Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].Cl[C:34]1[N:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=1>C1COCC1.CC(N(C)C)=O>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:8]2[N:7]([CH3:30])[N:6]=[C:5]([O:4][CH2:3][CH2:2][O:1][C:34]3[N:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][N:35]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:19])=[O:20])=[N:22][CH:23]=1)([CH3:28])[CH3:29]
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(S(C)(=O)=O)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 20.4 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (112 mg) in anhydrous THF (5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 21.8 mg) and the mixture was stirred for 5 minutes. To the mixture was added 2-chloro-5-(methylsulfonyl)pyrimidine (50 mg) in dimethylacetamide (1 ml). After stirring for 150 min, the reaction mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride solution (50 ml). The ethyl acetate layer was washed with brine (50 ml), dried (MgSO4), filtered and evaporated to dryness. Purification of the residue on a Phenomenex Magellen™ column using a 0.1M NH4OAc:MeCN gradient (95;5 to 60:40) over 5 min. and then an isocratic flow (60:40) for 15 minutes gave the title compound as a white solid (31 mg).
Reaction SMILES: C(OC1C=C(C(C)(C)O)C=C(C(C)(C)O)C=1)C1C=CC=CC=1.C([O:30][C:31]1[CH:32]=[C:33]([C:45]([CH2:50][CH2:51][CH3:52])([CH2:47][CH2:48][CH3:49])O)[CH:34]=[C:35]([C:37]([CH2:42][CH2:43][CH3:44])([CH2:39][CH2:40][CH3:41])O)[CH:36]=1)C1C=CC=CC=1>>[CH2:47]([CH:45]([C:33]1[CH:32]=[C:31]([OH:30])[CH:36]=[C:35]([CH:37]([CH2:39][CH2:40][CH3:41])[CH2:42][CH2:43][CH3:44])[CH:34]=1)[CH2:50][CH2:51][CH3:52])[CH2:48][CH3:49]
Reactant: CCCC(O)(CCC)c1cc(OCc2ccccc2)cc(C(O)(CCC)CCC)c1
Agent: CC(C)(O)c1cc(OCc2ccccc2)cc(C(C)(C)O)c1
Product: CCCC(CCC)c1cc(O)cc(C(CCC)CCC)c1

Procedure:
The procedure (including reaction and treatment) of Example 2 was repeated, except that 5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol was replaced by 5benzyloxy-α,α,α′,α′-tetrapropyl-1,3-benzenedimethanol, to thereby yield the above-described target as a pale yellow oil. IR(film)cm−1: 3348, 2957, 2929, 1617, 1595, 1502. 1H-NMR(CDCl3)δ: 0.83(12H,t,J=7.3 Hz), 1.08-1.22(8H,m), 1.41-1.60(8H,m), 2.42(2H,t,J=9.4,5.7 Hz), 4.59(1H,br.s), 6.42(2H,s), 6.48(1H,s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18](Cl)(=[O:20])=[O:19].[NH4+:22]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:22])(=[O:20])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(=O)(=O)Cl)c2)cc1
Reactant: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.45 g, 1.0 mmol) in methylene chloride is added aqueous ammonium solution (1 mL). The reaction mixture is stirred for 10 min at room temperature. The solvent is removed and the residue is redissolved in ethyl acetate and extracted with water. The organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. The residue is recrystallized with methylene chloride-hexane to give 100 mg (32% yield) of the title compound as pale yellow solid. 1 NMR (CDCl3): δ 8.40 (m, 1H), 8.05 (m, 1H), 7.80 (d, J=8 Hz, 2H), 7.32 (t, 1H), 7.00 (d, J=8 Hz, 2H), 5.15 (s, 1H), 3.90 (s, 3H). Analytics calculated for C14H12FNO4S: C, 54.36; H, 3.91; N, 4.53. Found: C, 53.89; H, 3.50; N, 4.50.
Reaction SMILES: [CH2:1]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br-:20].[Li+]>ClCCl>[Br:20][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:12]1[CH:18]=[CH:19][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: [Br-]
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Agent: [Li+]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(OCC(O)CBr)cc1
Reaction time: 3 h

Procedure:
1.17 g (4.46 mmol) 2-(4-octyl-phenoxymethyl)oxirane are dissolved in 10 ml absolute dichloromethane and mixed with 1.34 g (22.3 mmol) silica gel and with 1.16 g (13.4 mmol) lithium bromide. The suspension is concentrated almost to dryness on the rotary evaporator and allowed to stand at room temperature for 3 hours. The reaction batch is mixed with dichloromethane, filtrated on cotton wool and concentrated on the rotary evaporator. Taking up the suspension in diethyl ether, washing with water, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator yield the product as a yellowish oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18](O)=O)=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][S:21][C:7]=12.B.CSC.CO>O1CCCC1>[CH3:18][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2](=[O:1])[N:3]2[C:8]=1[C:7]1[S:21][CH:22]=[CH:23][C:6]=1[CH2:5][CH2:4]2
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Temperature: 25 °C

Procedure:
0.646 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid was dissolved in 20 ml of tetrahydrofuran. The solution was treated at -15° with 0.4 ml of a 10M solution of borane/methyl sulfide in tetrahydrofuran, left to warm to room temperature and subsequently heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was treated with methanol and evaporated in vacuo. The mixture was heated to boiling in 2N hydrochloric acid for a short time and extracted with chloroform. The organic extracts was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. After recrystallization from ethyl acetate/diethyl ether there was obtained pure 4,5-dihydro-10-methyl-8-phenyl-7H-thieno-[2,3-a]quinolizin-7-one of m.p. 80.5°-81°.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[CH:16]=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:19])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[S:12]1[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:19])[NH:8][C:17](=[O:18])[CH:16]=[C:11]12
Reactant: O=c1cc2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1cc2n(c(=O)[nH]1)CCCS2
Reaction time: 0.5 h

Procedure:
To a solution of 6.31 g (23 mmol) of 7-benzyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione in 200 ml of toluene, 12.5 g (50 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanoldiethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 3.25 g (76.7%, light white powder) of the desired product.
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:17])(=O)C>C(O)C.N>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]2[S:6][C:5](=[O:17])[NH:4][C:8]=2[CH:9]=1
Reactant: COc1cc2sc(=O)n(C(C)=O)c2cc1OC
Agent: N
Solvent: CCO
Product: COc1cc2[nH]c(=O)sc2cc1OC

Procedure:
2.533 gm (0.01 mol) of 3-acetyl-5,6-dimethoxy-2(3H)-benzothiazolone were refluxed for 2 hours in a mixture of 40 ml of ethanol and 50 ml of concentrated ammonia. The mixture was concentrated to one-fourth of its original volume, allowed to cool and filtered. The dried residue was purified by chromatography on silica gel, using 1,2-dichloroethane/acetone (volume ratio 9:1) for elution. The residues of the evaporated eluates were recrystallized from methanol in the presence of activated charcoal, yielding 1.78 gm (84% of theory) of the desired product having a melting point of 192°-193° C.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I:26][CH2:27][CH2:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].CCOCC>CS(C)=O>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:17])([CH3:18])[C:9](=[O:16])[CH:10]([CH2:30][CH2:29][CH2:28][CH2:27][I:26])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ICCCCI
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(CCCCI)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.5 g), 1,4-diiodobutane(0.23 ml) and potassium carbonate(1.0 g) was stirred in dimethylsulphoxide at 20° C. for 12 hours. The mixture was diluted (ether), washed (brine), dried (MgSO4), evaporated and the residue purified by column chromatography (ethyl acetate/hexane 1:3) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-(4'-iodobutyl)-4-methyl-3-oxo-pentanoate (0.3 g), NMR 1.24(3H, t), 1.3-1.4(2H, m), 1.43((3H, s), 1.48(3H, s), 1.7-2.0(7H, m), 3.12(2H, t), 3.8-3.9(1H, m), 4.1-4.2(2H, m), 5.28(2H, d), 7.2-7.4(5H, m).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C.O>[CH3:25][O:26][CH2:27][CH2:28][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COCCBr
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Oc1ccccc1
Product: COCCOc1cccc(C)c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The required 1-(2-methoxy-ethoxy)-3-methyl-2-nitrobenzene was prepared from 3-methyl-2-nitrophenol. To a stirred solution of the phenol (2.0 g, 13.1 mmol) in DMF (65 mL) was added potassium carbonate (2.16 g, 15.7 mmol) and bromoethyl methyl ether (1.47 mL, 15.7 mmol) at room temperature. After the mixture was stirred at 50° C. for 48 h, water was added. The mixture was extracted with EtOAc (3×), washed with brine, dried over anhydrous MgSO4 filtered and evaporated. After chromatographic purification on silica gel, 1-(2-methoxy-ethoxy)-3-methyl-2-nitrobenzene was obtained in 85% yield (2.34 g). 1H NMR (500 MHz, CDCl3) δ 7.28 (1H, t, J=8.0 Hz), 6.89 (1H, d, J=9.0 Hz), 6.85 (1H, d, J=8.0 Hz), 4.19 (2H, t, J=4.5 Hz), 3.72 (2H, t, J=5.0 Hz), 3.41 (3H, s), 2.30 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([O:23]CC)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=CC(F)=C(C(F)(F)F)C=3)=CC(C(O)=O)=N2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Br)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Product: O=C(O)c1cc(-c2ccc(F)c(Br)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 34A in analogy to the synthesis of the compound of Example 77A. 3.30 g (98% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11].N1C(C)=CC=CC=1C.[Si:23](OS(C(F)(F)F)(=O)=O)([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25].O>C(Cl)Cl>[CH3:12][CH:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([O:1][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:14])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC(CCCC=O)CCCC(C)(C)O
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)CCCC(C)CCCC=O
Temperature: -50 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of aldehyde 15 (16.5 mg, 82.5 μmol) and 2,6-lutidine (24 μL, 206 ,μmol) in anhydrous CH2Cl2 (1.1 mL) was added dropwise Et3SiOTf (42 μL, 165 μmol) at −78° C. The mixture was stirred for 2 hours at −78° C. and for one additional hour at −50° C. Water and CH2Cl2 were added, the organic layer was washed with water, dried over MgSO4, and evaporated. The residue was chromatographed on silica Sep-Pak cartridge using hexane/EtOAc (99.7:0.3) as an eluent to give oily aldehyde 16 (22 mg, 85%). An analytical sample was obtained using HPLC (10 mm ×25 cm Zorbax-Sil column, 4 mL/min) with a hexane/EtOAc (98:2) solvent system. Analytically pure aldehyde 16 was collected at Rv=33 mL.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1>>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:16]([NH:15][CH2:14][C:13]1[CH:18]=[CH:19][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:17]
Reactant: CC(C)(CN)CO
Reactant: COc1ccc(CN=C=O)cc1
Product: COc1ccc(CNC(=O)NCC(C)(C)CO)cc1
Yield: 100 %

Procedure:
Prepared as in Example 206d from 3-amino-2,2-dimethylpropan-1-ol and 4-methoxybenzyl isocyanate in 100% yield. MS 267 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][C@H:16]([C:18]2[O:22][NH:21][C:20](=[O:23])[CH:19]=2)[CH2:15][CH2:14][N:13]1C(OC)=O.Br>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][C@H:16]([C:18]2[O:22][NH:21][C:20](=[O:23])[CH:19]=2)[CH2:15][CH2:14][NH:13]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(C(F)(F)F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Trans-methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (400 mg, 1.03 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 8.12 mL, 46.35 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(2-fluoro-4-(trifluoromethyl)phenyl)-piperidin-4-yl)isoxazol-3(2H)-one (146 mg, 43%). 1H NMR (600 MHz, dmso) δ 1.63-1.71 (m, 1H), 1.78-1.86 (m, 1H), 1.91-1.99 (m, 1H), 2.04-2.11 (m, 1H), 2.69 (dt, 1H), 2.87-2.93 (m, 1H), 3.19-3.23 (m, 1H), 4.00 (d, 1H), 5.88 (d, 1H), 7.53-7.61 (m, 2H), 7.77 (t, 1H). HRMS Calculated for [C15H14F4N2O2+H]+: 331.1070. Found: 331.1074
Reaction SMILES: CS([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:29][CH:28]=1.O>CN(C=O)C>[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35](=[O:45])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:43][CH3:44])[CH:37]=3)=[CH:31][CH:32]=1)=[N+:18]=[N-:19]
Reactant: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Reactant: COc1ccc2cc(-c3ccc(O)cc3)[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3ccc(OCCOCCOCCOCCN=[N+]=[N-])cc3)[nH]c(=O)c2c1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl methanesulphonate (175 mg, 0.58 mmol) and Cs2CO3 (190 mg, 0.58 mmol) are added to a mixture of 3-(4-hydroxyphenyl)-7-methoxyisoquinolin-1(2H)-one (compound 45) (130 mg, 0.48 mmol) in DMF (6 mL). The reaction mixture is heated at 80° C. for 24 hours. Then the solvent is evaporated off, the reaction crude is added to water (100 mL) and extracted with CH2Cl2 (3×100 mL). The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column using a gradient of EtOH (1 to 3%) in CH2Cl2 as eluents. Intermediate 3-(4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-7-methoxyisoquinolin-1(2H)-one (52 mg, 23%) is obtained, which is used directly in the following stage.
Reaction SMILES: C[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC)=[CH:3][CH2:4][OH:5].[C:15](OCC)(=O)C>[Pd]>[CH3:15][C:4](=[O:5])[CH2:3][CH2:2][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCC(C)=CCO
Agent: [Pd]
Product: CCCCCCCCCC(C)=O

Procedure:
Pd-C (1.0 g) was added to an ethyl acetate solution (300 ml) of 3-methyl-2-dodecen-1-ol (3″) (30 g, 0.15 mol) obtained from 2-undecanone (1″) in the same manner as in Example 2, and the mixture was stirred for 3 days in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate obtained was concentrated and then distilled under reduced pressure to obtain 3-methyldodecan-1-ol (4″) (20 g, 67%). b.p. 122-123° C./4 torrs. 1H-NMR (90 MHz, CDCl3) 0.8-1.0 (6H,m,Me), 1.0-1.7 (20H,m,2˜11-H and OH), 3.66 (2H,q,J=7,1-H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:16])[C:3]=1[NH:17][C:18](=[O:32])[CH2:19][N:20]1[CH2:25][CH2:24][N:23]2C(C)(C)[NH:27][C:28](=[O:29])[CH:22]2[CH2:21]1.Cl.[OH-].[Na+]>>[NH2:27][C:28]([CH:22]1[NH:23][CH2:24][CH2:25][N:20]([CH2:19][C:18]([NH:17][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][C:4]=2[CH3:16])=[O:32])[CH2:21]1)=[O:29]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCN2C(C1)C(=O)NC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCNC(C(N)=O)C1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A mixture of 11.10 parts of N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]hexahydro-3,3-dimethyl-1-oxoimidazo[1,5-a]pyrazine-7(8H)-acetamide and 100 parts of a hydrochloric acid solution 0.5N was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was treated with a sodium hydroxide solution 50%. The product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 8.19 parts (82.6%) of 3-(aminocarbonyl)-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]-1-piperazineacetamide (int. 2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([C:24]2[C:25]3[CH:34]=[C:33]([C:35](=[O:37])[CH3:36])[O:32][C:26]=3[C:27]([O:30][CH3:31])=[N:28][CH:29]=2)=O)=CC=1)([O-])=O>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:22]([C:24]1[C:25]2[CH:34]=[C:33]([C:35](=[O:37])[CH3:36])[O:32][C:26]=2[C:27]([O:30][CH3:31])=[N:28][CH:29]=1)=[O:21]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ncc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)=O)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(C(=O)Nc2c(Cl)cncc2Cl)c2cc(C(C)=O)oc12
Reaction time: 0.75 h
Yield: 11.2 %

Procedure:
A solution of 4-amino-3,5-dichloropyridine (57 mg) in dry N,N-dimethylformamide (10 ml) was stirred at room temperature under an atmosphere of dry nitrogen. Sodium hydride (21 mg) was added and stirring continued for 45 minutes. 2-Acetyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) was added and the resulting mixture stirred overnight. The solvent was removed in vacuo, the residue taken up in water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (100 ml) then brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (12 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccncc1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccncc1
Yield: 36.4 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 4-pyridinecarboxylic acid (6.2 g), N,N'-carbonyldiimidazole (8.1 g) and 2-amino-7-chloro-1,8-naphthyridine (9 g). The product obtained, after precipitation in water (500 cc), washing with tetrahydrofuran (50 cc), then washing with water (200 cc) and drying (9.8 g; m.p. approximately 220° C.), is purified by crystallization in acetonitrile (850 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-pyridinecarboxamide (5.2 g), m.p. 228° C., is thereby obtained.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)[CH2:10][CH2:9]1)=O)(C)C.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][C:35]([CH2:37][N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]3)=[CH:34][CH:33]=2)[CH:29]=[CH:30][CH:31]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:51][C@@H:40]1[NH:41][CH2:42][CH2:43][N:38]([CH2:37][C:35]2[S:36][C:32]([C:28]3[CH:27]=[C:26]([CH2:25][NH:24][C:18](=[O:20])[C:17]4[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:16]=4)[CH:31]=[CH:30][CH:29]=3)=[CH:33][CH:34]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Reactant: C[C@H]1CN(Cc2ccc(-c3cccc(CN)c3)s2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(Cc2ccc(-c3cccc(CNC(=O)c4cccc(CC5CCNCC5)c4)c3)s2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (319 mg, 1.0 mmol) in CHCl3 (5.0 mL) was added 1,1-dimethylethyl (2S)-4-({5-[3-(aminomethyl)phenyl]-2-thienyl)methyl)-2-methyl-1-piperazinecarboxylate (401 mg, 1.0 mmol), TEA (0.26 ml, 2 mmol), EDC (288 mg, 1.5 mmol) and HOBt (150 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 2 h, followed by addition of 1 mL of saturated Na2CO3. The organic layer was dried over Na2SO4, and filtered. The filtrate was mixed with 1 mL of TFA, and stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (261 mg, 52%). LC/MS: m/z, 502 (M+H), 1.31 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=O.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:11](=[O:13])[CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)Cc1cc2ccccc2o1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cc2ccccc2o1

Procedure:
Following General Procedure BI above, and using benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.