Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[CH:13][C:12]=1[CH:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=2)[NH:24]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[CH:13][C:12]=1[CH:23]1[CH2:32][C:31]([CH3:33])([CH3:34])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:36])[CH:29]=2)[NH:24]1
Reactant: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a suspension of 60% sodium hydride (176 mg, 4.4 mmol) in N,N-dimethylformamide (3 mL) was added cyclopropanesulfonic acid amide (530 mg, 4.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A29. A solution of 2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (250 mg, 0.62 mmol) and 1,1′-carbonyldiimidazole (203 mg, 1.25 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B29. Solution B29 was added to Solution A29 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (85 mg, 27%) as a white solid: MS (ESI) M+1=504.0.
Reaction SMILES: [C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Na+:9].[Na+].[S:11](=[O:15])(=[O:14])([OH:13])[OH:12].C(O)C.C([O-])(=O)CCC([O-])=O.[Na+].[Na+]>C(O)C>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[Na+:9].[Na+:9]
Reactant: O=C([O-])CCC(=O)[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=O)O
Product: O=S(=O)([O-])[O-]
Temperature: 30 °C

Procedure:
A mixture of 31.83 g of 200 proof ethanol and 4.356 g of 98% sodium succinate was prepared and heated to 30° C. Sulfuric acid (2.817 g, 98%) was then added to the ethanol/sodium succinate slurry with stiffing to produce free succinic acid and sodium sulfate. Following the procedure described in Example 1, a conversion of 68.6% of sodium succinate was obtained after 1 hour.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N+:17]([O-:9])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: [O-][n+]1cc(Br)cc2cc[nH]c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
m-Chloroperbenzoic acid (25 wt % water content, 322 mg, 1.40 mmol) in ethyl acetate (5 mL) was gradually added dropwise to 5-bromo-1H-pyrrolo[2,3-b]pyridine (184 mg, 0.934 mmol) in ethyl acetate (10 mL), and the reaction mixture was stirred at room temperature for 6 hours. After addition of saturated aqueous sodium hydrogen carbonate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was mixed with a mixture of ethyl acetate/hexane=1/1 (v/v), and the solid was collected by filtration, washed with hexane and dried under reduced pressure to give the title compound as a light brown solid (150 mg, yield 75%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].F[C:8]1[N:13]=[CH:12][C:11]([C:14]2([OH:41])[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)=[O:26])[CH2:21]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>CN(C=O)C>[OH:41][C:14]1([C:11]2[CH:12]=[N:13][C:8]([O:6][CH:4]([CH3:5])[CH3:3])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH:17]([N:20]2[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)=[O:26])[CH2:21]2)[CH2:18][CH2:19]1
Reactant: CC(C)O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Temperature: 80 °C

Procedure:
NaH (95%, 51 mg, 2 mmol) was added into IPA (4 mL) at 0° C. slowly until bubble disappeared. To this solution was added N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (6a, 200 mg, 0.40 mmol) in DMF (1 mL). After addition, the reaction was heated for another 2 hours at 80° C. The reaction solution was quenched with MeOH and partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[OH-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CO.O1CCCC1.O>[CH2:14]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
In a mixed solvent of methanol and tetrahydrofuran was dissolved 5.17 g of 4-hydroxy-3-chlorobenzoic acid, and a solution of 2.4 g of sodium hydroxide in 5 ml of water was added to the solution. Then, 10 ml of benzyl chloride was added to the mixture and the liquid was refluxed for 4 hours. Then, 1.2 g of sodium hydroxide was further added to the mixture, the liquid was refluxed for 2 hours, and the reaction liquid was put into 1N hydrochloric acid, and the precipitate was recovered by filtration, washed with water, methanol and n-pentane in succession and recrystallized from a mixed solvent of benzene and tetrahydrofuran to obtain 2.7 g of 4-benzyloxy-3-chlorobenzoic acid. Then, 15 g of thionyl chloride was added to 2.7 g of this 4-benzyloxy-3-chlorobenzoic acid, and the mixture was reacted under reflux and reacted for 3 hours. Unreacted thionyl chloride was removed by distillation under reduced pressure. Thus, 4-benzyloxy-3-chlorobenzoic acid chloride was quantitatively obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[Cl:15])=[CH:6][CH:7]=1.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[CH3:17][C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=3[Cl:15])[CH:6]=[CH:7][C:2]2=[N:20][N:19]=1
Reactant: Cc1ccc(Cl)c(-c2ccc(Cl)nn2)c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1ccc(Cl)c(-c2ccc3nnc(C)n3n2)c1

Procedure:
As described in Example 35, 2-chloro-5-methylbenzaldehyde is reacted with morpholine and potassium cyanide to give γ-(2-chloro-5-methylphenyl)-4-morpholineacetonitrile. In a similar manner as described in Example 35, the preceding compound is converted to 3-chloro-6-(2-chloro-5-methylphenyl)pyridazine which is reacted with acetic acid hydrazide in refluxing n-butanol for 24 hours to give the product of the example.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][N:14]=1.[CH2:21]1[O:31][C:24]2([CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[O:23][CH2:22]1>C1(C)C=CC=CC=1.O>[Br:20][C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([C:27]2([OH:30])[CH2:28][CH2:29][C:24]3([O:31][CH2:21][CH2:22][O:23]3)[CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1cc(Br)cnc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Br)cnc1C1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
1.6M n-Hexane solution of n-butyl lithium (100 ml) was added dropwise under nitrogen atmosphere at −78° C. to a solution of 2,5-dibromo-3-picoline (38.3 g) in toluene (300 ml), and stirred at the same temperature for two hours. Then, a solution of 1,4-cyclohexanedione monoethyleneketal (25 g) in toluene (200 ml) was added slowly dropwise, and after the addition the mixture was stirred at the same temperature for an hour. Then, the reaction solution was warmed up slowly to room temperature under stirring. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. Acetonitrile and water were added to the residue and the precipitate was filtered and dried at 60° C. under air blow to give 8-(5-bromo-3-methylpyridin-2-yl)-1,4-dioxaspiro[4,5]decan-8-ol (28 g) as a light brown solid.
Reaction SMILES: [CH:1]1([N:5]([CH3:26])[C:6](=[O:25])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=3[Cl:23])[CH:10]=[CH:9][C:8]=2[OH:24])[CH2:4][CH2:3][CH2:2]1.[CH2:27]1[S:33][C:31](=[O:32])[NH:30][C:28]1=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH:1]1([N:5]([CH3:26])[C:6](=[O:25])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH:21]=[C:27]4[S:33][C:31](=[O:32])[NH:30][C:28]4=[O:29])=[CH:16][C:15]=3[Cl:23])[CH:10]=[CH:9][C:8]=2[OH:24])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CSC(=O)N1
Reactant: CN(C(=O)c1cc(Oc2c(Cl)cc(C=O)cc2Cl)ccc1O)C1CCC1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O)C1CCC1
Yield: 75 %

Procedure:
To a solution of the title compound of Step H (40 mg, 0.10 mmol) and thiazolidinedione (13 mg, 0.11 mmol) in toluene (2 ml) was added acetic acid (1.5 μl, 0.025 mmol), piperidine (2.5 μl, 0.025 mmol) and powdered 3 A° molecular sieves. The reaction mixture was heated to reflux and stirred at reflux for about 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was washed with 1N HCl (2×10 ml), brine (10 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (7% MeOH in dichloromethane) to afford the title compound (37 mg). MS (APCl−) Calc: 492.0, found: 491.0 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC[F:32]>CN(C=O)C.O.C(O)(=O)C.[Pd]>[F:32][CH2:2][CH2:1][O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: FCCBr
Reactant: Oc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(c1)[nH]c1cc(OCCF)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.2 %

Procedure:
To a round bottom flask containing Compound 8 (50 mg, 0.17 mmol) in DMF (1 ml), was added cesium carbonate (62 mg, 0.19 mmol) and 1-bromo-2-fluoroethane (33 mg, 0.26 mmol). The reaction was stirred at rt for 15 h and then diluted with water (15 mL). White precipitate (50 mg) was collected via filtration and dried in vacu. The solid was dissolved in MeOH (10 mL). To the reaction, was added Pd/C (30 mg) and acetic acid (5 drops). The mixture was stirred under hydrogen (1 atm) atmosphere for 20 h and then filtered through a celite plug, concentrated in vacuo. The residue was purified on HPLC to afford CB-25 (18 mg, 0.053 mmol, 31% yield). 1H NMR (400 MHz, CD3CN) δ: 8.99 (br, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.67 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.58 (dd, J=8.0 Hz, 2.0 Hz, 1H), 4.75-4.74 (m, 1H), 4.63-4.61 (m, 1H), 4.23-4.13 (m, 2H); LRMS for C16H12F4NO3+H+, calc'd: 343.1. found: 246.0 (M+H+-TFA).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH:8]1([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([CH2:37][NH:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:33][N:32]=5)[S:30][C:23]=34)=[C:17]([F:43])[CH:16]=2)=[O:13])[CH2:10][CH2:9]1.CO.C(Cl)Cl>C(O)=O>[CH:8]1([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29]([C:31]5[N:32]=[CH:33][C:34]([CH2:37][N:38]([CH2:39][CH2:40][O:41][CH3:42])[CH:1]=[O:3])=[CH:35][CH:36]=5)[S:30][C:23]=34)=[C:17]([F:43])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Solvent: O=CO
Solvent: ClCCl
Solvent: CO
Product: COCCN(C=O)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To solution of acetic anhydride (150 μL, 1.17 mmol) in formic acid (2 mL) stirred at RT for 20 min was added in one portion 1 (150 mg, 0.296 mmol). After 2 hr, 200 μL of acetic anhydride (1.57 mmol) were added dropwise. The reaction mixture was stirred at RT overnight, quenched by addition of MeOH and concentrated. The residue was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV, then 10/90 over 5 CV), to afford the title compound 6 (96 mg, 0.18 mmol, 76% yield) as an off-white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.75 (s, 1H), 8.60-8.50 (m, 2H), 8.37 and 8.34 (2s, 1H), 8.32-8.23 (m, 114), 8.15 (s, 1H), 7.90-7.77 (m, 1H), 7.73 (dd, J=13.5, 2.5 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (bd, J=10.2 Hz, 1H), 6.67-6.58 (m, 2H), 4.60 and 4.56 (2s, 2H), 3.46-3.36 (m, 4H), 3.21 and 3.19 (2s, 3H), 2.59-2.51 (m, 1H), 0.70-0.60 (m, 2H), 0.47-0.38 (m, 2H). MS (m/z): 536.4 (M+H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Cl:9][C:10]([Cl:17])([Cl:16])[CH2:11][O:12][C:13](Cl)=[O:14]>N1C=CC=CC=1>[C:3]1(=[O:8])[NH:2][C:6](=[O:7])[CH2:5][CH2:4]1.[C:13](=[O:1])([OH:14])[O:12][CH2:11][C:10]([Cl:17])([Cl:16])[Cl:9]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Product: O=C(O)OCC(Cl)(Cl)Cl
Product: O=C1CCC(=O)N1

Procedure:
A 4.6 gram portion of N-hydroxysuccinimide and 5.5 ml. of 2,2,2-trichloroethylchloroformate in 30 ml. of dry pyridine is reacted as described in Example 2. The product is recrystallized from diethyl ether giving 2,2,2-trichloroethyl carbonate succinimide. A 400 mg. portion of this product and 300 mg. of trans-BM123γ are reacted as described in Example 1 giving 273.9 mg. of trichloroacetyl-trans-BM123γ.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].O.[OH-].[Li+].C(O)C.O.O1CCCC1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18]2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Yield: 88.9 %

Procedure:
Prepared as described in example 5b) using 2-chloro-5-[4-[[(1,1-dimethylethoxy)-carbonyl]amino]-1-piperidinyl]-benzoic acid, ethyl ester (Example 6a, 0.17 g), lithium hydroxide monohydrate (0.88 ml of a 3M solution in water), 1:1 ethanol/water (7 ml) and tetrahydrofuran (1 ml) to give the subtitle compound as a solid (0.14 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([F:10])[CH:6]=[C:7](C)[CH:8]=1)[CH3:2].C=O.[BrH:13].[C:14](O)(=O)[CH3:15]>O>[CH2:1]([C:3]1[CH:4]=[C:5]([F:10])[CH:6]=[C:14]([CH3:15])[C:8]=1[CH2:7][Br:13])[CH3:2]
Reactant: Br
Reactant: CC(=O)O
Reactant: CCc1cc(C)cc(F)c1
Agent: C=O
Solvent: O
Product: CCc1cc(F)cc(C)c1CBr
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 3-ethyl-1-fluoro-5-methylbenzene (1.1 g, 0.008 mol), paraformaldehyde (1.5 g, 0.05 mol), hydrobromic acid (4.1 ml 0.017 mol) (4.1 M in acetic acid) and acetic acid (2.5 ml) was stirred at ambient temperature for 40 h. To the mixture were water and petroleum ether (40-60) added and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated carefully under reduced pressure. The desired product was obtain as a yellow oil (1.3 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[C:21]1([CH:27]2[CH2:31][C:30](=[O:32])[O:29][C:28]2=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:30](=[O:32])[CH2:31][CH:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:28]([OH:33])=[O:29]
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: Cc1ccccc1
Product: O=C(CC(C(=O)O)c1ccccc1)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.7 g, 2.6 mmol; prepared in a manner similar to that described in Example 23), 3-phenyldihydrofuran-2,5-dione (0.458 g, 2.6 mmol) and toluene (35 ml) was heated under reflux for 2 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with ethyl acetate (3 ml) and dried in vacuo to give N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-phenylsuccinamic acid (0.775 g) as an off-white solid, m.pt. 180–183° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 2.7–2.9 (m, 1H) (—CHHCHPh—), 3.1–3.3 (m, 1H) (—CHHCHPh—), 4.0–4.1 (m, 1H) (—CHPh—) 4.3 (s, 2H) (ArCH2—), 7.1–7.3 (m, 2H) (2×ArH), 7.3–7.5 (m, 5H) (5×ArH), 7.8–8.0 (m, 4H) (4×ArH), 8.3 (d, 1H) (ArH), 9.75 (s, 1H) (chain CONH), 12.5 (br s, 1H) (—CO2H), 12.65 (s, 1H) (ring CONH) ; m/z (M+H)+. 446, 100% purity.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:11][C:10]1[C:5]([CH2:3][OH:2])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)c1nccnc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nccnc1CO
Temperature: 9 °C
Reaction time: 3 h

Procedure:
Methyl-3-aminopyrazine-2-carboxylate (14.22 g, 93 mmol) was suspended in tetrahydrofuran (1 L) and cooled under a nitrogen atmosphere in a methanol/ice bath. Lithium aluminium hydride (100 ml, 1M solution in diethyl ether, 100 mmol) was added at such a rate to maintain the temperature between 8-10° C. Once addition was complete the reaction was stirred at room temperature for 3 hours and then heated at reflux for 20 minutes. The reaction was then cooled to 0° C. and quenched with water (30 mL in 100 mL tetrahydrofuran) keeping the temperature below 8° C. The reaction was then stirred at room temperature for 30 minutes and then filtered. The residue was washed with hot ethyl acetate (250 mL×2) filtered. The two filtrates were combined and evaporated to dryness. This produced (3-amino-pyrazin-2-yl)-methanol (7.38 g) as a pale orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:62]=[CH:61][C:55]([O:56][CH2:57][CH2:58]CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:58][CH2:57][O:56][C:55]2[CH:61]=[CH:62][C:52]([F:51])=[CH:53][CH:54]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCOc1ccc(F)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCOc4ccc(F)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 62.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (68 mg), was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (94 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-fluorophenoxy)-1-propanol (54 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 58%).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([S:1][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(S)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
Combine 4-mercapto-benzaldehyde (0.45 g, 3.3 mmol), 6-chloro-nicotinamide (0.52 g, 3.3 mmol), potassium carbonate (0.7 g, 5.1 mmol), and dimehtylformamide (15 mL) then heat at 70° C. overnight. Cool to room temperature, pour into water, and then extract with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (1 g). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-(4-formyl-phenylsulfanyl)-nicotinamide (120 mg). 1H NMR (DMSO-D6, 300.00 MHz): 10.08 (s, 1H), 8.91 (dd, 1H, J=2.3, 0.7 Hz), 8.18-8.12 (m, 2H), 8.03-7.98 (m, 2H), 7.83-7.78 (m, 2H), 7.61 (s, 1H), 7.34 (dd, 1H, J=8.4, 0.8 Hz). Step 3 6-[4-(Benzylamino-methyl)-phenylsulfanyl]-nicotinamide