Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.B.C1COCC1.C(O)(=O)C>C1COCC1.[Fe]>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)n1
Agent: [Fe]
Agent: B
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc(Br)nc(CO)c1
Yield: 33.9 %

Procedure:
A solution of 6-bromo-4-nitro-pyridine-2-carboxylic acid (6.60 g, 29.1 mmol) in THF (150 ml) was treated with borane/THF (87 ml of a 1M solution). The mixture was refluxed for 6 hr, then powdered iron (16.3 g, 291 mmol) was added, followed by acetic acid (150 ml). Reflux was maintained for 6 hr, the mixture was filtered, evaporated and partitioned (AcOEt/aqueous NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with CH2Cl2/MeOH=93/7) to provide 2.0 g (34%) of the title compound as a white solid material. Mp. 144–145° C. (AcOEt), MS: m/e=202 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](C(OCC)=O)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Yield: 142.5 %

Procedure:
To a solution 1-[(4-methoxy)phenyl]-3-(ethoxycarbonyl)-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide (2.05 g, 4.43 mmol) in 10 mL of THF and 10 mL of water was added potassium hydroxide (0.32 g, 5.76 mmol). The resulting solution was stirred at ambient temperature for 18. The THF was removed in vacuo and the aqueous was extracted with ether to remove unreacted ester. The aqueous layer was acidified with HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated to afford 1.1 g (57%) of the title compound, which was used without further purification. LRMS (ES−): 433.0 (M−H)−.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([O:19][CH3:20])[N:3]=1.N(OCCC(C)C)=O.[ClH:29]>C(#N)C.[Cu](Cl)Cl>[Cl:29][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([O:19][CH3:20])[N:3]=1
Reactant: COc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1nc(Cl)c(C#N)c(-c2ccc(O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.98 g (15.285 mmol) of 2-amino-4-(4-hydroxyphenyl)-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 120 ml of acetonitrile, 6.175 ml (45.855 mmol) of isoamyl nitrite and 6.165 g (45.855 mmol) of copper(II) chloride are added and the mixture is stirred at room temperature overnight. 1N hydrochloric acid is added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution and with water, dried over sodium sulphate and concentrated. The residue is purified on a silica gel column (mobile phase: toluene/ethyl acetate 2:1). This gives 1.3 g (23% of theory) of the target compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]=[CH:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[CH2:8][N:7]1C(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[C].[Pd]>[CH2:12]([O:11][C@H:9]1[CH2:8][NH:7][C@H:6]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:26])[CH3:1])[CH2:10]1)[CH:13]([CH3:15])[CH3:14]
Reactant: C=C(C)CO[C@@H]1C[C@@H](C=CCC(C)C)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCC[C@@H]1C[C@@H](OCC(C)C)CN1
Yield: 97.6 %

Procedure:
In 5.8 ml of ethanol is dissolved 0.29 g of benzyl (2S,4R)-2-(4-methyl-1-pentenyl)-4-[(2-methyl-2-propenyl)oxy]-1-pyrrolidinecarboxylate. After adding 0.06 g of 5% palladium-carbon, the mixture is stirred at ambient temperature for 1.5 hours in a stream of hydrogen. The reaction mixture is filtered with Celite, and the solvent is distilled off from the filtrate under reduced pressure. Thus, 0.18 g of (2R,4R)-4-isobutoxy-2-(4-methylpentyl)-pyrrolidine is obtained as a yellow oily product.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[C@H:11]1O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C(Cl)=S)C1C=CC=CC=1.[H-].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C.CN(C)C1C=CN=CC=1.O1CCOCC1>[C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1ncn2[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: CC#N
Solvent: C1COCCO1
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of compound 3 (1.00 g, 2.11 mmol) in dry acetonitrile (65 mL) were added 4-(dimethylamino)pyridine (0.77 g, 6.32 mmol) and phenoxythiocarbonyl chloride (0.44 mL, 3.16 mmol). The mixture was stirred at room temperature for 2 h. After concentration, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (2×30 mL), aqueous solution of hydrochloric acid 0.5 N (30 mL) and water (3×30 mL). The organic layer was dried, filtered and concentrated to dryness. The crude thiocarbonylated intermediate was directly treated with tris-(trimethylsilyl)silane hydride (0.78 mL, 5.23 mmol) and α,α-azoisobutyronitrile (AIBN, 0.112 g, 0.69 mmol) in dry dioxane (17 mL) at reflux for 2 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane) to give pure 4 (0.93 g, 96%) as a foam: 1H NMR (DMSO-d6): δ 2.9-3.1 (m, 2H, H-2′ and H-2″), 4.6-4.7 (m, 3H, H-4′, H-5′ and H-5″), 5.8 (br s, 1H, H-3′), 6.43 (dd, 1H, H-1′, J1′,2′=3.1 Hz, J1′,2″=7.6 Hz), 7.3 (br s, 2H, NH2-6), 7.4-7.9 (m, 10H, 2 benzoyls), 8.05 and 8.33 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+m/z 460 [M+H]+, 325 [S]+, 136 [BH2]+, (FAB) m/z 458 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 261 nm (ε 14400), 231 nm (ε 26300), λmin 249 nm (ε 12000); [α]D20=−38 (c 1.04, DMSO).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[N:6]=[CH:5][C:4]=2[C:3]=1[OH:12].[CH:13]1([CH2:16]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:12][CH2:16][CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2
Reactant: Cn1ncc2c(O)c(Br)ccc21
Reactant: OCC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(OCC3CC3)c(Br)ccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A solution of 5-bromo-1-methyl-1H-indazol-4-ol (73.7 mg, 0.324 mmol) and cyclopropyl carbinol (0.0386 mL, 0.489 mmol) in tetrahydrofuran (2.80 mL) was treated with triphenylphosphine (0.102 g, 0.390 mmol), cooled to 0° C., followed by dropwise addition of diisopropyl azodicarboxylate (0.0767 mL, 0.390 mmol). Reaction mixture was warmed to RT and stirred at RT for 16 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 100% CH2Cl2) gave the desired product (72 mg, 78%) as a yellow solid. LCMS calculated for C12H14BrN2O (M+H)+: m/z=281.0, 283.0. found: 281.0, 283.0.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[N:41][CH:42]=[C:16]23)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[N:41][CH:42]=[C:16]23)[CH2:11][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2cnnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2cnnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.58 g) in tetrahydrofuran (10 mL) was added 1 M tetra-n-butylammonium fluoride-tetrahydrofuran solution (10 mL), and the mixture was stirred at room temperature for 15 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=50/50→25/75 (volume ratio)] to give the title compound as a colorless amorphous compound (293 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][C:6](=O)[CH2:5]2.[Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CNc2ccc(Br)cc2C1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCCN2
Yield: 86.1 %

Procedure:
A solution of 6-bromo-2,3-dihydro-1H-quinolin-3-one (0.05 g, 0.219 mmol) in THF (20 mL) and aqueous sodium carbonate (5 mL) was treated with aluminum trichloride (0.116 g, 0.9 mmol) and lithium aluminum hydride (33 mg, 0.9 mmol) The reaction was refluxed for 18 h. and cooled down. The filtrate evaporated to dryness, taken up in water and extracted with EtOAc (3×). Ethyl acetate extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography (hexane/EtOAc, 1:3) to afford 6-bromo-2,3-dihydro-1H-quinoline (0.040 g, 87%). LRMS (ES+): 211.3 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[CH2:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>>[CH2:37]([S:39]([N:33]1[CH2:32][CH2:31][CH:30]([C:23]2[CH:22]=[C:21]3[C:26]([CH2:27][CH:28]([CH3:29])[N:19]([C:17]4[CH:18]=[C:13]([N:10]5[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]5)[N:14]=[C:15]([NH2:36])[N:16]=4)[CH2:20]3)=[CH:25][CH:24]=2)[CH2:35][CH2:34]1)(=[O:41])=[O:40])[CH3:38]
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and ethanesulfonyl chloride. LCMS (M+H)+: m/z=514.2.
Reaction SMILES: CC1(C)O[C:6](=O)[CH:5]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=3)[NH:12][CH:11]=2)C(=O)O1.[NH2:22][C:23]1[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH:35]([CH3:37])[CH3:36])[CH:29]=1)=[O:26].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>N1C=CC=CC=1>[Br:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:9][CH2:5][C:6]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH:35]([CH3:36])[CH3:37])[CH:29]=2)[C:25](=[O:26])[C:24]2[C:23](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:22]=1
Reactant: CC(C)Oc1cccc(NC(=O)c2ccccc2N)c1
Reactant: CC1(C)OC(=O)C(Cc2c[nH]c3ccc(Br)cc23)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CC(C)Oc1cccc(-n2c(CCc3c[nH]c4ccc(Br)cc34)nc3ccccc3c2=O)c1

Procedure:
A solution of 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl-5-bromoindole (4.12 g, 12 mmol), 2-amino-N-(3-isopropoxyphenyl)benzamide (3.48 g, 13 mmol), and PPTS (1.64 g, 6.5 mmol) in 50 ml of pyridine was refluxed for 3.5 days. The reaction mixture was then evaporated in vacuo to dryness, and the residue was taken up in methylene chloride. The product was chromatographed (30% ethyl acetate/hexanes, SiO2) and the title product (2.13 g, 36%) crystallized by allowing the fractions containing product to evaporate: mp 179°-181° C.
Reaction SMILES: [C:1]1([CH3:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:6]=[C:5]([C:9](=[O:12])[CH:10]=[CH2:11])[CH:4]=[CH:3][C:2]=1[CH3:7]
Reactant: Cc1ccccc1C
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(C)c(C)c1

Procedure:
Orthoxylene (0.5 mL), acryloyl chloride (120 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (160 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.Br[C:26]1[C:31]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][C:34]2=[O:39])=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:26]2[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][C:34]4=[O:39])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: O=C1COCCN1Cc1cccnc1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ncccc2CN2CCOCC2=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 130 °C
Yield: 30.1 %

Procedure:
A mixture of 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (0.20 g, 0.53 mmol), 4-[(2-bromo-3-pyridyl)methyl]morpholin-3-one (0.21 g, 0.77 mmol), copper(I) iodide (0.015 g, 0.078 mmol) and cesium carbonate (0.36 g, 1.10 mmol) in dimethylformamide (5 mL) is degassed by bubbling argon for 15 minutes. (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.02 g, 0.14 mmol) is added while degassing for 15 minutes and then the mixture is heated to 130° C. for 16 hours. After completion, the reaction mixture is allowed to cool to room temperature and filtered through celite. The residue is washed with ethyl acetate (2×25 mL) and the filtrate is washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (96:4) to yield 0.09 g (30%) of the title compound. MS (m/z): 564 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:22]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N+:10]([O-:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Product: CCOC(=O)N1CCc2c(C)c3ccccc3[n+]([O-])c2CC1
Yield: 66 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester 6-oxide was prepared analogous to Example 111 from 1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][N:24]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[C:25](=[O:38])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.[I-].[Na+]>CN(C=O)C>[F:18][C:19]1[CH:46]=[CH:45][C:22]([CH2:23][N:24]([CH:39]2[CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]3=[O:11])[CH2:41][CH2:40]2)[C:25](=[O:38])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: CC(C)COc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCNCC2)cc1
Reactant: O=C1CCCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCN(CCCN3CCCCC3=O)CC2)cc1
Temperature: 48 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
A solution of 1-(3-chloropropyl)-piperidin-2-one (32 mg, 0.18 mmol) in dry DMF (2 mL) was added to a suspension of potassium carbonate (52 mg, 0.38 mmol) and N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide 103NLS56 (62 mg, 0.15 mmol) in dry DMF (2 mL). After addition of sodium iodide (25 mg, 0.17 mmol) the mixture was stirred overnight at 48° C. Afterwards it was partitioned between water and dichloromethane. The organic layer were dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by reversed phase HPLC (C18) afforded the desired compound (2.6 mg, 3%).
Reaction SMILES: C([O:4][CH:5]([CH3:18])[CH2:6][CH2:7][C:8]1[CH:13]=[C:12](Cl)[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=1)(=O)C.[NH3:19]>>[NH2:19][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([CH2:7][CH2:6][CH:5]([OH:4])[CH3:18])[CH:13]=1
Reactant: CC(=O)OC(C)CCc1cc(Cl)n2nccc2n1
Reactant: N
Product: CC(O)CCc1cc(N)n2nccc2n1
Temperature: 105 °C

Procedure:
The compound prepared in step (5) (4.3 g) and 25% aqueous ammonia (50 ml) were enclosed in a stainless steel sealed tube, heated at 105° C. for 14 hours and allowed to cool. The crystals precipitated were collected by filtration, washed with water and dried to provide 3.2 g of 7-amino-5-(3-hydroxybutyl)pyrazolo[1,5-a]pyrimidine as light yellow crystals.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:31][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:22])([F:23])[F:24])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Reactant: NC1CCCC1
Product: CC(=O)c1c(NC2CCCC2)c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O
Yield: 67.1 %

Procedure:
3-Acetyl-6-chloro-8-trifluoromethyl-4-methylsulfoxy-2-quinolinone (3.5g, 0.01 mol) and cyclopentylamine (0.86g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.5g, yield: 67 % ).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][CH:12]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(C(N[C@H](C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(N[C@H](C)c2cc(F)cc(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 2.59 g of N -[(R)-1-(3,5-difluorophenyl)ethyl]-N-[(4-methylphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.23 g of nickel chloride hexahydrate and 1.03 g of sodium borohydride were reacted, to obtain 1.02 g of isomer A and 1.08 g of isomer B of the title compound, each as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][O:30][C:31](=[O:51])[CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35](OS(C(F)(F)F)(=O)=O)[CH:34]=1>>[CH3:29][O:30][C:31](=[O:51])[CH2:32][C:33]1[CH:34]=[C:35]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[CH2:9][N:3]([C:4]([CH:6]2[CH2:7][CH2:8]2)=[O:5])[CH2:1][CH3:2])[CH:36]=[C:37]([C:39]([F:41])([F:40])[F:42])[CH:38]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]amide and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21])([O-:11])=[O:10]>C(#N)C>[Br:1][C:16]1[N:15]=[CH:14][C:13]([NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](CO)Nc1cnccc1[N+](=O)[O-]
Solvent: CC#N
Product: C[C@@H](CO)Nc1cnc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 40 %

Procedure:
N-Bromosuccinimide (0.090 g, 0.507 mmol) was added in one portion to a 0° C. solution of (S)-2-(4-nitropyridin-3-ylamino)propane-1-ol (0.100 g, 0.507 mmol) in acetonitrile (2.0 mL). The mixture stirred at 0° C. and was allowed to warm to room temperature over 16 h. The solution was then concentrated to remove most (>90%) of the acetonitrile. Ethyl acetate was added, and the solution was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-2-(6-bromo-4-nitropyridin-3-ylamino)propane-1-ol (0.056 g, 40%) as an orange solid. MS (ESI, pos. ion) m/z 276, 278.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:56][CH2:57][C@H:58]([NH2:69])[C:59]1[NH:63][C:62]2[CH:64]=[CH:65][C:66]([Cl:68])=[CH:67][C:61]=2[N:60]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.BrCl>O1CCCC1.ClCCl.C(O)C>[CH2:49]([O:56][CH2:57][C@H:58]([NH:69][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:12])=[C:2]([Br:1])[CH:3]=1)[C:59]1[NH:63][C:62]2[CH:64]=[CH:65][C:66]([Cl:68])=[CH:67][C:61]=2[N:60]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Reactant: N[C@@H](COCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](COCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Yield: 86 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-2-benzyloxy-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 86%; Rf value: 0.53 (silica gel: dichloromethane/ethanol=9:1); C28H24BrClN4O3 (579.88); mass spectrum: (M+H)+=579/581/583 (bromo-chlorine isotope).