Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=1[CH3:39].O>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:30]=2[CH3:39])[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(Cl)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(Cl)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To the mixture of methyl 2-chloro-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 65 (0.5 g, 1.691 mmol) in N,N-Dimethylformamide (DMF) (10 ml) was added in potassium carbonate (0.467 g, 3.38 mmol) and 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (0.428 g, 1.691 mmol). The reaction mixture was stirred at 80° C. for 1 h. The reaction was cooled down. Water (100 mL) was added in. The solid precipitated. Filtration gave the solid which was purified on a silica column (20-60% EtOAc/Hexane) to give the product as white solid (0.66 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H) 3.07-3.16 (m, 4H) 3.68-3.78 (m, 4H) 3.91 (s, 3H) 5.63 (s, 2H) 6.41 (d, J=7.83 Hz, 1H) 7.28 (t, J=7.83 Hz, 1H) 7.39 (d, J=2.27 Hz, 1H) 7.50 (d, J=2.53 Hz, 1H) 7.63 (d, 1H). MS (ES+) m/e 468.0 [M+H]+.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:9]1[C:20]([CH2:21]O)=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]>ClCCl.C(=O)([O-])O.[Na+]>[CH2:7]([C:9]1[C:20]([CH2:21][C:5]#[N:6])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: CCc1nn2ccc3c(c2c1CO)CCO3
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nn2ccc3c(c2c1CC#N)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (836 μL, 6.60 mmol) and trimethylsilyl cyanide (1.17 mL, 8.77 mmol) in dichloromethane (5 mL) was added a solution of (2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (480 mg, 2.20 mmol) in dichloromethane (10 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (296 mg, yield 59%).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[OH:26])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[CH3:46][O-:47].[Na+]>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([O:47][CH3:46])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(O)(c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1)c1ncccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1nc2ccc(C(O)(c3ncccn3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (58 mg, 0.107 mmol, Example 130), toluene (2 mL), and sodium methoxide (116 mg, 2.14 mmol) were combined in a round bottom flask equipped with a stirbar and condenser under an N2 atmosphere. The reaction contents were heated to reflux and refluxed overnight. The reaction was cooled to room temperature and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C29H24ClN7O2, 537.2. m/z found, 538.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.84 (d, J=4.9 Hz, 2H), 8.39 (d, J=1.8 Hz, 1H), 8.13-8.07 (m, 1H), 7.86 (dd, J=8.8, 2.0 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.66 (d, J=1.3 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.42 (t, J=4.9 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.50-6.45 (m, 1H), 6.42 (s, 1H), 4.27 (s, 2H), 4.04 (s, 3H), 3.39 (s, 3H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[C:4]([O:8][C:9]([NH:11][C:12]1[C:17]([C:18]([O:20]C)=O)=[CH:16][C:15]([F:22])=[N:14][CH:13]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[F:22][C:15]1[N:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[C:17]([C:18](=[O:20])[CH2:2][C:1]#[N:3])[CH:16]=1
Reactant: COC(=O)c1cc(F)ncc1NC(=O)OC(C)(C)C
Reactant: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)CC#N
Reaction time: 1 h

Procedure:
To 140 mL of 2.5 M n-butyllithium/hexanes in 300 mL of tetrahydrofuran at −78° C. was slowly added 14.4 g of anhydrous acetonitrile in 100 mL of tetrahydrofuran. After 30 minutes was added 32 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, methyl ester in 100 mL of tetrahydrofuran. After a further 60 minutes, the reaction was quenched with 35 mL of glacial acetic acid. The reaction was diluted with equal volumes of ethyl acetate and saturated sodium bicarbonate and the aqueous phase was washed twice with ethyl acetate. The pooled organic phases were washed with saturated sodium bicarbonate, dried, and stripped of solvent. This material was further purified by passing through a plug of silica gel with a gradient of 0-5% methanol/chloroform to give a crude product that was used as is for the following step. This material can be further purified by recrystallization from chloroform/hexanes to give a white, crystalline solid: melting point 106-115° C.; mass spectrum (m/e): M+H 279.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)#[N:2].[OH-:23].[Na+].OO>CCO.O.[Na+].[Cl-]>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:23]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C#N)CC1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(N)=O)CC1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[(2-cyanophenyl)amino]-1-piperidinecarboxylate (D17) (355 mg, 1.18 mmol) in EtOH (6 ml) at 40° C. was added 2M NaOH solution (2.6 ml) followed by a mixture of hydrogen peroxide solution (27% w/w, 3.7 ml) in water (2.9 ml) and the reaction stirred for 2 h. Further hydrogen peroxide solution (27% w/w, 3.7 ml) in water (2.9 ml) was added and the reaction stirred at 40° C. for 1.5 h. Another portion of hydrogen peroxide solution (27% w/w, 7.4 ml) in water (5.8 ml) was added and stirring and heating were continued overnight. The reaction mixture was diluted with saturated aqueous NaCl solution (4 ml) and extracted with tBuOH (5 ml). The organic extract was diluted with EtOAc (15 ml), dried (MgSO4) and concentrated. Column chromatography eluting with 0-100% EtOAc/petroleum ether gave the title compound (150 mg). δH (CDCl3, 250 MHz) 7.96 (1H, br d), 7.40 (1H, m), 7.31 (1H, m), 6.71 (1H, d), 6.57 (1H, t), 5.80 (2H, br s), 3.93 (2H, m), 3.53 (1H, m), 3.06 (2H, m), 1.99 (2H, m), 1.50 (2H, m), 1.47 (9H, s). MS (ES): MH+ 320.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCNCc1ccc(F)cc1

Procedure:
Tert-butyl 4-bromobutylcarbamate (0.735 g, 2.91 mmoles), (4-fluorophenyl)methanamine (0.333 g, 2.91 mmoles) and potassium carbonate (0.806 g, 5.83 mmoles) were stirred in acetonitrile (15 mL) at 100° C. for 1 hour. The reaction mixture was cooled, the solvent waqs concentrated and the residue was taken into dichloromethane and washed with water twice. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to provide the title compound which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:20]2[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH:21]=2)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C)(C)CNc1c(Br)ccc(C(=O)O)c1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CNc1c(Br)ccc(C(=O)OC2=CC(=O)CCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
190 mg (0.574 mmol) of 4-bromo-3-[(2,2-dimethylpropyl)amino]-2-nitrobenzoic acid, 198 mg (1.713 mmol) of cyclohexane-1,3-dione, 145 mg (0.741 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 7 mg (0.057 mmol) of 4-(dimethylamino)pyridine were dissolved in 5 ml of methylene dichloride and stirred at RT for 24 h. The solution was then washed with water and saturated NaHCO3 solution, the organic phase was dried over MgSO4, and then the whole was filtered with suction through a glass frit, filled with 1 cm of silica gel, and the filter product was washed with heptane/ethyl acetate 1:2. The filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:26])[CH:3]=1.[NH2:27][CH2:28][CH2:29][OH:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12]([NH:27][CH2:28][CH2:29][OH:30])[N:13]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2C(C)C
Reactant: NCCO
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2C(C)C

Procedure:
The product of Example 56 and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.78 (m, 6H), 2.29 (s, 3H), 3.70 (br s, 2H), 3.89 (br s, 3H), 5.81 (m 1H), 6.02 (br s, 1H), 6.23 (d, 1H, J=9.7 Hz), 7.00 (m, 2H). 7.11 (d, 1H, J=9.7 Hz), 7.19 (m, 1H), LC MS (m/e)=357.2 (MH+). Rt=1.80 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2ccccn2)co1

Procedure:
The title compound was prepared by a method analog to that described in Example 14 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The title compound (20 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:29](=[O:30])[N:16]2[C:17]([C:26]([OH:28])=[O:27])=[C:18]([CH2:21][O:22][C:23](=[O:25])[NH2:24])[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:29](=[O:30])[N:16]2[C:17]([C:26]([OH:28])=[O:27])=[C:18]([CH2:21][O:22][C:23](=[O:25])[NH2:24])[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csnn1
Yield: 45.6 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer)(0.65 g) and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (0.96 g) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:27]([S:29]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH3:28]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])=[CH:39][CH:38]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(CN)cc1
Product: CCS(=O)(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 0.35 mmol) and 4-ethanesulfonyl-benzylamine (0.2 g, 1.06 mmol) to give 7-chloro-6-(4-ethanesulfonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([N:11]([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:32]N>>[Cl:1][C:2]1[C:3]([C:9]([N:11]([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:10])=[N:4][C:5]([NH:8][CH3:32])=[N:6][CH:7]=1
Reactant: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(N)ncc2Cl)c1
Reactant: CN
Product: CNc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2cccc(OC)c2)n1

Procedure:
This was prepared in the same manner as the product of example 249, using methylamine as the amine, to give the title compound as a foam, 0.24 g, (88%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([OH:15])=[C:10]([C:12](O)=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([OH:15])=[C:10]([C:12]([Cl:18])=[O:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCn1ncc2nc(C(=O)O)c(O)nc21
Product: CCn1ncc2nc(C(=O)Cl)c(O)nc21

Procedure:
31.3 g. of 1-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]-pyrazine-5-carboxylic acid (0.15 mol.) are carefully added in portions to 300 ml. of thionyl chloride. As soon as the gas evolution has ceased, the mixture is heated at reflux for 3 hours. After removal of excess thionyl chloride under vacuum, the residue is dissolved in benzene. Evaporation of the benzene provides 30.5 g. (90%) of amorphous 1-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carbonyl chloride which is used without further purification.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]3([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]3([CH2:20][CH2:19][CH:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH2:17][CH2:16]3)[C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1Nc2cc(Br)ccc2C12CCC(N1CCOCC1)CC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Acetic acid (74 μl, 1.29 mmol) was added to a stirred solution of 6′-bromospiro[cyclohexane-1,3′-indoline]-2′,4-dione (preparation 21a, 0.38 g, 1.29 mmol) and morpholine (123 μl, 1.1 mmol) in 1,2-dichloroethane (5 mL). The mixture was cooled to 0° C. and sodium triacetoxy borohydride (0.356 g, 1.68 mmol) was added portionwise. After the addition, the cooling bath was removed and the mixture was stirred at room temperature for 18 hours. Water and dichloromethane were added to the reaction mixture and the organic layer was washed with water, dried (MgSO4) and the solvent was evaporated to give the crude oily product as a mixture of isomers. Separation of the isomers was achieved by flash chromatography (98:2 dichloromethane/methanol):
Reaction SMILES: [NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[O:24][CH3:25])(=[O:14])=[O:13])[C:3]1=[O:26].[C:34](Cl)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[C:34]([NH:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[O:24][CH3:25])(=[O:13])=[O:14])[C:3]1=[O:26])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Solvent: c1ccncc1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(NC(C)=O)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.8 g of the compound obtained in EXAMPLE 16 in 10 ml of pyridine is cooled in an ice bath and 0.51 ml of acetyl chloride is added. The reaction medium is stirred for 3 hours at RT and poured into water. It is extracted with AcOEt, washed with water and with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue is taken up with DCM and the precipitate formed is filtered off to give 2.8 g of the expected product, a sample of which is crystallized from an MeOH/iso ether mixture. M.p.=205°-210° C.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:31][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:12][O:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[C:32]([O:31][CH:11]([CH2:12][O:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][S:9][CH2:8][CH2:7][C:6]([OH:49])=[O:5])(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 23 (4.84 g) in dichloromethane (1 ml), trifiuoroacetic acid (4 ml) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated; the residue was washed with hexane to yield the title compound (4.46 g, yield 100%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:27])[CH2:24][CH2:25][CH:26]=2)=[CH:18][CH:17]=1>CCOCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2([OH:27])[CH2:24][CH2:25][CH:26]=[C:22]2[C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: O=C1CCC=C1c1ccc(F)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CSc1ccc(C2(O)CCC=C2c2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et2O cooled at -78° C., was added 22 mL of 1.7 M solution of t-BuLi in penlane (38 mmol) dropwise. The reaction mixture was stirred for 15 min at -78° C. and a solution of 2.23 g of 2-(4-Fluorophenyl)-2-cyclopenten-1-one in 10 mL of Et2O was added. After stirring for 15 min at -78° C., the reaction mixture was warmed to 0° C., and quenched with 50 mL of sat. NH4Cl. The product was extracted with 100 mL EtOAc, dried over Na2SO4, and purified by flash chromatography, eluted with 4:1 hexane/EtOAc to give 3.4 g of the desired product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100° C. for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with 1N NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)=O)C>C1COCC1>[F:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Yield: 97.9 %

Procedure:
To a suspension of LiAlH4 (8.60 g, 0.23 mole) in 400 mL of dry THF was added 5-fluoro-3-indoleglyoxylic acid ethyl ester (13.50 g, 0.057 mole) portionwise at room temperature. Preparation of this ester intermediate is given hereinbelow. The mixture was heated to reflux under Ar for 1 h and was then cooled at 0° C. and quenched according to the method of Fieser (Fieser and Fieser, "Reagents for Organic Synthesis", Vol. 1, pg. 584). The resulting slurry was filtered and the filter cake was washed with THF. The filtrate was dried (Na2SO4) and evaporated to give the product (10.00 g, 100%) as a yellow oil. It was used as such without further purification; IR (neat) 3420 cm-1. 1Hnmr (80 MHz, CDCl3). δ: 7.73 (br s, 1H), 7.1-6.4 (m, 4H), 3.57 (t, J=8 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 1.20 (br s, 1H).