Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[N:12][N:13]=2)[CH:10]=1)[OH:4].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.[Sn](Cl)(Cl)(Cl)Cl>Cl.CO>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[N:12][N:13]=2)[CH:10]=1)[CH2:2][NH:1][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1ccc2nnnn2c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4ccc5nnnn5c4)CC3)cc2)S1

Procedure:
5-[4-(4-{[(2R)-2-Hydroxy-2-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-ylethyl]amino}-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione was prepared from (1R)-2amino-1-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-yl-1-ethanol (which was obtained in Example 132) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione(which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp: 130–132° C. This solid was dissolved in concentrated aqueous hydrochloric acid (0.3 mL) and methyl alcohol (2 mL). Tin chloride (0.196 g, 0.87 mmol) was added to the solution at room temperature. The mixture was then stirred at reflux for 2 hours. Evaporation and purification by flash column chromatography (dichloromethane/methyl alcohol 7/3)] gave a yellow solid. This solid was further purified by reverse phase HPLC to give a yellow solid (0.117 g, 61% yield); mp 182° C. (decomposed); 1H NMR (400 MHz, DMSO-d6) δ 1.90 (brs, 2 H), 2.21 (brs, 2 H), 3.03–3.36 (m, 8 H), 3.75–3.79 (m, 1 H), 4.86–4.90 (m, 1 H), 4.98–5.01 (m, 1 H), 7.03–7.05 (m, 1 H), 1.20 (brs, 4 H), 7.95–7.99 (m, 2 H), 8.21 (brs, 1 H), 9.13 (brs, 1 H), 9.45 (brs, 1 H), 12.04 (brs, 1 H), 14.13 (brs, 1 H); MS (ES) m/z: 442 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([NH:13][C:14](=[O:17])[CH2:15]Cl)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[Na+].[I-]>CC(O)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH2:11][OH:12])[NH:13][C:14](=[O:17])[CH2:15][O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(CCl)NC(CO)(CO)c1ccnc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1COCC(CO)(c2ccnc(Br)c2)N1
Temperature: 90 °C

Procedure:
To a solution of N-[1-(2-bromo-pyridin-4-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (8.0 g, 24.8 mmol) in t-BuOH (50 ml) was added t-BuOK (5.5 g, 49.6 mmol) and NaI (0.375 g, 2.48 mmol) and heated to 90° C. for 1 h. Reaction mass was concentrated under reduced pressure and diluted the residue with EtOAc. Organic layer was separated and washed with ammonium chloride solution, brine followed by drying over anhy. Na2SO4. The crude product was purified by column chromatography using 5% methanol in DCM to obtain title compound as a pale brown gum. Yield=3.25 g (46%). TLC (ethyl acetate) Rf=0.17; LCMS: RtH8=0.12; [M+1]+=286.7 and 289.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH:4]=[CH:3]1.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>CO>[CH:4]1[CH2:5][CH2:6][CH:2]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:3]=1
Reactant: ClC1C=CCC1
Reactant: C1CNCCN1
Solvent: CO
Product: C1=CC(N2CCNCC2)CC1
Yield: 21.5 %

Procedure:
3-chlorocyclopentene (306 mmoles, 36.9 g) was added dropwise to a solution of anhydrous piperazine (496 mmoles, 36.9 g) in dry methanol (350 mL) at -13° C. The final solution was stirred at -13° C. for 15 minutes and at room temperature for one hour. The solvent was evaporated to dryness, and the residue was first taken up with chloroform and then filtered to eliminate the precipitate. After elimination of chloroform by evaporation the filtrate give 10 g of 1-(cyclopenten-3-yl) piperazine (yellow oil).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]([C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)=[N:31]1>>[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:32]([C:44]2[CH:45]=[CH:46][C:47]([C:2]3[N:6]4[N:7]=[CH:8][CH:9]=[C:10]([N:11]5[CH2:16][CH2:15][O:14][CH2:13][CH2:12]5)[C:5]4=[N:4][C:3]=3[CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:48][CH:49]=2)=[N:31]1
Reactant: Cn1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n(COCC[Si](C)(C)C)c1=O
Reactant: Brc1c(CCc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Product: Cn1nc(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)n(COCC[Si](C)(C)C)c1=O

Procedure:
Compound 46a was subjected to Suzuki coupling conditions with compound 51d as described in Example 38, Step A to obtain compound 51e as a light yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C36H42N8O3Si: 663.3 (M+H). Found: 663.4.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br.Br[CH2:25][C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:25]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Product: O=C(O)c1cc(-c2nc(-c3cccnc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 47 %

Procedure:
2′-Nitro-4-(4-pyridin-3-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (120 mg, 47%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-(bromoacetyl)pyridine hydrobromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 9.32 (d, J=1.9 Hz, 1H), 8.64 (dd, J=4.8, 1.4 Hz, 1H), 8.55-8.58 (m, 2H), 8.50 (s, 1H), 8.29 (dd, J=8.0, 2.0 Hz, 1H), 8.14 (dd, J=8.0, 1.2 Hz, 1H), 7.76-7.81 (m, 1H), 7.62-7.68 (m, 2H), 7.41-7.49 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([S:12]([O-:15])(=[O:14])=[O:13])=[N:3][CH:4]=[CH:5][CH:6]=1.[Na+:16]
Reactant: O=S([O-])O
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ncccc1C(F)(F)F
Yield: 67.9 %

Procedure:
In a flask, 2-chloro-3-(trifluoromethyl)pyridine (20.0 g, 110 mmol) , sodium hydrogen sulfite (46 g, 442 mmol), ethanol (200 ml) and water (200 ml) were charged and heated under reflux for 138 hours. After evaporating off the solvent from the reaction mixture, conc. hydrochloric acid was added to the residue and then evaporated to dryness. This residue was extracted with methanol, and the methanol phase was filtered and evaporated to dryness to obtain sodium 3-(trifluoromethyl)pyridine-2-sulfonate (18.6 g). Yield, 68%.
Reaction SMILES: C([N:8]([CH2:18][C:19]1C=CC=CC=1)[CH2:9][C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.F[C:26](F)(F)C(O)=O.CC(C)=O.C([O-])(=O)C.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CCO.[Cl-].[Na+].O.[OH-].[OH-].[Pd+2]>[F:17][C:10]([F:16])([CH2:9][NH:8][CH:18]([CH3:19])[CH3:26])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)C(F)(F)CNC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (5.00 g, 15.0 mmol) was dissolved in EtOH (25 mL) and trifluoroacetic acid was added (1.15 mL, 15.5 mmol). To this mixture, Pd(OH)2/C (20%, 250 mg) was added, and the reaction mixture was hydrogenated at 60 psi overnight. The mixture was filtered through a pad of Celite, the Celite pad was washed with ethanol and the filtrate was concentrated in vacuo. The residue was dissolved in THF (65 mL) and to the solution was added acetone (0.872 g, 15.0 mmol) and sodium acetate (1.23 g, 15.0 mmol). The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (4.77 g, 22.5 mmol) was added in portions over 5 min. The mixture was stirred vigorously at room temperature overnight and then was poured into a cold (0° C.) brine solution (100 mL). The pH was adjusted to 12.5 with NaOH (50%) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extract were dried (MgSO4) and concentrated in vacuo to afford the title compound as a clear light yellow oil (1.54 g, 54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.32 Hz, 6H) 1.36 (t, J=7.20 Hz, 3H) 2.73-2.94 (m, 1H) 3.20 (t, J=13.52 Hz, 2H) 4.34 (q, J=7.24 Hz, 2H)
Reaction SMILES: [K].[CH3:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[N:28]=[N:27][NH:26][N:25]=3)=[CH:16][CH:17]=2)[C:9]([CH2:29][OH:30])=[C:8]([Cl:31])[N:7]=1.[CH3:32][O:33][C@@H:34]1[C@@H:38]([O:39][N+:40]([O-:42])=[O:41])[CH2:37][C@H:36]([C:43](O)=[O:44])[CH2:35]1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:32][O:33][C@@H:34]1[C@@H:38]([O:39][N+:40]([O-:42])=[O:41])[CH2:37][C@H:36]([C:43]([O:30][CH2:29][C:9]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]4[NH:28][N:27]=[N:26][N:25]=4)=[CH:16][CH:17]=3)[C:6]([CH2:5][CH2:4][CH2:3][CH3:2])=[N:7][C:8]=2[Cl:31])=[O:44])[CH2:35]1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCc1nc(Cl)c(COC(=O)[C@@H]2C[C@H](OC)[C@@H](O[N+](=O)[O-])C2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of potassium losartan (974 mg, 2.11 mmol), (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylic acid (intermediate 1, 429 mg, 2.09 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (447 mg, 2.33 mmol), and N-methylmorpholine (0.50 mL, 4.6 mmol) was dissolved in dichloromethane (20 mL) and stirred for 2 days with catalytic amounts of 4-(dimethylamino)pyridine. 1H NMR (500 MHz, CDCl3) δ 0.84 (t, J=7.3 Hz, 3H), 1.28 (sextet, J=7.3 Hz, 2H), 1.56 (quintet, J=7.3 Hz, 2H), 1.78-1.84 (m, 1H), 1.88-1.92 (m, 1H), 2.08-2.15 (m, 1H), 2.30-2.36 (m, 1H), 2.38 (t, J=6.7 Hz, 2H), 2.71 (quintet, J=8.2 Hz, 1H), 3.26 (s, 3H), 3.70-3.75 (m, 1H), 4.87 (d, J=13.9 Hz, 1H), 4.91 (d, J=13.7 Hz, 1H), 5.13 (s, 2H), 5.15-5.19 (m, 1H), 6.77 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.52 (td, J=1.4, 7.6 Hz, 1H), 7.61 (td, J=1.4, 7.6 Hz, 1H), 7.84 (dd, J=0.9, 7.7 Hz, 1H); LC-MS: m/z 610.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH:5]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=1
Reactant: COC(=O)c1cccc(CCCNCCCc2cccc(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CCCN(CCCc2cccc(Cl)c2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 115.5 %

Procedure:
To a solution of 3-(3-{[3-(3-chloro-phenyl)-propyl]- amino}-propyl)-benzoic acid methyl ester (50.3 mg, 0.145 mmol) and triethylamine (32.4 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (18.3 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature and was diluted with CH2Cl2. The organic solution was washed consecutively with aqueous HCl (5.5%, 1×), H2O (1×), NaHCO3 (1×) and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford the title product of Step A as an oil (71 mg). MS 424 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])=[O:9])=[N:6][CH:7]=1.[C:28]([N:35]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].N1C=CC=CC=1.CCOCC>CS(C)=O.C(OCC)(=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:41][CH2:40][CH2:39][N:38]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:12]=3[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[O:14])=[O:9])=[N:6][CH:7]=2)[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2cnc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (or suspension) of 2-(5-chloropyrazin-2-ylcarbonylamino)-5-fluoro-N-(5-chloropyridin-2-yl)benzamide (Intermediate A-1, 10 g, 24.62 mmol) in DMSO (30 mL) was added 1-Boc-hexahydro-1,4-diazepine (9.86 g, 49.23 mmol) and pyridine (2.4 mL, 30 mmol). The reaction mixture was stirred for one hour at room temperature before it was heated in a sealed tube at 75–80° C. for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate (800 mL), washed with saturated aqueous citric acid solution (3×200 mL), water (200 mL), saturated sodium bicarbonate solution (2×200 mL), and dried over magnesium sulfate. Activated charcoal (3 g) was added to decolorize the product. Evaporation of the solvent under vacuum provided 13.9 g of crude product. Ether (150 mL) was added to this solid, the mixture was sonicated 20 min, and the solids were filtered and dried under vacuum to afford the title compound as a solid which was analytically pure. Yield=12.6 g
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:14]=2)[NH:9][CH:8]=1)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)NCCc1c[nH]c2ccc(OCCCCO)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.2 g of the compound obtained in Step A in 50 ml of anhydrous THF is added dropwise to a suspension of 1.42 g of lithium aluminum hydride in 50 ml of anhydrous THF cooled in an ice-bath. After stirring for 30 minutes at room temperature, a solution of 5% sodium hydroxide is added dropwise until the evolution of gas ceases. The precipitate that forms is filtered off, the organic phase is evaporated and the residue is taken up in 70 ml of ethyl acetate. The organic phase is washed with water until neutrality, dried over magnesium sulphate and evaporated in vacuo to yield the title product in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:23])[CH3:22]>>[C:21]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:23])[CH3:22]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Product: COc1ccc(C(C)=O)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methylacetamide. It is used in crude form in the following reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=[O:16])[CH:13](Cl)[CH3:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.[Li+].[Cl-]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:12](=[O:16])[CH:13]([N:21]2[CH2:22][CH2:23][C:18]([OH:17])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)[CH3:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: CC(Cl)C(=O)c1cc(F)c2c(c1)CC(=O)N2
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cc(F)c2c(c1)CC(=O)N2)N1CCC(O)(c2ccccc2)CC1
Yield: 36.6 %

Procedure:
A mixture of 7-fluoro-5-(2-chloropropionyl)-2(1H,3H)-indolone (1.0 g, 4.14 mmol), 4-hydroxy-4-phenylpiperidine (0.74 g, 4.17 mmol) and triethylamine (1.2 ml, 8.6 mmol) in anhydrous dimethylformamide was heated to between 70 and 90° C. for 3 hours. The mixture was poured into 1N aqueous LiCl and extracted with two portions of ethyl acetate. The combined organic phase was washed with 1N HCI, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to 1.6 g of a reddish solid. The crude product was purified by flash chromatography on silica gel (2×4 inches {50×100 mm}, 50% ethyl acetate/hexane eluent) to yield 0.58 g of the desired product. This product was further purified by recrystallization from acetonitrile/ether to give 0.2 g of light yellow solid; m.p. 197°-199.5° C. NMR (DMSO-d6) 11.25 (s, 1H), 7.90 (d, J=11.6 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J=7.2 Hz, 2H), 7.28 (t, J=7.4 Hz, 2H), 7.17 (t, J=7.2 Hz, 1H), 4.76 (s, 1H), 4.25 (q, J=6.6 Hz, 1H), 3.66 (s, 2H), 2.88-2.63 (m, 2H), 2.60-2.55 (m, 1h), 2.49-2.38 (m, 1H), 1.88 (dt, J=12.2, 4.3 Hz, 1H), 1.77-1.49 (m, 3H), 1.16 (d, J=6.6 Hz, 3H). The mother liquors were rechromatographed to afford another 0.15 g of product for a total yield of 0.35 g (22%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([NH:14][NH2:15])=[N:12][C:11]([Br:16])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]([CH2:21][C:22]([CH3:24])=O)=O>C(O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([N:14]2[C:22]([CH3:24])=[CH:21][C:19]([CH3:18])=[N:15]2)=[N:12][C:11]([Br:16])=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1NN
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(C)n(-c2nc(Br)cnc2NC(=O)OC(C)(C)C)n1

Procedure:
(5-Bromo-3-hydrazino-pyrazin-2-yl)-carbamic acid tert-butyl ester (513 mg, 1.6 mmol) and 2,4-pentadione (0.18 mL, 1.7 mmol) in ethanol (25 mL) were heated to reflux for 45 min. The mixture was concentrated in vacuo followed by co-evaporation with ethyl acetate to give [5-bromo-3-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-carbamic acid tert-butyl ester as the crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[O:23][CH3:24])([O-:3])=[O:2].[H-].[Na+].[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>CN(C)C=O>[C:27]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:8]1)(=[O:29])[CH3:28]
Reactant: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc([N+](=O)[O-])cc12
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
A solution of 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.6 g.) in N,N-dimethylformamide (DMF), (3 ml.) was added to a stirred suspension of oil-free sodium hydride (0.088 g.) in DMF (8 ml.) under a nitrogen atmosphere at ambient temperature. The red solution was stirred for 20 minutes, and acetic anhydride (0.187 g.) added. After 1 hour, the mixture was poured into hydrochloric acid (1N, 30 ml.), extracted with ethyl acetate (3×50 ml), the combined extracts washed with water (2×20 ml.), brine, dried (MgSO4) and evaporated. The product was crystallized from a mixture of tetrahydrofuran and ether to give 4-(1-acetyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.455 g., 67%) as a yellow powder; partial NMR (250 MHz, DMSO-d6): 2.68(s,3H, NCOCH3); 3.95(s,3H, OMe); 4.13(s,2H, ArCH3).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[Cl:23])[C:9](=O)[C:10](=O)[NH:11][C:5]2=[N:4][CH:3]=1.S(C)C>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[Cl:23])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1
Reactant: O=c1[nH]c2ncc(Br)nc2n(Cc2c(F)ccc(F)c2Cl)c1=O
Solvent: C1CCOC1
Solvent: CSC
Product: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Yield: 20 %

Procedure:
To a solution of 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydropyrazino[2,3-b]pyrazine-2,3-dione (2.5 mmol, 1.0 g) in THF (5 mL) was added BH3.Me2S (7.5 mmol, 3.75 mL, 2.0 M in THF). The resulting solution was refluxed for 2 hrs under N2. Excessive BH3 was quenched by addition of MeOH at rt then heating the reaction mixture for 10 min. After volatile components were removed on rotavap, the residue was subjected to a silica gel column chromatography by using 4:1 ratio of CH2Cl2/MeOH (pre-saturated with ammonia gas) as eluents, furnishing 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine in 20% yield (0.19 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](=[O:17])[CH:3]=1.[OH-:18].[Na+]>>[NH2:1][C:2]1[NH:7][C:6](=[O:18])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: CSc1nc(N)cc(=O)n1Cc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Product: Nc1cc(=O)n(Cc2ccccc2)c(=O)[nH]1

Procedure:
Reflux 6-amino-3-(phenylmethyl)-2-methylthiopyrimidin-4(3H)-one (2.5 g=10 mmol) in 40 ml 10% aqueous NaOH for four hours. Cool, acidify the solution and collect the precipitate. Water wash and dry to give the title compound, a white solid, EI MS: M+=217.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H-].[Na+].Cl[C:15]1[CH:16]=[C:17]2[N:24]([CH3:25])[CH2:23][CH2:22][N:18]2[C:19](=[O:21])[N:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[CH2:10][O:11][C:15]1[CH:16]=[C:17]2[N:24]([CH3:25])[CH2:23][CH2:22][N:18]2[C:19](=[O:21])[N:20]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(F)c(Cl)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3-chloro-4,5-difluorophen-yl)methanol (192 mg, 1.078 mmol) in DMF (4 mL), sodium hydride (129 mg, 3.23 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (200 mg, 1.078 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:5]=1[C:6](OC)=[O:7])(=O)[CH3:2].O.[NH2:17][NH2:18]>CO.O>[CH3:15][O:14][C:11]1[CH:10]=[C:5]2[C:4]([C:1]([CH3:2])=[N:17][NH:18][C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(OC)ccc1C(C)=O
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(C)n[nH]c(=O)c2c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a solution of methyl 2-acetyl-5-methoxybenzoate (2) (2.21 g, 10.60 mmol) in methanol (13 mL) is added hydrazine monohydrate (1.59 g, 31.80 mmol). The mixture is stirred at 95° C. under argon for 5 h, then cooled to room temperature, diluted with H2O (50 mL), and extracted with ethyl acetate (2×100 mL, 2×50 mL, and 2×30 mL). The extract is washed (brine), dried, and concentrated at reduced pressure. The residue is suspended in ethyl acetate (20 mL), heated, then cooled, and filtered to give 1.92 g (95%) of 3 as a white solid, mp 203-205° C. IR 3314, 2918, 1652, 1241 cm−1; 1H NMR (CDCl3) δ 2.60 (s, 3H, CH3), 4.01 (s, 3H, CH3O), 7.42 (dd, J=9.0, 2.7 Hz, 1H, 6-PhthH), 7.75 (d, J=9.0 Hz, 1H, 5-PhthH), 7.88 (d, J=2.7 Hz, 1H, 8-PhthH), 10.75 ppm (s, 1H, NH).