Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]#[C:17][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccc(Br)cn1
Reactant: C#Cc1ccccc1
Product: OCc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, light brown solid, MS: m/e=210.2 (M+H+), can be prepared in accordance with the general method of example 1, step 1 from (5-bromopyridin-2-yl)methanol and phenylacetylene.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]=[C:11]([CH:14]([OH:16])[CH3:15])[CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)[C:21]1[CH:26]=[CH:25]C(C2C(C=O)=CSC=2)=[CH:23][CH:22]=1.C1([Mg]Br)C=CC=CC=1>>[C:15]1([CH:14]([C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)[S:13][CH:12]=2)[OH:16])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cscc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(O)c1csc(-c2ccc(C(F)(F)F)cc2)c1
Agent: Br[Mg]c1ccccc1
Product: OC(c1ccccc1)c1csc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of 1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate 126) using 4-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde (intermediate 125) and phenyl magnesium bromide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc4[nH]ccc34)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 4-hydroxyindole (200 mg) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (3/1) to obtain 51 mg of the title compound (yield: 32%).
Reaction SMILES: C([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:13][C@H:12]1[NH:8][C@H:9]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2)cc1
Reaction time: 0.58 h
Yield: 94.4 %

Procedure:
To a stirred solution of methyl 4-[N-Boc-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.29 g, 3.70 mmol) in CH2Cl2 (30 ml) was added trifluoroacetic acid (10 ml) at rt, and the resulting mixture was stirred for 35 min. The mixture was concentrated in vacuo and poured into aq.NaHCO3, then extracted with CHCl3. The organic layer was washed with water, drying over anhydrous Na2SO4, and concentrated in vacuo to give methyl 4-[5-(R)-methyl-2-(S)-pirrolidinyl methoxy]benzate (871 mg, 95%) as a colorless oil. The product was used for next reactions without further purification. 1H-NMR (CDCl3) δ 1.18 (d, J=6.4 Hz, 3 H), 1.30–1.40 (m, 1 H), 1.59–1.67 (m, 1 H), 1.87–1.97 (m, 2 H), 3.19–3.27 (m, 1 H), 3.49–3.55 (m, 1 H), 3.87 (s, 3 1), 3.89–4.05 (m, 2 H), 6.89 (d, J=8.8 Hz, 2 H), 7.96 (d, J=8.8 Hz, 2 H); MS (ESI) m/z, 250 (M++H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.O.O.O.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:14]1[C:13]([CH3:12])=[N:17][CH:16]=[N:15]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Yield: 22.3 %

Procedure:
3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), 3-methyl-1H-1,2,4-triazole (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in dimethyl sulfoxide (1.5 mL) were stirred for 6 hours at 70° C. The mixture was concentrated in vacuo; the residue was diluted in water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried with magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (160 mg, 22%) as white crystals MS ISP (m/e): 223.2[(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.22 (m, 2H), 8.04 (s, 1H), 7.74 (dd, 1H), 2.48 (d, 3H). Mp 56-58° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:28]O)[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[C:30]1(=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[NH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:40]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]1[CH2:28][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:6]2[N:7]([C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCc1c(CN2C(=O)c3ccccc3C2=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A mixture of ethyl 5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100 mg), 1H-isoindole-1,3(2H) dione (44.6 mg) diisopropyl azodicarboxylate (76.7 mg) and triphenylphosphine (99.5 mg) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 1 hour. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-1:1) to give ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (107 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:1]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 25 °C

Procedure:
41.1 g (0.3 mol) of p-aminobenzoic acid and 300 M of acetic acid were put into a 250 M flask to dissolve the p-aminobenzoic acid in the acetic acid, and then 29.4 g (0.3 mol) of maleic anhydride was slowly added thereto at 10° C. to obtain a yellow precipitate. This precipitate was recrystallized with a solution of DMF (dimethylformamide) and ethanol (50:50, w/w) to form an intermediate. The intermediate was treated at 85° C. for 15 minutes using sodium acetate and acetic anhydride, was cooled to room temperature, and was then precipitated in an ice water bath to obtain a precipitate. The obtained precipitate was recrystallized with a solution of ethyl acetate and n-hexane (50:50, w/w) to obtain N-(p-carboxyphenyl)maleimide.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cu][C:26]#[N:27]>N1C=CC=CC=1.CN1CCCC1=O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(CCc3ccc(Br)cc3)cc2)CC1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](c2ccc(CCc3ccc(C#N)cc3)cc2)CC1

Procedure:
Analogously to Example 4(b), 1-[4-(trans-4-n-propylcyclohexyl)-phenyl]-2-(4-bromophenyl)-ethane is reacted with copper(I) cyanide in pyridine/N-methylpyrrolidone to give 1-[4-(trans-4-n-propylcyclohexyl)-phenyl]-2-(4-cyanophenyl)-ethane; m.p. 36°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=4)[CH2:27][CH2:26]3)=[CH:3][CH:4]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(F)cc2)n1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nsc(-c2ccc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)n1
Temperature: 140 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
A mixture of 5-(4-fluorophenyl)-3-methyl-1,2,4-thiadiazole (0.012 mol), 1-[3-(trifluoromethyl)phenyl]-piperazine (0.014 mol) and sodium carbonate (0.024 mol) in DMF (10 ml) was stirred at 140° C. for 24 hours, then at 150° C. for 24 hours, cooled, poured out into ice water (200 ml) and stirred. The precipitate was filtered off, taken up in DCM, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 2.5 g (52%) of 1-[4-(3-methyl-1,2,4-thiadiazol-5-yl)phenyl]-4-[3-(trifluoromethyl)phenyl]piperazine (compound 2).
Reaction SMILES: CO[C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11]N=[CH:9][N:8]=1.S1C(N)=N[CH:20]=N1.S1C=CN=C1N>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][NH:6][C:7]2[S:11][CH:20]=[CH:9][N:8]=2)=[CH:3][CH:15]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: Nc1ncns1
Agent: Nc1nccs1
Product: COc1ccc(CNc2nccs2)cc1

Procedure:
N-(4-methoxybenzyl)thiazol-2-amine (INTERMEDIATE W) was prepared in a manner analogous to INTERMEDIATE A wherein 1,2,4-thiadiazol-5-amine was replaced with thiazole-2-amine
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][O:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=1[CH3:23])([O-:9])=[O:8].[Cl:28]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N+:7]([C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[CH2:12][O:13][C:14]1[C:21]([CH3:22])=[CH:20][C:17]([CH2:18][Cl:28])=[CH:16][C:15]=1[CH3:23])([O-:9])=[O:8]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(CO)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(CCl)cc(C)c1OCc1ccccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 165.6 %

Procedure:
Pyridine (79 mL, 0.97 mmol) was added to a stirring mixture of 8b (112 mg, 0.39 mmol) and triphosgene (46 mg, 0.16 mmol) in CH2Cl2 (5 mL) at r.t. After 15 minutes, the reaction mixture was concentrated in vacuo. Flash chromatography (20 g, 5:1 hexanes/ethyl acetate) yielded 9b (81 mg, 68%) as a white solid: 1H NMR (270 MHz, CDCI3) d 2.27 (s, 6H), 4.52 (s, 2H), 5.23(s, 2H), 7.09 (s, 2H), 7.51 (t, J=8.2 Hz, 1H), 7.76 (t, J=7.4 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.18 (d, J=7.4 Hz, 1H); 13C NMR (68 MHz, CDCI3) d 16.4, 46.2, 70.1, 124.9, 128.2, 128.4, 129.5, 131.5, 133.5, 134.2, 134.7, 146.6, 155.6.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]#[N:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([CH3:14])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1cc(C#N)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(C)(C)C)cc1CN

Procedure:
3-tert.-butyl-1H-pyrazol-5-carbonitrile (J-IV) (10 mmol) was added to a suspension of NaH (60%) (12.5 mmol) in DMF (20 ml) at room temperature while stirring. After stirring for 15 minutes, methyl iodide (37.5 mmol) was added dropwise to this reaction mixture at room temperature. After stirring for 30 min at 100° C., the reaction mixture was mixed with water (150 ml) and extracted with dichloromethane (3×75 ml). The combined organic extracts were washed with water (100 ml) and sat. NaCl solution (100 ml) and dried over magnesium sulphate. After removal of the solvent under vacuum, the residue was purified by column chromatography (SiO2, various mixtures of EE and cyclohexane as the mobile solvent) and the product J-V was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH3:16])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([CH3:16])[CH2:9][C:10](=[O:11])[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c1cccc(Br)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C[C@](C)(N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a −78° C. solution of (S)-3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-(R)-(2-methyl-propane-2-sulfinylamino)-butyramide (1.5 g, 3.7 mmoles; 1.0 equiv) in THF (53 mL) is added methylmagnesium bromide (6.2 mL, 18.5 mmoles, 5.0 equiv) and the reaction is allowed to warmed to ambient temperature. After 1 h, the reaction is cooled to −78° C. and quenched with saturated aqueous ammonium chloride. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (>95% yield): MS (m/z) 360, 362 (M+1)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].N1CC[CH2:15][CH2:14][CH2:13]1.FC(F)(F)C(O)=O>CC(C)=O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:14]([CH3:15])([CH3:13])[CH2:2][C:1]2=[O:3]
Reactant: C1CCNCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1

Procedure:
In another exemplary reaction sequence shown in Reaction Scheme 15, 4-bromophenol is reacted with acetyl chloride (AcCl) to provide the corresponding ester, and the ester made to undergo a Fries rearrangement under Friedel Crafts conditions to provide 2-acetyl-4-bromophenol. 2-Acetyl-4-bromophenol is reacted with acetone in the presence of piperidine and trifluoroacetic acid (TFA) to give 6-bromo-2,2-dimethyl-chroman-4-one. The latter compound is reacted with the Grignard reagent of the formula R1MgX and then with acid to provide the 6-bromo-2,2-dimethyl-chromene derivative of Formula 17.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11](=[O:13])C>C1COCC1.CCCCC>[CH2:1]([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH2:11][OH:13])=[O:5])[CH3:2]
Reactant: CC=O
Reactant: CCNC(=O)c1cccs1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCNC(=O)c1sccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 500 %

Procedure:
A solution of thiophene-2-carboxylic acid ethylamide (465 mg, 3 mmol) in dry THF (12 mL) is cooled to −78° C. under an argon atmosphere. Tert-BuLi (5.3 mL of a 1.7 M solution in pentane, 9.0 mmol) is added dropwise at −78° C. and the reaction mixture is stirred for 3 h. The reaction mixture is treated with neat acetaldehyde (3 mL, 53 mmol) and is stirred at −78° C. for 2 h and then warmed to room temperature overnight. The reaction mixture is quenched by the addition of water (35 mL). The reaction mixture is transferred to a separatory funnel and the organic phase is collected. The aqueous layer is extracted 5 times with Dichloromethane. The combined organic extracts are washed with water, and saturated aqueous NaCl, dried over Na2SO4 and concentrated. The residue is purified by chromatography (silica gel, 25% EtOAc/hexane) to give the title compound (298 mg, 15 mmol) in 50% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][C:17]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:32]([NH:39][C:24]([C:23]1[N:19]([C:17]2[S:18][C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:31])=[CH:15][CH:16]=2)[N:20]=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:22]=1)=[O:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a stirred solution of 25 (45 mg, 0.097 mmol) in CH2Cl2 (0.65 mL) were added benzylamine (0.016 mL, 0.146 mmol), EDC (37.3 mg, 0.195 mmol) followed by DMAP (4.76 mg, 0.039 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 26a (24 mg, 45%) as a white solid. LRMS (ESI): calc. 551.2; found 574.6 (MNa)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]=[CH:6]2
Reactant: OC1CCc2c(Br)cc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(Br)c2c(c1)C=CC2
Yield: 97.6 %

Procedure:
According to Scheme 2, step 2: A mixture of 4-bromo-6-fluoro-indan-1-ol (4a) (10.0 g, 43.3 mmol) and para-toluene sulfonic acid monohydrate (372 mg, 2.16 mmol) in toluene was heated at reflux for 2.5 h. The solution was washed with aqueous saturated NaHCO3 and brine, dried over MgSO4 and solvents evaporated to give 9.0 g of 7-Bromo-5-fluoro-1H-indene (5a) which was used immediately in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide as a solid in quantitative yield. MS: 294 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28](#[N:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]#[N:31])=[O:15])[CH3:14]
Reactant: C=CC#N
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCC#N)CCCCc1ccccc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.341 ml, 0.0024 mole), trimethyl silylchloride (0.303 ml, 0.0024 mole) and acrylonitrile (0.17 ml, 0.0024 mole). The reaction mixture was stirred at reflux temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a thick oil (0.6 g, 97% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH2:22][CH:21]4[N:23]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:30]([Cu])#[N:31].O>CN(C=O)C>[F:27][C:25]([F:26])([F:28])[C:24]([N:23]1[CH:21]2[CH2:20][CH2:19][CH:18]1[CH2:17][C:16](=[C:6]1[C:5]3[CH:4]=[CH:3][C:2]([C:30]#[N:31])=[CH:15][C:14]=3[O:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22]2)=[O:29]
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(Br)ccc31)C2)C(F)(F)F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of Compound 5d (3 g, 6.46 mmol) in DMF (100 mL) was added CuCN (0.69 g, 7.70 mmol). The reaction mixture was refluxed for 2 d and then cooled to room temperature. The mixture was poured into water (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed sequentially with H2O (100 mL), brine (100 mL), then dried (MgSO4) and concentrated. The crude product was purified by normal phase chromatography, using a gradient of ethyl acetate (0% to 10%) in heptane to give compound 5e. MS m/z (M+H+) 410.9; 1H NMR (CDCl3) δ 1.41 (m, 2H), 1.85 (m, 2H), 2.96 (m, 4H), 4.44 (m, 1H), 4.73 (m, 1H), 7.23 (m, 3H), 7.33 (m, 2H), 7.43 (dt, 1H), 7.51 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCCC=2C=1C(OCC)=O.[F:40]C1C=CC(S(Cl)(=O)=O)=CC=1>>[F:40][C:4]1[CH:3]=[CH:2][C:1]([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CCOC(=O)c1c(N)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 4-fluorobenzene-sulphonyl chloride