Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4]1.I[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.O>CN(C=O)C.C(OCC)(=O)C>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][CH2:15][CH2:14][N:9]1[CH:10]=[CH:11][C:6]2[CH:5]=[CH:4][O:3][C:7]=2[C:8]1=[O:12]
Reactant: ICCOC1CCCCO1
Reactant: O=c1[nH]ccc2ccoc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2occc2ccn1CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Sodium hydride (60% in oil, 138 mg, 3.5 mmol) was suspended in DMF (10 ml). A DMF solution (5 ml) of 6H-furo[2,3-c]pyridin-7-one (310 mg, 2.3 mmol) was added thereto at 0° C., and stirring was conducted at the same temperature for 1 hour. A DMF solution (5 ml) of 2-(2-iodoethoxy)tetrahydropyran (1175 mg, 4.6 mmol) was added thereto, and stirring was conducted at room temperature overnight. Water was added to the reaction mixture and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated under reduced pressure to thereby obtain 450 mg (yield: 74%) of 6-[2-(tetrahydropyran-2-yloxy)ethyl]-6H-furo[2,3-c]pyridin-7-one as a yellow oil.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C)=[CH:22][CH:21]=2)=[N:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OC1C=NC(C2C=CC(CCCCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCC>>[CH2:1]([O:13][C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:21]=2)=[N:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCCCC)cc2)nc1
Product: CCCCCCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1

Procedure:
5-dodecyloxy-2-(4-hexylphenyl)pyrimidine ##STR30## 5-dodecyloxy-2-(4-heptylphenyl)pyrimidine ##STR31## 5-dodecyloxy-2-(4-octylphenyl)pyrimidine ##STR32## 5-dodecyloxy-2-(4-nonylphenyl)pyrimidine ##STR33## 5-dodecyloxy-2-(4-decylphenyl)pyrimidine ##STR34## 5-dodecyloxy-2-(4-undecylphenyl)pyrimidine 5-dodecyloxy-2-(4-dodecylphenyl)pyrimidine
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[OH-].[Na+].[C:12](Cl)(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15].CCOCC>O.C1COCC1>[OH:9][CH2:8][C@H:4]1[CH2:5][CH2:6][CH2:7][N:2]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3]1
Reactant: CC(C)CC(=O)Cl
Reactant: OC[C@H]1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@H](CO)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 125.3 %

Procedure:
(S)-piperidin-3-ylmethanol hydrochloride (10 g, 65.95 mmol) in water (25 mL) was treated dropwise at 0° C. with a solution of NaOH (13.2 g, 330 mmol, 5 eq.) in water (25 mL). The mixture was stirred for 15 min and a solution of isovaleryl chloride (15.90 g, 131.9 mmol, 2 eq.) in anhydrous THF (25 mL) was added dropwise while stirring vigorously. After 30 minutes at 0° C. the reaction was slowly warmed up to room temperature and stirred overnight. Et2O (500 mL) was added to the reaction mixture with vigorous stirring. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated to give a residue that was purified by chromatography on silica (Hex/EtOAc 0-100 to yield the desired compound as a colorless oil (16.27 g, 82.62 mmol, 94%). 1H NMR (400 MHz, DMSO-d6, 20° C.) δ 0.88 (pseudo d, J=6.4 Hz, 6H), 1.06-1.75 (m, 5H), 1.88-2.05 (m, 1H), 2.07-2.23 (m, 2H), 2.30 (dd, J=10.8, 12.8 Hz, 0.5H), 2.64 (ddd, J=3.2, 10.8, 13.2 Hz, 0.5H), 2.78 (dd, J=10.4, 13.2 Hz, 0.5H), 2.93 (ddd, J=2.4, 11.6, 13.6 Hz, 0.5H), 3.14-3.35 (m, 2H), 3.70-3.85 (m, 1H), 4.08-4.18 (dm, 0.5H), 4.31-4.40 (dm, 0.5H), 4.49 (t, J=5.2 Hz, 0.5H), 4.58 (t, J=5.2 Hz, 0.5H). MS 200 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[C:4]([F:17])[CH:3]=1.[N:18]([CH:21]1[CH2:23][CH2:22]1)=[C:19]=[O:20]>C(Cl)Cl>[CH:21]1([NH:18][C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([B:8]3[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16]3)=[C:4]([F:17])[CH:3]=2)=[O:20])[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: O=C=NC1CC1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Temperature: 37 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a stirred solution of 4-amino-2-fluorophenyl boronic acid pinacol ester (1.185 g, 5.0 mmol) in DCM (17 ml) was added isocyanato cyclopropane (830 mg, 10.0 mmol) and stirred overnight at 37° C. The reaction mixture was washed with water (20 mL), passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a white solid (1.56 g) used without further purification.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[CH:17]=[CH:16][N:15]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:12]2=[N:13][CH:14]=1)=C\C1C=CC=CC=1.[O:28]1CCOCC1>O.O=[Os](=O)(=O)=O>[S:18]([N:15]1[C:12]2=[N:13][CH:14]=[C:9]([CH:1]=[O:28])[N:10]=[C:11]2[CH:17]=[CH:16]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/c4ccccc4)cnc32)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of (E)-2-styryl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (72.3 g, 193 mmol) in 1,4-dioxane (1500 mL) and water (300 mL) was added NaIO4 (165 g, 770 mmol) followed by OsO4 (5.00 g, 19.7 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was concentrated under reduced pressure then was partitioned with 10% aqueous Na2S2O3 (1000 mL) and DCM (1000 mL). The organic layer was washed with water (2×500 mL) and the layers were filtered to remove undissolved precipitate and separated. The organic layer was dried over anhydrous Na2SO4, filtered through Celite®, and concentrated. The residue was purified by filtration through a pad of silica gel (1000 g) eluting with 0-5% EtOAc in DCM. The fractions were concentrated and the solid was triturated with heptane. The mixture was filtered and the filter cake was washed with heptane. This procedure was repeated for the collected undissolved precipitate. The collected solid was then dissolved in 2% EtOAc in DCM and passed through a pad of silica gel (100 g) eluting with 2% EtOAc in DCM. The filtrate was concentrated under reduced pressure. The two batches were combined to give 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (39.1 g, 67%) as an off-white solid: LC/MS (Table 2, Method a) Rt=2.17 min; MS m/z: 302 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[C:5]=12.[H-].[Na+].Cl[C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:23]5[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=5[N:21]=4)=[CH:12][CH:11]=3)[C:5]=12
Reactant: Oc1ccc(-c2cccn3ccnc23)cc1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(-c3cccn4ccnc34)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a solution of 4-(imidazo[1,2-a]pyridin-8-yl)phenol (0.68 g) in DMF (10 ml) was added sodium hydride (60% in oil, 0.13 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.53 g) obtained in Example 1, step A), and the mixture was stirred under microwave irradiation at 150° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.53 g).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6]([F:9])[CH:5]1[C:10]1[C:15](F)=[CH:14][C:13]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=O)=[C:12]([N+:26]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([F:9])[CH:5]1[C:10]1[C:15]([O:42][C:39]2[CH:38]=[CH:37][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])=[CH:41][CH:40]=2)=[CH:14][C:13]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:26][C:12]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(F)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Reactant: Oc1ccc(-c2ccccc2F)cc1
Product: CC(=O)N1CCC(F)C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2ccccc2F)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using N-(4-(1-acetyl-3-fluoropyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyridin-2-carboxamide enantiomer A and 2′-fluorobiphenyl-4-ol.
Reaction SMILES: C(=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:20])=[C:14]([CH:17]=[CH2:18])[CH2:15][S:16][C@H:11]12)C1C(=CC=CC=1)O.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH:17]=[CH2:18])[CH2:15][S:16][C@H:11]12
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N=Cc3ccccc3O)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Yield: 54.9 %

Procedure:
To a solution of benzhydryl 7-salicylideneamino-3-vinyl-3-cephem-4-carboxylate (1.6 g) in methylene chloride (20 ml) and anisole (5 ml) was added dropwise trifluoroacetic acid (6 ml) with stirring, and the stirring was continued at ambient temperature for an hour. The reaction mixture was poured into diisopropyl ether, and the precipitates were collected by filtration and then suspended in water, followed by adjusting to pH 3.5 with a saturated aqueous sodium bicarbonate. The solid was collected by filtration to give 7-amino-3-vinyl-3-cephem-4-carboxylic acid (0.4 g).
Reaction SMILES: [NH:1]1[C:6](=O)[C:5](=[O:8])[NH:4][C:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:2]1=2.O.[CH2:18]([SH:21])[CH2:19][SH:20].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:18]1[S:21][C:6]2([C:5](=[O:8])[NH:4][C:3]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15](=[O:16])[C:2]=3[NH:1]2)[S:20][CH2:19]1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C2=C(NC(=O)C3(N2)SCCS3)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-2,3,9(1H, 4H)-trione. 0.9 H2O (2.0 g, 8.68 mmol) in toluene (50 ml), 1,2-ethanedithiol (2.19 ml, 26.04 mmol) and boron trifluoride etherate (1.07 ml, 8.68 mmol) was refluxed for 20 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with toluene, ethanol-water (2:1) and ethanol. The crude material (2.40 g) was recrystallized from DMF-water to give 2.09 g (83%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 3.68 (m, 2H), 3.91 (m, 2H), 7.2 (t, 1H), 7.3 (t, 1H), 7.51 (d, 1H), 7.59 (d, 1H), 12.05 (s, 1H), 12.38 (s, 1H).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[C:49]1([C:55]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([CH3:59])[C:56](O)=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[O:57]=[C:56]([C:16]1[C:17]([CH:30]([CH3:31])[CH3:32])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[C:55]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:59]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C(C)(c2ccccc2)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6 - diisopropylphenylacetic acid was replaced with 2,2-diphenylpropionic acid, mp 140°-145° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)[CH3:21]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:31])=[CH:25][CH:26]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127, 65.0 mg, 0.27 mmol) and ethyl-4-iodo benzoate (Reagent A, 68.0 mg, 0.27 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide (16.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc—hexanes) afforded 90 mg (90%) of the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[OH-].[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[S:23][C:14]=12>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:14]=23)=[C:4]([F:9])[CH:3]=1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Oc1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1cnc2c(sc3ccccc32)c1Oc1ccc(Cl)cc1F
Yield: 55 %

Procedure:
A mixture of 0.59 mL (5.5 mmol) of 4-chloro-2-fluorophenol and 100 mg (1.78 mmol) of potassium hydroxide is heated until a homogeneous solution is formed. To this is added 245 mg (1.00 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and the mixture is heated for 2 hours. Ethyl acetate is added and the solution is washed with 1N NaOH. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The solid is collected and recrystallized from ethyl acetate to give 195 mg (55%) of a light beige solid, mp 174-175° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH2:15])=O)=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]#[N:15])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)sc2-c2ccc(F)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)sc2-c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide (4.8 g) and methanesulfonyl chloride (8.8 g) in pyridine (25 ml) was stirred at 50° C. for 4 hours. The mixture was concentrated and the residue was triturated in dilute hydrochloric acid. The precipitates were collected and recrystallized from ethanol to give crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (3.6 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:11]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH:9]=[CH:10]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1ncc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (373 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (120 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-fluorobenzoyl)benzyl bromide (806 mg) in DMF (20 ml) was added and the mixture was further stirred at room temperature for 13 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; dichloromethane: methanol=99:1) to provide the title compound as white powder (615 mg, yield 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[C:13]([NH:15][N:16]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]1[C:22]([O:24]C)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[N:32][CH:33]=1>>[Br:21][C:18]1[CH:19]=[CH:20][N:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])[C:17]=1[C:22](=[O:24])[NH:34][C:30]1[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=1
Reactant: Nc1cncc(F)c1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cncc(F)c1
Yield: 69.6 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(benzyloxycarbonylamino)propanamido)-3-bromo-1H-pyrrole-2-carboxylate (2.00 g, 4.7 mmol) and 5-fluoropyridin-3-amine (4.23 g, 37.6 mmol) following the experimental procedure described in Preparation 44a. 1.65 g (69% yield) of the desired compound were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:24][CH2:25][N:26]=[C:27]=[O:28].[Cl-].[NH4+]>ClCCl>[O:28]=[C:27]1[NH:26][CH2:25][CH2:24][N:2]1[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: O=C=NCCCl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cccc(N2CCNC2=O)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Methyl (3-aminophenyl)acetate hydrochloride was suspended in dichloromethane (7 vol) under nitrogen. Diisopropylethylamine (1.04 vol) was added at 20° C. over 30 minutes, and the reaction mixture was stirred for 30 minutes at 20° C. 2-Chloroethyl isocyanate (0.44 vol) was added dropwise at 20° C. over 100 minutes. The reaction mixture was stirred at 20° C. for three hours. A saturated solution of ammonium chloride (5 vol) was added dropwise over 10 mins and the resultant mixture was stirred for ten minutes. The organic phase was separated and washed with water (5 vol). Tetrahydrofuran (2×3 vol) was added and the mixture was concentrated to 2 vol. Dry tetrahydrofuran (5 vol) was added, and the mixture was concentrated to 2 vol. Dry THF (3 vol) was added, under nitrogen at 20° C. The reaction mixture was cooled to 0° C., and potassium tert-butoxide (0.56 wt) was added portion-wise in 5 stages, allowing 20 minutes between two subsequent additions. The reaction mixture was stirred at 20° C. for one hour. Hydrochloric acid (0.5N, 2 vol) was added dropwise over 20 minutes. Ethyl acetate (10 vol) was added and the organic phase was separated. The organic layer was washed with aqueous sodium hydrogencarboante solution (4%, 2 vol) and brine (2 vol), and the organic layer was then evaporated to dryness under vacuum to give the title compound (overall yield: 90% w/w).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[NH2:10][C:11]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>C(O)=O.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:17]/[C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccnc(N)n1
Reactant: O=Cc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: Nc1nccc(/C=C/c2cncc(Br)c2)n1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of 5-bromo-pyridine-3-carbaldehyde (436 mg, 2.34 mmol) and 2-amino-4-methylpyrimidine (246 mg, 2.35 mmol) in formic acid (96%, 3 mL) was heated for 18 h. After cooling to rt, it was then diluted with water and basified to pH ˜13 with 1 N NaOH. The mixture was then extracted with methylene chloride. The combined extracts was washed with water (1×), dried over MgSO4 and concentrated. The residue was chromatographed on silica gel eluting with CH2Cl2:MeOH:NH4OH (100:5:0.5) to give the title compound (463 mg, 71%). MS (DCI/NH3) m/z 277, 279 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([F:9])[CH:3]=1)[N:6]=[CH:18][CH:13]=[CH:14]2
Reactant: Nc1ccc(Br)cc1F
Reactant: O=[N+]([O-])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1cc(Br)cc2cccnc12
Reaction time: 7 h

Procedure:
A mixture of 4-bromo-2-fluoroaniline (12.825 g, 67.5 mmol), 4.275 g of ferrous sulfate, 25.46 g (20.2 ml) of glycerol, 5.067 g (4.2 ml) of nitrobenzene and 11.79 ml of concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for 7 hours. The nitrobenzene was removed in vacuo. Water was added. The aqueous solution was acidified with glacial acetic acid, and the dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1) to return the title compound as white solid (9.72 g, 63.7%).