvent of the filtrate was evaporated to get 2-(4-aminophenyl)propane-1,2,3-triol (900 mg, 95%, solid; TLC system: MeOH/CHCl3 (1:9), Rf: 0.3).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C([N:14]1[CH2:26][C@H:25]2[C@H:17]([CH2:18][C:19]3[C:24]2=[CH:23][C:22]([Br:27])=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15]1)C1C=CC=CC=1>C1COCC1>[CH2:5]([O:4][C:2]([N:14]1[CH2:26][C@H:25]2[C@H:17]([CH2:18][C:19]3[C:24]2=[CH:23][C:22]([Br:27])=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15]1)=[O:3])[CH3:6]
Reactant: Cc1cc(Br)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(Br)cc3[C@H]2C1
Temperature: 20 °C
Reaction time: 15 h
Yield: 42.2 %

Procedure:
To a solution of ethyl chloroformate (293 mg, 2.7 mmol) in THF (1.5 mL) was added a solution of cis-3-benzyl-6-bromo-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (320 mg, 0.90 mmol) in dry THF (1.5 mL) dropwise over 10 min at 0° C. The reaction mixture was warmed to 20° C., stirred for 15 h and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 7/3) to yield cis-6-bromo-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (130 mg, 0.38 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19](Cl)(=[O:21])=[O:20])=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19]([NH:28][CH:25]([CH3:27])[CH3:26])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(S(=O)(=O)Cl)n2Cc1ccc(Cl)cc1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonyl chloride (115 mg, 0.295 mmol, intermediate 64) in DCM (5 mL) was added isopropylamine (17.4 mg, 0.59 mmol) followed by TEA (60 mg, 0.59 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed brine. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (50:1) to give 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (59 mg, 48.6% yield) as yellow syrup. LCMS retention time 1.436 min; LCMS MH+ 412.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([C:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]=2[O:15][CH3:17])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CCC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Temperature: 27.5 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)cyclopentane-1,3-dione (40 g, 0.143 mol) in acetone (2000 ml) is added anhydrous potassium carbonate (98.5 g, 0.714 mol) and iodomethane (45 ml, 0.72 mol). The resulting mixture is stirred at 25-30°C. for 16 hours, then volatile solvents are removed in vacuo, and the residue is diluted with distilled water (200 ml) and extracted with ethyl acetate (3×500 ml). Organic fractions are combined, washed with distilled water, brine, then dried over sodium sulphate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography to afford 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH2:13]([C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:24][C:23]3[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:3][CH:4]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)[CH3:14]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (300 mg, 1.14 mmol) and 2-chloro-6-fluorobenzaldehyde (360 mg, 2.27 mmol) in 5% HOAc/MeOH (6 mL) at room temperature under argon was added sodium cyanoborohydride (180 mg, 2.86 mmol). The reaction mixture was stirred at room temperature for 4 h and then concentrated, diluted with water, extracted into ethyl acetate and washed with brine. The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 25-50% EtOAc in hexane) to provide the title compound as an oil which solidified on trituration with ether/petroleum (152 mg, 32%). m.p. 123-5° C. NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.6 (br, 1H); 8.2 (br, 1H); 7.4-7.2 (overlapping m, 5H), 7.05 (m, 1H), 6.8 (d, 2H), 6.6 (s, 1H), 4.6 (s, 2H), 4.4 (br, 1H), 2.7 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:30])[CH3:29])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 36 mg, 100 μmol) and acetic anhydride (30 mg, 300 μmol). Yield 37 mg (92%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=O)=[CH:4][C:3]=1[F:16].C(O)(C(F)(F)F)=O.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:37]([N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([F:16])[CH:4]=3)=[N:30][CH:29]=2)[CH2:36][CH2:35]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CC(C)(C)OC(=O)Cc1cnc(Cl)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(6-chloro-5-fluoropyridin-3-yl)acetate 190-3 (123 mg, 0.50 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(6-chloro-5-fluoropyridin-3-yl)acetic acid 190-4, was dissolved in DMF (3 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (110 mg, 0.50 mmol) and DIEA (500 uL, 2.87 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (285 mg, 0.75 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by silica gel flash chromatography and eluted with 5% MeOH in CH2Cl2 to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-fluoropyridin-3-yl)acetamide 190-5. MS m/z 392.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH2:16][C:17]#[N:18])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH2:16][C:17](=[N:22][OH:23])[NH2:18])[N:9]=2)=[CH:19][CH:20]=1
Reactant: NO
Reactant: Cc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(NCc2ccc(Cl)cc2)nc(SCC(N)=NO)n1

Procedure:
A mixture of 10.6g. (0.035 mole) of [4-(p-chlorobenzylamino)-6-methyl-2-pyrimidinylthio]acetonitrile, 4.83 g. (0.07 mole) of hydroxylamine hydrochloride and 14.7 g. (0.14 mole) of sodium carbonate in 100 ml of N,N-dimethylformamide was heated on a steam bath for 3 hours. The mixture was filtered and the filtrate evaporated in a rotary-evaporator. The residue was triturated with petroleum ether containing a little ethyl acetate. The solid which crystallized was collected and recrystallized from ethyl acetate to give pure free base, m.p. 113°-116°. This free base was dissolved in absolute ethanol and acidified with an ethereal hydrochloric acid solution to give 3.5 g. of product, as the dihydrochloric salt, m.p. 230°-232° d.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 56.9 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (388 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (261 mg) and triphenylphosphine (413 mg) in THF (10 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (620 μL) at 0° C., and the mixture was stirred at room temperature for 70 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (310 mg) as a pale-yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:15][OH:16]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1
Reactant: O=C1CCN(Cc2cccs2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2cccs2)CC1

Procedure:
1-(2-Thiopheneyl)methyl-4-piperidone oxime is prepared from 1-(2-thiopheneyl)methyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH:13]([OH:21])[CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=[CH:8]2.[CH3:22][S:23]([Cl:26])(=[O:25])=[O:24]>C(N(CC)CC)C>[ClH:26].[CH3:20][N:18]([CH2:17][CH2:16][O:15][CH2:14][CH:13]([C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:9][CH:10]=1)[OH:21])[CH3:19]
Reactant: CN(C)CCOCC(O)c1cccc2cccc(N)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)CCOCC(O)c1cccc2cccc(NS(C)(=O)=O)c12

Procedure:
Triethylamine was added to 1-(8-amino-1-naphthyl)-2 -[2-(N,N-dimethylamino)ethoxy]ethanol hydrochloride. The resulting mixture was reacted with methanesulfonyl chloride to obtain oily 2-[2-(N,N-dimethylamino)ethoxy]-1-(8-methylsulfonylamino-1-naphthyl)ethanol hydrochloride (compound No. 291).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:25])([CH2:23]Cl)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(#N)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:25])([CH2:23][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1Cl)c1ccc(C2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: OC(Cc1ccc(Cl)cc1Cl)(Cn1ccnc1)c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 58 %

Procedure:
A solution of 39.8 g (0.1 mol) of 2-(4-cyclohexylphenyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol in 200 ml of acetonitrile is added dropwise to a suspension of 3.6 g (0.12 mol) of sodium hydride and 8.2 g (0.12 mol) of imidazole in 200 ml of acetonitrile. After heating the mixture to 80° C. for three hours, it is filtered and the crystal mass is washed with water and recrystallised from acetonitrile. 24.9 g (58% of theory) of 2-(4-cyclohexylphenyl)-1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-propan-2-ol of melting point 142° C. are obtained.