Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=2)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)[CH:26]=1)C.CCOC(C)=O>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:30]=[C:29]([C:31]3[CH:32]=[C:33]([CH3:38])[CH:34]=[C:35]([CH3:37])[CH:36]=3)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]3[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=3)[CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cc(C)cc(C)c2)c(OCCO)c(-c2cc(C)cc(C)c2)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCCO)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a cooled solution (0° C.) of 8-phenyloctyl amine (1.56 g, 7.58 mmol, 1.51 ml) in 10 mL anhydrous THF was added n-BuLi (5.1 mL, 7.96 mmol) as a solution in hexanes dropwise. After the addition, the reaction was warmed up to room temperature and was stirred for one-half hour at room temperature. Then the lithiated amine was cooled back down to 0° C. and was added to a cooled (0° C.) solution of 3,5-bis-(3,5-dimethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (1.04 g, 2.49 mmol) in 10 mL anhydrous THF. The resulting reaction mixture was stirred for 5 min at 0° C. then allowed to warm up to room temperature. At that point, additional n-BuLi was added (2.04 mL, 3.18 mmol). When the reaction appeared to be practically complete (by TLC), it was worked up as in Step 2 of Example 135. After flash chromatography (25% EtOAc: 75% Hexanes), there yielded 850 mg, 59.4% of the amide as a yellow oil. 1H NMR (CDCl3) δ 1.25–1.40 (m, 8H); 1.40–1.64 (m, 5H); 2.37 (s, 12H); 2.57 (t, J=8.18 Hz, 2H); 3.25 (t, J=4.09 Hz, 2H); 3.36–3.47 (m, 4H); 6.06 (t, J=6.54 Hz, 1H); 7.02 (s, 2H); 7.11–7.19 (m, 4H); 7.20–7.48 (m, 5H); 7.69 (s, 2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][NH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[CH3:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:8]([CH3:7])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNc1cc([N+](=O)[O-])ccc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1N(C)Cc1ccccc1

Procedure:
K2CO3 (270 mg) is added to a solution of N,2-dimethyl-5-nitro-aniline (214.5 mg, 1.29 mmol) and benzyl bromide (0.2 mL, 1.7 mmol) in DMF (4 mL). The mixture is heated for 12 h to 70° C. under stirring. Volatiles are evaporated at reduced pressure. Chromatography of the residue (silica gel, hexane/EtOAc 4:1) yields N-Benzyl-N,2-dimethyl-5-nitro-aniline.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[C:6]([O:10][C:11](=[O:14])[NH:12][NH2:13])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([NH:12][N:13]=[CH:1][CH:2]([CH3:4])[CH3:3])=[O:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)C=O
Product: CC(C)C=NNC(=O)OC(C)(C)C

Procedure:
B-21a is prepared analogously to B-19a starting from isobutyraldehyde (1.26 mL, 13.9 mmol) and tert-butylcarbazate (1.83 g, 13.9 mmol). Yield: 2.56 g.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=O)#[N:2].[CH3:21][NH2:22]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH:22][CH3:21])=[O:18])#[N:2]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Temperature: 25 °C

Procedure:
To a solution of 2.5 g of 5-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 20 ml of DMF was added 20 ml of 40% aqueous monomethylamine. The reaction mixture was stirred at room temperature for approximately two and one-half hours whereupon the solution was poured into ice water. The precipitate was collected by filtration and recrystallized from methanol/water to afford 1.3 g of 5-cyano-1-(2,4-dichlorophenyl)-N-methyl-1H-pyrazole-4-carboxamide. MP=182°-183° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.ClCCl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[O:22][C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCc3ccccc3)[C@H](NC(=O)OCc3ccccc3)[C@@H](O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 30 g of benzyl 2-benzyloxycarbonylamino-2-desoxy-α-D-glucopyranoside (Heyns and Paulsen, Chem. Ber. 88, 188 (1955)) in 116 ml of pyridine was treated at 0° C. with a solution of 19.85 g of p-tolylsulfonyl chloride in 30 ml of 30 dichloromethane and stirred at room temperature for 4 hours. Then, the mixture was poured into ice-cold 2N sulfuric acid and extracted with dichloromethane. The organic phases were washed with aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel with hexane/ethyl acetate and gave benzyl 2-benzyloxycarbonylamino-2-desoxy-6-O-(p-tolyl-sulfonyl)-α-D-glucopyranoside, [α]+101.80 (c 0.5; dioxan), MS: m/z 580 ([M+Na]+).
Reaction SMILES: [CH:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[CH2:11][C:12]([OH:14])=[O:13])(=[O:28])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(O)CC1NCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.91 g of (1,2,3,4-tetrahydro-1-isoquinolyl)acetic acid (Preparation 2.18) are suspended in 25 ml of dioxane, 10 ml of 1N NaOH are added, followed by portionwise addition of 2.3 g of 2-naphthalenesulphonyl chloride, and the mixture is maintained at pH=10.5-12 by addition of 1N NaOH. The mixture is kept stirring as a constant pH for 2 hours at RT. The reaction medium is diluted with 100 ml of water and is then washed twice with EtOAc and brought to pH=1.2 by addition of 6N HCl in the presence of EtOAc. This mixture is extracted with EtOAc, washed with saturated NaCl solution, dried over Na2SO4 and evaporated to dryness. The expected product crystallizes from heptane, and is drained, washed with heptane and then dried to give 3.14 g, m.p=132° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[O:21]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
4-Bromo-benzenesulfonyl chloride 27.5 g (107 mmol) was dissolved in 180 ml of anhydrous pyridine. To this solution was added (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone 25 g (107 mmol). The reaction mixture was stirred under nitrogen 5 hour at 80° C. and pyridine was then evaporated under vacuum. The resulting crude material was dissolved in dichloromethane, and extracted with saturated bicarbonate solution. The combined organic layer was washed with brine dried over magnesium sulfate, filtered and concentrated, then ethyl acetate (50 mL) added to the solid, the solid was filtered, washed again with ethyl acetate, to yield a pale yellow solid: LC-MSD, m/z for C18H12BrClN2O3S [M+H]+: 452.9
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([OH:31])[CH2:29][CH3:30])=[CH:6][CH:5]=1.[CH3:32]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([O:31][CH3:32])[CH2:29][CH3:30])=[CH:6][CH:5]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 78.3 %

Procedure:
Sodium hydride (60% in oil, 40.0 mg, 1.00 mmol) was added to a stirred solution of 1-{9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (370 mg, 0.833 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After stirring 5 min, methyl iodide (177 mg, 1.25 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (299 mg, 0.652 mmol, 78%).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[C:35]([O:43][CH2:44][C:45]1[O:49][N:48]=[C:47]([CH3:50])[C:46]=1Br)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(CC)CC.[CH3:59][C:60]1([CH3:67])[C:64]([CH3:66])([CH3:65])[O:63][BH:62][O:61]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:35]([O:43][CH2:44][C:45]1[O:49][N:48]=[C:47]([CH3:50])[C:46]=1[B:62]1[O:63][C:64]([CH3:66])([CH3:65])[C:60]([CH3:67])([CH3:59])[O:61]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1noc(COC(=O)c2ccccc2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1noc(COC(=O)c2ccccc2)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a resealable vial was added Pd(OAc)2 (3.87 mg, 0.017 mmol) and X-phos (16.42 mg, 0.034 mmol) before the vial was sealed and evacuated and purged with N2 (3×). To this vial was added (4-bromo-3-methylisoxazol-5-yl)methyl benzoate (102 mg, 0.344 mmol) in dioxane (1 mL), Et3N (144 μl, 1.033 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution (517 μl, 1M in THF, 0.517 mmol). The reaction was stirred overnight at 80° C., cooled to room temperature and filtered. The filtrate was concentrated to afford crude (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methyl benzoate. To a resealable vial was added K2CO3 (47.5 mg, 0.344 mmol), PdCl2(dppf)-CH2Cl2 Adduct (20.06 mg, 0.025 mmol), (2-bromophenyl)(4-chlorophenyl)methanone (72.6 mg, 0.246 mmol). The vial was sealed and evacuated and purged with N2 (3×) before addition of crude (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methyl benzoate (118 mg, 0.344 mmol) dissolved in dioxane (2 mL). Water (0.5 mL) was then added to this solution before the vial was heated to 110° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 432 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Br[C:35]1[N:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:41][C:38]1[CH:37]=[N:36][C:35]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH2:4][CH2:3][C:2]([F:1])([F:32])[F:33])=[C:7]([CH3:21])[CH:8]=2)=[N:40][CH:39]=1
Reactant: Clc1cnc(Br)nc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A reaction mixture of 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoic acid (0.500 g), 2-bromo-5-chloropyrimidine (0.251 g), tetrakistriphenylphosphinepalladium (0.125 g), sodium carbonate (0.343 g), DME (3 mL) and water (1 mL) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.407 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:7][CH:6]=1.[C:30]1(=[O:40])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][NH:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:40]=[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][N:31]1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCBr)cc2)nc1-c1ccccc1
Reactant: O=c1[nH]ncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(OCCn3ncc4ccccc4c3=O)cc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 128.6 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1050 mg), 1(2H)-phthalazinone (530 mg), potassium carbonate (1000 mg) and N,N-dimethylformamide (15 ml) was stirred at 90° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-[2-[1-oxophthalazin-2(1H)-yl]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (1460 mg, yield 90%). This was recrystallized from acetone-hexane. Melting point: 155–156° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (60) (44 mg, 0.23 mmol) using Method C. The crude residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH:12](Cl)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C.C(OCC)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: COc1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(Oc1ccc(OC)cc1)Oc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Sodium (5.4 g) is dissolved in absolute ethanol (160 cc). 4-Methoxyphenol (29.2 g) dissolved in absolute ethanol (20 cc) is added. The mixture is stirred for 1 hour at ambient temperature. Ethyl 2,2-dichloro-acetate (20 g) dissolved in absolute ethanol (20 cc) is then added and the mixture is heated under reflux for 20 hours. The ethanol is driven off under reduced pressure (20 mmHg) at 40° C. and the residue is taken up in diethyl ether (100 cc). The organic phase is washed with 0.1 N sodium hydroxide solution (100 cc) and with water (2×100 cc) and is then dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methoxyphenoxy)-acetate (30 g) is thus obtained in the form of an oil.
Reaction SMILES: C[O:2][C:3](=[O:6])[CH:4]=[CH2:5].[F:7][C:8]([F:21])([F:20])[C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:11][N:10]=1.[OH-].[Li+:23]>O.C(#N)C>[Li+:23].[F:21][C:8]([F:7])([F:20])[C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:5][CH2:4][C:3]([O-:2])=[O:6])[CH2:16][CH2:15]2)=[N:11][N:10]=1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C([O-])CCN1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 92 %

Procedure:
Acrylic acid methyl ester (189 mg; 2.20 mmol) is added to 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine (476 mg; 2.00 mmol) in water (1.6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 30 minutes at 120° C. Lithium hydroxide (92 mg; 4.00 mmol) in water (2 mL) is then added and the reaction mixture is again irradiated in a mono-mode microwave oven for 10 minutes at 100° C. The mixture is then diluted with acetonitrile and the precipitate formed is filtered, collected and dried under high vacuum to afford the desired compound (580 mg; 1.84 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH:14]4[CH2:15][CH2:16][O:17][C:5]34[C:4]=2[CH:3]=1.[H-].[Na+].[C:20]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CO>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:7](=[O:12])[CH:6]3[CH2:13][CH:14]4[CH2:15][CH2:16][O:17][C:5]34[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: O=C1Nc2ccc(Cl)cc2C23OCCC2CC13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)C2CC3CCOC32c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 9-chloro-3,3a,4,4a-tetrahydro-2H-furo[2′,3′:2,3]cyclobuta[1,2-c]quinolin-5(6H)-one (200 mg, 0.801 mmol) in dimethylformamide (4 ml) at 0° C. was slowly added sodium hydride (19 mg, 0.801 mmol) over 15 minutes. The suspension was allowed to warm to room temperature. The mixture stirred for 45 minutes and 4-(Boc-amino)butyl bromide (202 mg, 0.801 mmol) was added. The solution was stirred for 15 hours, followed by addition of 0.25 mL methanol. Column chromatography provided the title compound.
Reaction SMILES: [C-]#N.[Na+].C1N2CC[N:6](CC2)[CH2:5]1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1>CS(C)=O.O>[Br:12][C:13]1[CH:14]=[N:15][C:16]([C:5]#[N:6])=[N:17][CH:18]=1
Reactant: C1CN2CCN1CC2
Reactant: Clc1ncc(Br)cn1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 345.1 %

Procedure:
To a solution of NaCN (0.849 g, 17.32 mmol) and DABCO (0.390 g, 3.48 mmol) in a mixture of DMSO (4 ml) and H2O (9 ml) was added a solution of 5-bromo-2-chloropyrimidine (3.05 g, 15.75 mmol) in DMSO (9 ml). The solution was stirred at room temperature overnight, and then diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-bromopyrimidine-2-carbonitrile (2,327 g, 12.01 mmol, 76% yield, 1H NMR (CDCl3 500 MHz): δ 8.94 (s, 2H)).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(CN2CCCCCC2)cc1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 80.9 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-azepan-1-ylmethylbenzoic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (52 mg) was obtained.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.[Cl-].[NH4+]>O1CCCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([CH2:14][CH2:15][C:16]([OH:19])([CH3:1])[CH2:17][CH2:18]3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)C(=O)Nc1cc(Br)ccc12
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
Methyllithium (1.6 M in diethyl ether, 4.89 mL, 7.82 mmol) was added dropwise to a stirred solution of 6′-bromospiro[cyclohexane-1,3′-indoline]-2′,4-dione (preparation 10a, 1.00 g, 3.40 mmol) in tetrahydrofuran (30 mL) at −78° C. The mixture was warmed to 0° C. over 3 hours and stirred at room temperature for additional 4.5 hours. Saturated aqueous ammonium chloride (20 mL) was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (97:3 dichloromethane/methanol) gave the two pure isomers of the title compound.