Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])#[N:3]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)N=C=O
Agent: [Cl-]
Product: CC(C)(C)NC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and tert-butyl isocyanate in 100% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.s7 (s, 9H), 1.86 (m, 1H), 1.95 (m, 2H), 2.12 (m, 1H), 3.18 (m, 1H), 3.37 (m, 1H), 4.20 (m, 1H), 4.23 (dd, J=16.0, 6.3 Hz, 1H), 4.31 (dd, J=9.7, 2.7 Hz, 1H), 5.36 (s, 1H), 7.84 (dd, J=7.4, 0.9 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[C:2](=[C:4](\[CH:6]=O)/[Br:5])/Br.S(O)(O)(=O)=O.[CH3:15][S:16][C:17](=[NH:19])[NH2:18].C(N(CC)CC)C.C>O>[Br:5][C:4]1[C:2]([C:1]([OH:9])=[O:8])=[N:18][C:17]([S:16][CH3:15])=[N:19][CH:6]=1
Reactant: CSC(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ncc(Br)c(C(=O)O)n1
Reaction time: 24 h
Yield: 59.1 %

Procedure:
Mucobromic acid (58.05 g, 0.225 mol) was added to a stirred solution of 2-methyl-2-thio-pseudourea sulfate (62.66 g, 0.225 mol) in water (500 mL) at r.t. The suspension was cooled to 10° C. (ice bath) and triethylamine (94.1 mL, 0.675 mol) was added dropwise over 4 h. The reaction mixture was then left to stand at r.t. for 24 h. Activated carbon (Darco G-60) was added to the now dark red/brown solution and after stirring for 10 min the charcoal was filtered off. The filtrate was acidified with concentrated hydrochloric acid (50 mL) and the yellow precipitate was filtered off, washed with water (2×80 mL) and diethyl ether (2×100 mL), and then placed in a vacuum oven at 50° C. for 2 days to yield 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (33.13 g, 59%) as a yellow amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 2.75 (s, 3 H), 9.20 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1.[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
2′,6′-Dimethylbiphenyl-3-carbaldehyde (18.5 g, 88.0 mmol) was dissolved in a mixed solvent of 1,2-dimethoxyethane (100 mL) and tetrahydrofuran (100 mL), and sodium borohydride (1.66 g, 44.0 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 3 hr, further at room temperature for 3 hr. Diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-50% ethyl acetate/hexane) to give the title compound (15.6 g, yield 83%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]([OH:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]([O:28][C:41](=[O:43])[CH3:42])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1CC(O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(Cc1ccccc1C)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonyl-methyl]-1-{4-[2-(2-methylphenyl)-1-hydroxyethyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g), acetic acid (5 ml) and acetic anhydride (3 ml) is added a drop of conc. sulfuric acid, and the mixture is stirred at room temperature for 12 hours, and subsequently stirred at a temperature from 60-70° C. for 6 hours. The reaction mixture is poured into ice-water, and thereto is added ethyl acetate (30 ml). The mixture is basified with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methylphenyl)-1-acetyloxyethyl]-benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.36 g) as colorless amorphous.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.Cl[Si](C)(C)C.C(N(CC)CC)C.Cl[C:26]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1(OC)[O:35]C)=[O:27]>ClCCl>[C:30]1(=[O:35])[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: COC1(OC)CCCCC1OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CC1(CNC(=O)OC2CCCCC2=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of gabapentin (2.56 g, 15 mmol) and chlorotrimethylsilane (3.7 mL, 30 mmol) in dichloromethane (25 mL) at 0° C. under nitrogen atmosphere was added triethylamine in portions. After having stirred for 15 min at 0° C. the chloroformate (45) was added dropwise into the reaction mixture. The mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h (monitored by TLC). The reaction mixture was concentrated in vacuo and the residue was poured into cold water (50 mL) and then acidified to about pH 5.0 using 0.1 N HCl. The crude product was then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and the solvent removed in vacuo. The crude product was dissolved in acetone (25 mL) and treated using Amberlyst-15 (1.0 g) for 1.5 h (monitored by LC/MS). The reaction mixture was filtered and the filtercake was washed with acetone (2×15 mL). The combined extracts were evaporated under reduced pressure and the residue was purified using prep-HPLC/MS method to provide 1.71 g (55% yield) of compound 46 as a white solid. 1H NMR (CDCl3, 400 MHz): 5.42 (1H, t), 5.12 (1H, m), 3.35–3.16 (2H, m), 2.39 (4H, m), 1.80–1.40 (16H, m). MS (ESI): m/z=310.27 (M−H−), and 312.28 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].[CH3:17][O:18][C:19](=[O:41])[C@@H:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:21]([CH3:23])[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[CH3:17][O:18][C:19](=[O:41])[C@@H:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([I:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: COc1c(I)ccc2oc(C(=O)O)c(C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(I)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
To 110 mg (0.33 mmol) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 132 mg (1.1 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, BOP (34 mg, 1.2 eq), N,N-diisopropylethylamine (52 mg, 1.2 eq) and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. Brine was added and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2N HCl and water. Concentration of the organics in vacuo gave the crude product which was purified by column chromatography on silica gel to give 106 mg (47% yield) of (S)-2-{4′-[(5-iodo-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester was obtained as an off-white solid.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:24])=[O:23])=[C:17]([NH:25][CH2:26][C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)[CH:16]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:35][C:36]([CH3:38])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C>[F:33][C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([F:34])[CH:30]=1)[CH2:26][NH:25][C:17]1[CH:16]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH:36]([CH3:38])[CH3:35])[CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[N:20]=[CH:19][C:18]=1[CH2:21][C:22]([NH2:24])=[O:23]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1cc(F)cc(F)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)N1CCCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
60 mg of 6-{[4-(1,4-diazepan-1-yl)phenyl]amino}-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 227) was suspended in 1.5 mL of chloroform, to which 0.2 mL of acetone, 4.1 mg of acetic acid and 58 mg of sodium triacetoxyborohydride were added, and stirred at room temperature for 4 hours. To the reaction mixture, saturated sodium bicarbonate in water was added, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=20:1), recrystallized from methanol-ether to obtain 37 mg (53%) of the title compound as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11]C.Br.C(O)(=O)C>O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1O

Procedure:
2-Methyl-4-nitroanisole (4.0 g) in 50 ml 1:1 hydrobromic acid:acetic acid is heated 12 hours at 120°. Solvent is stripped, the residue taken up in water and ethyl acetate, the mixture is filtered to remove insolubles, and the layers are separated. The organic phase is dried, filtered, and stripped to afford 2-methyl-4-nitrophenol. NMR (CDCl3): δ 2.3 (3H, s), 6.8 (1H,d), 7.9 (1H,d of d), 8.0 (1H,d).
Reaction SMILES: C12BC(CCC1)CCC2.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH2:28])[C:22]1=[O:29].[OH-:30].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][OH:30])[C:22]1=[O:29]
Reactant: [OH-]
Reactant: C=Cc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With ice-cooling, 1.15 l (575 mmol) of a 0.5 molar solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran are added to 70.7 g (262 mmol) of the compound from Example 60A (alternative synthesis) such that the internal temperature does not exceed 10-15° C. The mixture is then warmed to RT and stirred at room temperature for 1.5 h. The mixture is then cooled and, at 0° C.-5° C., 653 ml (1.31 mol) of a 2-molar aqueous solution of sodium hydroxide are added. The mixture is stirred briefly, and 296 g (2.51 mol) of a 30% strength hydrogen peroxide solution are then added such that the temperature does not exceed 30° C. and does not fall below 25° C. After the addition has ended, the mixture is stirred for another 30 min. Water and ethyl acetate are added to the reaction mixture. After phase separation, the aqueous phase is once more extracted with ethyl acetate. The combined organic phases are washed with an aqueous sodium bisulphite solution. The organic phase is removed and evaporated to dryness under reduced pressure. The residue is dissolved in dichloromethane and purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:2, then ethyl acetate). This gives 66.5 g (88% of theory) of the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH3:14][C:15]([OH:29])([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([C:15]([OH:29])([CH3:14])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:24][CH2:25]2)=[CH:8][CH:9]=1
Reactant: CC(O)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(O)(c1ccc(F)cc1)C1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 2.7 g of 4-chloro-4'-fluorobutyrophenone, 2.5 g of α-methyl-α-(4-piperidyl)-p-fluorobenzyl alcohol, 8 g of sodium carbonate, a crystal of sodium iodide and 30 ml of 4-methyl-2-pentanone is stirred and refluxed for 72 hours. The reaction mixture is worked up in the usual manner as described in the previous Examples. The product is isolated as described above and recrystallized from isopropanol to afford the 4'-fluoro-4-[4-(α-hydroxy-α-methyl-p-fluorobenzyl)-piperidino]-butyrophenone, melting at 116°-118°.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:35](=[CH:36][CH:37]=2)[O:34][C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]5[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[O:19])[CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:38])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:39][C:40](OC(C)=O)=[O:41].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:35](=[CH:36][CH:37]=2)[O:34][C:12]2([CH2:13][CH2:14][N:15]([C:18]([C:20]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]5[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[O:19])[CH2:16][CH2:17]2)[CH2:11][C:10]3=[O:38])[CH2:2][CH2:3]1)(=[O:41])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N4CCNCC4)ccc2O3)nc2c(OC)cccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N4CCN(C(C)=O)CC4)ccc2O3)nc2c(OC)cccc12
Reaction time: 4 h

Procedure:
To a solution of 165 mg of 6-(piperazin-1-yl)-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one in 2 mL of CHCl3 was added 0.165 mL of Ac2O and 0.33 ml of triethylamine and the mixture was stirred for 4 hrs. The mixture was partitioned between CHCl3 and 1N NaOHaq, and the organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified on preparative TLC (SiO2, CHCl3/MeOH=9/1) to afford the intended compound as a yellow powder. 1H-NMR (400 MHz, CDCl3) δ7.74 (1H, d, J=8.4 Hz), 7.45 (1H, ddd, J=8.4, 8.0, 0.8 Hz), 7.32-7.34 (1H, m), 7.18 (1H, dd, J=8.8, 1.4 Hz), 7.16 (1H, s), 7.06 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=8.8 Hz), 4.50-4.60 (1H, m), 4.00-4.20 (1H, m), 4.06 (3H, s), 4.02 (3H, s), 3.70-3.80 (2H, m), 3.50-3.70 (3H, m), 3.33-3.40 (1H, m), 3.00-3.20 (4H, m), 2.78 (1H, d, J=16.8 Hz), 2.72 (1H, d, J=16.8 Hz), 2.21-2.30 (1H, m), 2.10-2.20 (1H, m), 1.70-2.95 (2H, m). MS [M+H]+=559.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>CCOCC>[Br:34][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1)[CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Cc1cccc(C(C)O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)Cc1cccc(C(C)Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of 1-(3-isobutylphenyl)ethanol (1.1 g), triphenylphosphine (3.24 g) and carbon tetrabromide (4.09 g) in ether (20 ml) was stirred at 25° C. for 1 hour. The precipitates were filtered off, and the liltrate was evaporated to give 1-(1-bromoethyl)-3-isobutylbenzene (1.49 g) as an oil.
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:9]=[CH:8][CH:7]=[CH:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(N(CC)CC)C.Br[CH2:25][C:26]([C:28]([F:31])([F:30])[F:29])=O>O1CCOCC1>[F:29][C:28]([F:31])([F:30])[C:26]1[N:2]=[C:3]2[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1C=CC=NC(=N)C1
Reactant: O=C(CBr)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: FC(F)(F)c1cn2c(n1)CNCCC2
Temperature: 120 °C

Procedure:
To a stirred mixture of compound from Step B (0.42 g, 1.68 mmol) and triethylamine (0.64 mL, 4.6 mmol) in dioxane was added 1-bromo-3,3,3-trifluoroacetone. The resultant mixture was heated at 50° C. overnight. After solvent was removed, the residue was dissolved in isopropanol and refluxed overnight. After an aqueous work-up, the residue purified by flash chromatography (silica gel, 4% of 10% methanolic ammonium hydroxide solution in dichloromethane). The intermediate was dissolved in acidic (three drops of concentration hydrochloric acid) methoxyethanol (8 mL) and heated at 120° C. overnight. After solvent was removed, the residue was treated with 4 N hydrogen chloride in dioxane for 3 h. Purification by flash chromatography (silica gel, eluting with 6% of 10% methanolic ammonium hydroxide in dichloromethane) gave the title compound.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[C:36]([OH:38])[CH:35]=[N:34][C:33]=23)=[O:28])[CH2:12][CH2:11]1)(C)(C)C>ClCCl.N1C=CC=CC=1.O>[ClH:1].[NH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[C:36]([OH:38])[CH:35]=[N:34][C:33]=23)=[O:28])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc3ncccc3cc2NC(=O)c2cnn3cc(O)cnc23)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: NCC1CCN(c2cc3ncccc3cc2NC(=O)c2cnn3cc(O)cnc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydrochloric acid (1 M in Et2O, 5 mL) was added to a solution of (1-{6-[(6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (0.22 g) in a mixture of dichloromethane and methanol (1/1, 10 mL) and the resulting mixture was stirred at room temperature overnight. The solid formed was collected by filtration, washed with ethanol and dried under reduced pressure to give 224 mg of 6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide hydrochloride as a light yellow powder. MS=418 [M+H]+; MP>300° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].OC1N=CC=CC=1C(O)=O.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.N>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5](=[O:12])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: COC(=O)c1cc(Br)cnc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(Br)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
4.5 g of methyl 5-bromo-2-hydroxynicotinate synthesized by a known method from 2-hydroxynicotinic acid, and 4.7 g of phenylboronic acid were dissolved in 200 ml of tetrahydrofuran. To the mixture were added 705 mg of copper acetate and 1 ml of pyridine, followed by stirring at room temperature for 3 nights in a flow of air. Aqueous ammonia water was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue obtained as a solid was washed with diethyl ether, to obtain 3.59 g of 5-bromo-3-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one as white crystals. 3.2 g of the product was dissolved in 100 ml of dimethylformamide, to which 7.7 g of tri-N-butyl-(2-pyridyl)tin [CAS No. 59020-10-9] and 240 mg of tetrakistriphenylphosphine palladium were added, followed by stirring at 110° C. for 3 hours in nitrogen atmosphere. After cooling to room temperature, the reaction solution was poured into water, extracted with ethyl acetate. Then, the extract was successively washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered through NH silica gel and silica gel. Then, the filtrate was evaporated, and the resulting precipitates were washed with ether and hexane, and dried, to give 1.59 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OC)c(OCc2nc(-c3ccco3)oc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (1.50 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.11 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.90 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give {1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol as colorless crystals (1.20 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 108-109° C.