Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][CH:30]=2)=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccn3C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3cccn3C)nc2c1C#N
Temperature: 110 °C
Yield: 26.9 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (53 μl, 0.42 mmol) and triethylamine (100 μl) were added to a dimethyl sulfoxide (2 ml) solution of 7-fluoro-5-methyl-2-(1-methyl-1H-pyrrol-2-yl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-166) (69 mg, 0.21 mmol). The system was purged with nitrogen, then sealed up, and heated at 110° C. for 3.5 hours. After cooling, the solvent was evaporated away under reduced pressure, the resulting residue was dissolved in chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was separated and purified by preparative TLC to obtain a main product. This was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by filtration to obtain the entitled compound (24 mg, 27%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15](N(OC)C)=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:23])#[N:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C(Cl)Cl>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][CH:15]=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CON(C)C(=O)CCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCC=O)cc1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[1-(4-cyano-3-fluorobenzyl)-1H-imidazol-5-yl]-N-methoxy-N-methylpropionamide, as described above in Step A, (505 mg, 1.60 mmol) in dry THF (30 mL) at −78° C., under argon, was added diisobutylaluminum hydride (3.5 mL of a 1.0 M solution in CH2Cl2, 3.5 mmol), dropwise. The reaction mixture was stirred at −78° C. for 2 hours, then quenched with MeOH (1 mL) followed by saturated aqueous sodium potassium tartrate (20 mL). The mixture was allowed to warm to ambient temperature, then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography, eluting with a gradient of CH2Cl2—1% to 6% MeOH—0.1% to 0.6% NH4OH to give a mixture of the desired aldehyde and its methyl hemiacetal. Treatment of this mixture with dilute HCl in MeOH/H2O followed by concentration from toluene afforded the desired aldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=[C:19]([CH3:20])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:21]([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:15]=3[CH:16]=2)=[O:22])=[CH:37][CH:36]=1)[CH3:35]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(C)cc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. Orange solid, MS (ISP)=530.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[C:7]1(=[O:11])[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)[CH2:5][NH:6]1
Reactant: O=C1NCc2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To a slurry of Nail (0.39 g, 16.1 mmol) in DMF at 0° C. was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70° C. for 3 h. The mixture was cooled to 0° C. and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH2:9][C:10](=S)[NH:11][C:5]=2[CH:4]=1)#[N:2].[C:25]([NH:30][NH2:31])(=O)[CH2:26][CH2:27][CH3:28]>C(O)C>[C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH2:9][C:10]3[N:11]([C:25]([CH2:26][CH2:27][CH3:28])=[N:30][N:31]=3)[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCCC(=O)NN
Reactant: N#Cc1ccc2c(c1)NC(=S)CN=C2c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCCc1nnc2n1-c1cc(C#N)ccc1C(c1ccc(C(F)(F)F)cc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 8-cyano-1,3-dihydro-5-[p-(trifluoromethyl)phenyl]-2H-1,4-benzodiazepine-2-thione is heated in ethanol with butyric acid hydrazide and the resulting product heated to 250° C. to give 9-cyano-1-propyl-6-[p-(trifluoromethyl)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22]#N)=[CH:17][CH:16]=1.C([O:29][C:30](=O)[C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32])(=O)C>>[OH:32][C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30]([N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C@H:5]2[OH:12])[CH2:22][CH2:21][C:18]1[CH:19]=[N:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1)=[O:29]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: Nc1ccc2c(c1)C(O)CCO2
Product: O=C([C@@H](O)c1ccccc1)N(CCc1ccc(C(F)(F)F)nc1)c1ccc2c(c1)[C@H](O)CCO2

Procedure:
In analogy to example 55, 6-Amino-chroman-4-ol (WO 2003063794), (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give after silica gel chromatography the target compound. MS(m/e): 473.1 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([NH:5][CH:6]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:16]C)[O:8][CH2:7]2)[CH2:4][CH2:3]1.B(Br)(Br)Br.N>C(Cl)Cl>[CH:2]1([NH:5][CH:6]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[OH:16])[O:8][CH2:7]2)[CH2:4][CH2:3]1
Reactant: COc1cccc2c1CC(NC1CC1)CO2
Agent: BrB(Br)Br
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Oc1cccc2c1CC(NC1CC1)CO2
Temperature: -20 °C
Yield: 86.4 %

Procedure:
3-(N-Cyclopropylamino)-5-metoxychroman hydrochloride (5.6 g, 22 mmol) was suspended in CH2Cl2 (140 mL) under N2. The mixture was cooled on a dry-ice/EtOH bath to -20° C. BBr3 (4.1 mL, 44 mmol) dissolved in CH2Cl2 (60 mL) was added to the stirred mixture during 0.5 hour the yellow clear solution was slowly warmed to 0° C. and kept at that temperature until GC indicated a complete reaction (after 3-5 hours). Then the solution was poured on crushed ice (200 g) and enough conc. NH3 (aq.) to make a pH of 8-9. The mixture was extracted with ether (3×200 mL). The collected ether phases were dried (MgSO4), filtered and concentrated in vacou to afford a white solid. Crystallization from absolute EtOH afforded 3-(N-cyclopropylamino)-5-hydroxychroman (3.9 g, 88% yield) as colourless needles. Mp 147°-148° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC(N(C)C)=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: BrC1CCCC1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCCC1
Reaction time: 8 h

Procedure:
4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 15) (0.91 g) in 50 mL dry dimethylacetamide was stirred under nitrogen at 25° C. while adding 60% sodium hydride (0.20 g). After stirring for 30 minutes bromocyclopentane (0.8 mL) was added and the mixture stirred overnight. After evaporation in vacuo the residue was treated with water and extracted into ethyl acetate. Flash chromatography (3:2 cyclohexane:ethyl acetate) eluted 0.36 g of 1-Cyclopentyl-4-(cyclopentylamino)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine as colourless oil. 1H n.m.r. (DMSO) 8.319(s, 1H), 7.65-7.69(m, 2H), 7.40-7.48(m, 2H), 7.09-7.23(m, 5H), 5.926/5.955(d, 1H), 5.17-5.29(quin, 1H), 4.44-4.52(m, 1H), 1.86-2.12(m, 8H), 1.39-1.72(m, 8H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=2)[CH:10]=1.[NH2:19][C@@H:20]([CH3:37])[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:34]=[C:33]([F:35])[C:30]([C:31]#[N:32])=[C:29]([Cl:36])[CH:28]=2)=[N:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:36][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][N:22]([CH2:21][C@@H:20]([NH:19][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([NH:4][C:3]([N:2]([CH3:1])[CH3:18])=[O:17])=[CH:10][N:9]4[CH:11]=3)=[O:16])[CH3:37])[N:23]=2)[CH:34]=[C:33]([F:35])[C:30]=1[C:31]#[N:32]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CN(C)C(=O)Nc1ccc2nc(C(=O)O)cn2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cc(NC(=O)N(C)C)ccc2n1
Yield: 34.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylic acid (0.270 mmol, 0.067 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.108 mmol, 0.04 g) using DMF (4 ml) as the solvent. HBTU (0.027 mmol, 10.24 mg) was used instead of HOBt. The product precipitated into the water phase and was separated by filtration. The organic phase also contained the product. The organic phase was dried, filtered and evaporated. The combined precipitates were purified by preparative HPLC. 0.0192 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, 3H), 2.95 (s, 6H), 4.30-4.54 (m, 3H), 7.01 (d, 1H), 7.40-7.45 (m, 1H), 7.47-7.52 (m, 1H), 7.87 (d, 1H), 7.93 (dd, 1H), 7.97 (s, 1H), 8.30 (s, 1H), 8.39 (bs, 1H), 8.49 (d, 1H), 8.87-8.91 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:19]=2>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:19]=3)=[CH:5][N:4]=1
Reactant: Brc1cnc2cc(CCN3CCCCC3)cnc2c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2cnc3cc(CCN4CCCCC4)cnc3c2)c(OC)n1

Procedure:
The title compound was prepared by the method described in Example 156, using 2,4-dimethoxypyrimidin-5-ylboronic acid and the product from Example 155 in place of 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and the product from Example 154. 1H NMR (CDCl3, 300 MHz) δ 1.40-1.55 (m, 6H), 2.45 (m, 4H), 2.65 (m, 4H), 3.70 (s, 3H), 3.80 (s, 3H), 8.35 (m, 1H), 8.75 (m, 1H), 8.80 (s, 1H), 8.95 (m, 1H), 9.30 (m, 1H). MS (ESI) [M+H]+ at 380.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:28])[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33]>C(OCC)(=O)C>[Cl:37][C:36]([Cl:39])([Cl:38])[CH2:35][O:34][C:32](=[O:33])[NH:28][C:7]1[N:8]([C:10]2[CH:15]=[C:14]([O:16][Si:17]([CH:18]([CH3:20])[CH3:19])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:22])[CH3:23])[CH:13]=[C:12]([CH3:27])[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Reaction time: 0.08 h
Yield: 103 %

Procedure:
To a solution of Intermediate 54b (0.73 g, assumed 1.70 mmol) in ethyl acetate (8 mL) was added 1N sodium hydroxide solution (4.5 mL, 4.50 mmol). Stirred for 5 min then 2,2,2-trichloroethyl chloroformate (275 μL, 2.00 mmol) was added and the mixture stirred vigorously at RT for 3.5 h. Diluted with EtOAc, washed with water and brine, dried, and concentrated in vacuo. The residue was purified by FCC, using 0-15% EtOAc in cyclohexane, to give the still impure title compound (1.01 g). 1H NMR (300 MHz, CDCl3): inter alia 1.02-1.15 (18H, m), 1.18-1.38 (12H, m), 2.34 (3H, s), 4.82 (2H, s), 6.43 (1H, s), 6.69-6.77 (2H, m), 6.84-6.96 (2H, m).
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[C:11]2[CH:29]=[C:30]([Cl:34])[C:31]([F:33])=[CH:32][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH:41]=[O:42])CCCCC1.[Cl:43]C1C=C(C=CC=1)C=O.ClC1C=C(CC(O)=O)C=CC=1.C1(C(OC)C(O)=O)CCCCC1>>[Cl:34][C:30]1[C:31]([F:33])=[CH:32][C:10]2[N:9]=[C:8]([CH:1]([CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[O:42][CH3:41])[N:12]([CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:43])[CH:24]=3)[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:15])[C:11]=2[CH:29]=1
Reactant: O=CC1CCCCC1
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(Cc2ccccc2)nc2cc(F)c(Cl)cc21
Reactant: O=Cc1cccc(Cl)c1
Agent: COC(C(=O)O)C1CCCCC1
Agent: O=C(O)Cc1cccc(Cl)c1
Product: COC(c1nc2cc(F)c(Cl)cc2n1C(C(=O)NC1CCCCC1)c1cccc(Cl)c1)C1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with 3-chlorobenzaldehyde ([CAS RN 587-04-2]) and (3-chloro-phenyl)-acetic acid with DL-cyclohexyl-methoxy-acetic acid ([CAS RN 15540-18-8]). MS (ISP): 546.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]=[CH:39][CH:38]=[CH:37]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:30]([OH:29])[CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[N:40]=[CH:39][CH:38]=[CH:37]4)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2ccc(OC[C@H]3CO3)cc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2ccc3ncccc3c2)CC1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (100.0 mg; 0.264 mmol) is dissolved in ethanol (10 mL) at ambient temperature. (R)-6-Oxiranylmethoxy-quinoline (89) (53.0 mg; 0.264 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (70%→90% ethyl acetate in hexanes, then 50%→70% acetone in hexanes) affording the desired product (50 mg) as a white solid. ESMS: MH+ 580.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(O)C>[N:1]1([CH2:13][C:12]2[CH:11]=[C:10]([OH:9])[CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Piperidine (26 g) and 4.7 g of sodium borohydride were added to a solution of 15 g of 3-hydroxybenzaldehyde in 100 ml of ethanol, and the mixture was stirred until a complete solution formed. The solution was allowed to stand overnight at room temperature. Under reduced pressure, the solvent was distilled off, and 200 ml of ice water was added to the residue. The mixture was acidified with hydrochloric acid, and allowed to stand for 1 hour. The raw material was extracted away using ethyl acetate, and the aqueous solution was separated. The aqueous layer was alkalized with aqueous ammonia, and the precipitated oily product was extracted with ethyl acetate. The solvent was distilled off, and the residue was recrystallized from acetone/n-hexane to afford 17.5 g of 3-(1-piperidinylmethyl)phenol.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][C:7]([I:10])=[CH:8][CH:9]=1.[CH3:11]I.P([O-])([O-])([O-])=O>CN(C)C=O>[CH3:11][O:3][C:4]1[CH:5]=[N:6][C:7]([I:10])=[CH:8][CH:9]=1
Reactant: Oc1ccc(I)nc1
Reactant: CI
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To 647 mg (16.2 mmol) of 60% sodium hydride was added 20 ml of N,N-dimethylformamide, and then 20 ml of an N,N-dimethylformamide solution containing 2.38 g (10.8 mmol) of 3-hydroxy-6-iodopyridine was added thereto. The mixture was stirred in an argon atmosphere at room temperature for 2 hours. To the reaction mixture were added 2.14 g (15.12 mmol) of methyl iodide, and the mixture was stirred for 1 hour. To the reaction mixture was added a 0.01M phosphate buffer of pH7, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica-gel column chromatography (20 ml of silica gel, hexane:ethyl acetate=5:1 to 4:1) to give 2.57 g of 3-methoxy-6-iodopyridine (yield: 100%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.CCCCCCC>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)=[O:18]
Reactant: CSc1ncc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ncc(Br)cn1
Yield: 90 %

Procedure:
The title compound was prepared by oxidation of 2-methylthio-5-bromopyrimidine by m-chloroperbenzoic acid in chloroform as described in Example 39; yield 90%, m.p. 90° C. (n-heptane). 1H NMR (CDCl3): δ2.91 (Me),. 8.90 (H-4, H-6).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: OB(O)c1ccccc1O
Product: Cc1ccc(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c(O)c1
Yield: 68 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxyphenylboronic acid in 68% yield using method F; δH [2H6]-DMSO 13.55,(1H, b), 13.39,(1H, b), 8.38-8.32,(4H, m), 8.30-8.20,(4H, m), 8.13,(3H, d), 8.03,(1H, d), 7.37,(1H, t), 7.00,(2H, m), 6.81,(2H, m), 2.30,(3H, s); MS 355 (MH)+; HPLC retention time (system 1) 4.34 minutes.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)(=O)=O)=CC=1.[ClH:42].Cl.C(O)(C)C>>[OH2:8].[ClH:42].[F:38][C:37]([F:39])([F:40])[C:33]1[CH:32]=[C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CC(C)O
Product: O
Product: O=C(N[C@H]1CCN(CCc2cccc(C(F)(F)F)c2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(3-trifluoromethylphenyl)ethyl p-toluenesulfonate (0.69 g) were reacted under the same conditions as in Example 1. After the same post-treatment as in Example 1, the obtained compound was converted to hydrochloride with 30% hydrochloric acid-isopropanol to give (S)-N-(1-(2-(3-trifluoromethylphenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide hydrochloride monohydrate (0.44 g), melting point 160-163° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].C(O)(=O)C.CO>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)CCc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: NCCCc1ccc([N+](=O)[O-])cc1
Yield: 64.7 %

Procedure:
10.0 g of the amide compound and 9.5 g of sodium borohydride were suspended in 250 ml of dioxane, followed by the dropwise addition of 15 ml of acetic acid. The resultant mixture was stirred for 10 hours under reflux. The reaction mixture was added with 10 ml of methanol and then concentrated to dryness. The residue was dissolved in chloroform. The solution thus obtained was washed with water and then concentrated to dryness, thereby obtaining 6.0 g of 3-(4-nitrophenyl)propylamine as an oily substance. This compound was provided for the next reaction without any further purification.