Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]=[CH:18][N:19]([CH2:21][CH2:22][N:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)[CH:20]=4)[S:15][C:8]=23)=[C:4]([F:38])[CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=C[CH:40]=1.ClC(OC1C=CC=CC=1)=[O:47].C1(N)CC1>CN(C=O)C>[CH:44]1([NH:39][C:40](=[O:47])[NH:1][C:2]2[CH:37]=[CH:36][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:17]=[CH:18][N:19]([CH2:21][CH2:22][N:23]6[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH2:28]6)[CH:20]=5)[S:15][C:8]=34)=[C:4]([F:38])[CH:3]=2)[CH2:42][CH2:43]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)c2)CC1
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Temperature: 60 °C
Yield: 57.7 %

Procedure:
To a stirred solution of 306 (2.10 g, 3.90 mmol) and pyridine (631 μl, 4.68 mmol) in DMF (20 ml) at 0° C. was added phenyl chloroformate (587 μl, 4.68 mmol). After 45 min cyclopropylamine (687 μl, 9.75 mmol) was added at 0° C. and the reaction mixture was heated at 60° C. for 30 min. After cooling to RT the reaction mixture was quenched by addition of water and extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 100 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 307 (1.4 g, 2.25 mmol, 58% yield) as a beige solid. MS (m/z): 622.33 (M+H).
Reaction SMILES: ClC1C=C(N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])C=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(#N)CC#N.O.[NH2:29][NH2:30]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][N:9]=[C:10]2[C:11]([NH2:12])=[N:30][N:29]=[C:13]2[NH2:14])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(Cl)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(Cl)c1

Procedure:
4-[(3-chlorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 102 mg (0.5 mmol) of 2-[(3-chlorophenyl)hydrazono]malononitrile, which was derived from 3-chloroaniline (106 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 2, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 17 mg (14%) of the compound as a yellow solid; 1H NMR (ppm, DMSO-d6): 5.98 (br, s, 2H), 6.38 (br, s, 2H), 7.18 (d, 1H), 7.40 (t, 1H), 7.60 (d, 1H), 7.69 (s, 1H), 10.78 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@@H:5]([CH2:12][C:13]1[C:14]([CH2:23][O:24][C:25](=[O:27])[CH3:26])=[C:15]2[C:19](=[C:20](Br)[CH:21]=1)[NH:18][N:17]=[CH:16]2)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH3:29][Sn](C)(C)C>>[CH2:1]([O:3][C:4](=[O:28])[C@@H:5]([CH2:12][C:13]1[C:14]([CH2:23][O:24][C:25](=[O:27])[CH3:26])=[C:15]2[C:19](=[C:20]([CH3:29])[CH:21]=1)[NH:18][N:17]=[CH:16]2)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Reactant: C[Sn](C)(C)C
Product: CCOC(=O)C[C@H](Cc1cc(C)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Yield: 68 %

Procedure:
2-(S)-(4-Acetoxymethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic acid diethyl ester (350 mg, 0.77 mmol) and tetramethyltin (150 μL, 1.1 mmol) were reacted in a manner analogous to the preparation of [4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-acetic acid methyl ester. Title compound was obtained as pale yellow solid in 68% yield. MS m/e (M−H)−=389.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([CH3:13])[CH3:12])[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([CH3:13])[CH3:12])[N:9]=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:25]4[N:24]([CH3:23])[C:28]5=[N:29][CH:30]=[CH:31][CH:32]=[C:27]5[N:26]=4)=[CH:18][CH:19]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)n1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a stirred solution of 4-[6-fluoro-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (76 mg) in DMF (4 mL) was added NaH (60% in oil, 11.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (59.2 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (60.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:11]([F:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1O.[CH2:23]([CH:28]1[CH2:31][CH:30]([C:32](Cl)=[O:33])[CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27].C(C1CC(C(Cl)=[O:48])C1)CCCCCCC>>[CH2:23]([CH:28]1[CH2:31][CH:30]([C:32]([O:33][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:11]([F:22])[CH:10]=3)=[CH:3][C:2]=2[F:1])=[O:48])[CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCC1CC(C(=O)Cl)C1
Reactant: CCCCCC1CC(C(=O)Cl)C1
Reactant: CCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Product: CCCCCCOc1ccc(-c2ccc(OC(=O)C3CC(CCCCC)C3)c(F)c2)cc1F
Yield: 61.2 %

Procedure:
Except that 0.60 g of the crude 3,3'-difluoro-4-hydroxy-4'-hexyloxybiphenyl obtained in Example 12-(c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.4 g of 3-pentylcyclobutanecarboxylic acid chloride obtained in Example 1-(a) in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=3/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.55 g (yield 65.5%) of 3,3'-difluoro-4-hexyloxybiphenyl-4'-Yl 3-pentylcyclobutanecarboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9](C)([CH3:11])[CH2:8][C:7]2NC=[C:4]([C:13]([OH:15])=O)[C:3]1=2.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].FC1C=CC=CC=1N.Cl>CN(C)C=O>[O:1]=[C:2]1[C:3]2[C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:13][O:15][C:7]=2[CH2:8][CH:9]([CH3:11])[CH2:10]1
Reactant: CCOC(=O)Cl
Reactant: CC1(C)CC(=O)c2c(C(=O)O)c[nH]c2C1
Agent: Cl
Agent: Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Reaction time: 0.75 h
Yield: 33 %

Procedure:
To a stirred solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (155 mg, 0.75 mmol) and triethylamine (209 μL, 1.5 mmol) in dimethylformamide (4 mL) at 0° C. was added ethyl chloroformate (143 μL, 1.5 mmol). After stirring an additional 45 minutes, 2-fluoroaniline (145 μL, 1.5 mmol) was added. The reaction mixture was stirred for 30 minutes, then poured into aqueous 3.6N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo . To the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL), and the mixture was heated at reflux for 30 minutes. After cooling in an ice water bath, the reaction mixture was acidified with hydrochloric acid, the precipitate was collected, rinsed with water, and dried to give 55 mg of N-(2-fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3 oxamide (Compound 2).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:7]=2)[C:3]=1[CH3:23].[C:24]([O-:27])(=[O:26])C.[K+].[CH3:29]O>>[C:19]([O:18][C:16]([N:14]1[CH2:15][CH:12]([CH2:11][N:6]2[CH:5]=[C:4]3[C:8]([CH:9]=[CH:10][C:2]([C:24]([O:27][CH3:29])=[O:26])=[C:3]3[CH3:23])=[N:7]2)[CH2:13]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CO
Reactant: Cc1c(Br)ccc2nn(CC3CN(C(=O)OC(C)(C)C)C3)cc12
Reactant: CC(=O)[O-]
Agent: [K+]
Product: COC(=O)c1ccc2nn(CC3CN(C(=O)OC(C)(C)C)C3)cc2c1C
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of 8.16 g of the bromide prepared in Example 117a in 65.4 ml methanol, 6.5 g of 1,1 bis(diphenylphosphino)ferrocen-palladium(II) dichloride and 15 g of potassium acetate were added at 25° C. and the mixture was stirred under CO at 10.15 bar and 120° C. for 24 hours in an autoclave. The reaction mixture was then cooled, filtered through Celite at the pump and the filtrate concentrated in vacuo. The residue thus obtained was purified by chromatography on the Flashmaster (hexane/ethyl acetate 1:0-0:1). 6.97 g of the title compound was obtained.
Reaction SMILES: N[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[I:17]I.N(OCCCCC)=O>C(Cl)(Cl)Cl>[I:17][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1snc(-c2ccccc2)c1N
Reactant: II
Agent: CCCCCON=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1snc(-c2ccccc2)c1I
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of methyl 4-amino-3-phenylisothiazole-5-carboxylate (Preparation 103C, 700 mg, 2.99 mmol) in chloroform (80 mL) were added iodine (4019 mg, 15.84 mmol) and amyl nitrite (0.602 mL, 4.48 mmol). The resulting mixture was heated to reflux for 30 min. The reaction mixture was cooled to room temperature and washed with aqueous sodium thiosulfate and then water. The organic layer was dried over sodium sulfate. Removal of the solvent in vacuo and crystallization from ethanol yielded methyl 4-iodo-3-phenylisothiazole-5-carboxylate (600 mg, 1.738 mmol, 58.2% yield) as a pale yellow solid. The compound had an LC/MS M+1=346.0.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:23][C@@H:24]1[S:30][C@@H:29]([C:31]([OH:33])=O)[CH2:28][C:27]2[CH:34]=[C:35]3[O:40][CH2:39][O:38][C:36]3=[CH:37][C:26]=2[C:25]1=[O:41].[NH2:42][C:43]1[CH:55]=[CH:54][C:46]([CH2:47][P:48](=[O:53])([O:51][CH3:52])[O:49][CH3:50])=[CH:45][CH:44]=1>CN(C)C=O.O>[CH3:50][O:49][P:48]([CH2:47][C:46]1[CH:54]=[CH:55][C:43]([NH:42][C:31]([C@H:29]2[CH2:28][C:27]3[CH:34]=[C:35]4[O:40][CH2:39][O:38][C:36]4=[CH:37][C:26]=3[C:25](=[O:41])[C@H:24]([CH3:23])[S:30]2)=[O:33])=[CH:44][CH:45]=1)([O:51][CH3:52])=[O:53]
Reactant: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc4c(cc3C(=O)[C@H](C)S2)OCO4)cc1)OC
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.3 %

Procedure:
1-Hydroxybenzotriazole (HOBt) (0.51 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) were added to a solution of (2R,4S)-(−)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.84 g) and dimethyl 4-aminobenzylphosphonate (0.65 g) in N,N-dimethylformamide (DMF) (10 ml) at 0° C. This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1). The ethyl acetate layer was washed successively with 1N HCl, water, a saturated sodium hydrogencarbonate solution, water and brine, and dried (MgSO4), after which the solvent was distilled off. The residual solid was collected by filtration, followed by recrystallization from ethanol-hexane to yield (2R,4S)-(−)-N-[4-(dimethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (0.92 g, 64%). Colorless needles. Melting point 198-199° C. Optical rotation [α]D (23° C.) −198.8° (c=0.50, CHCl3).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@@H:10]1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH3:33]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:33])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[C@@H:10]1[F:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@H](F)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (2.0 g, 4.7 mmol) in anhydrous THF (40 mL), at 0° C. and under N2, was added MeMgBr (1.4 M in THF/toluene, 8.0 mL, 11.2 mmol). After addition the mixture was stirred at room temperature for 3 h. The reaction was diluted with Et2O (50 mL) and then quenched with saturated NaHCO3 aqueous solution (50 mL). The organic layer was collected, and the aqueous was extracted with DCM (3×40 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 mL) and Boc2O (2.0 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:2 to 3:2), affording tert-butyl ((3aR,5R,6R,7S,7aR)-6-(benzyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (1.0 g, 48%), as a mixture of diastereomers.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][C:29]=1[O:37][CH3:38])(=O)=O>N1C=CC=CC=1>[C:1]([O:7][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:35])[NH2:36])=[CH:30][C:29]=1[O:37][CH3:38])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: COc1cc(C(=N)N)ccc1OS(C)(=O)=O
Reactant: CC(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: COc1cc(C(=N)N)ccc1OC(=O)CC(C)C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
Into 40 ml of anhydrous pyridine, was dissolved 1.5 g of isovaleric acid. To the solution, while being cooled in ice, was added 3.7 g of DCC and the resulting mixture was stirred for 30 minutes. After addition of 3.9 g of 4-amidino-2-methoxyphenol methanesulfonate, the mixture was stirred overnight at room temperature. The precipitate which was formed was separated by filtration and washed with pyridine. Ethyl ether was added to the filtrate to precipitate colorless crystals. The crystals were washed with ethyl ether, dissolved in DMF, and recrystallized by adding ethyl ether. The crystals were further purified by recrystallizing from an ethanol-ethyl ether mixture to obtain 3.4 g of colorless flaky crystals of 4-amidino-2-methoxyphenyl isovalerate methanesulfonate.
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C1C=CC=CN=1)C.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=1.C(N(CC)CC)C>ClCCl.O>[Cl:28][C:24]1[CH:23]=[C:22]([NH:21][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:27]=[CH:26][N:25]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
1.69 g (7.78 mmol, 1 eq) of tert-butyl dicarbonate dissolved in 50 ml of dichloromethane, in the presence of 95 mg of dimethylaminopyridine, are added to a solution of 1 g (7.78 mmol, 1 eq) of 4-amino-2-chloropyridine in 30 mL of dichloromethane in the presence of 1.19 mL (1.19 mmol, 1.1 eq) of triethylamine. The reaction mixture is stirred overnight at room temperature. The reaction is stopped by adding 100 ml of water and is then extracted with dichloromethane. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 to 50/50 heptane/ethyl acetate). The oil obtained is crystallized from pentane. 1.40 g of tert-butyl (2-chloropyrid-4-yl)carbamate are obtained. Yield=80%.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11])[CH3:2].N([O-])=O.[Na+].[BrH:17]>O>[Br:17][C:6]1[CH:8]=[CH:9][C:3]([CH2:1][CH3:2])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: Br
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 240 ml) is added dropwise to a suspension of 4-ethyl-3-nitroaniline (20 g, 0.12 mol) in water (80 ml), and the mixture is stirred until the solid dissolves. The mixture is cooled to −5° C. and a solution of sodium nitrite (19.8 g, 0.28 mol) in water (100 ml) is added dropwise, maintaining the temperature at 0-5° C. Once the addition is complete, the cooling bath is removed and the reaction mixture is stirred for one hour at room temperature. The mixture is added dropwise to a pre-cooled solution of cuprous bromide (22.4 g, 0.16 mol) in hydrobromic acid (48% wt. in water) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature over three hours. The mixture is extracted with diethyl ether, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with hexane to give 4-bromo-1-ethyl-2-nitrobenzene (18 g)
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[I:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.CCN(CC)CC.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1C=CC=CC=1.CCOC(C)=O>[I:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:3](=[O:4])[CH2:2][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(I)cc1
Reactant: C1COCCN1
Reactant: O=C(Br)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CN1CCOCC1)Nc1ccc(I)cc1
Reaction time: 1 h
Yield: 91 %

Procedure:
Bromoacetyl bromide (175 mL, 2.00 mmol) was added dropwise over 5 minutes to a solution of 4-iodoaniline (438 mg, 2.00 mmol) and Et3N (280 μL, 2.00 mmol) in benzene (5 mL). The reaction was stirred 1 hour, treated with morpholine (1.0 mL, 11.5 mmol) and stirred overnight. The reaction mixture was diluted with EtOAc (200 mL), washed with aqueous 0.1 M KOH (50 mL), H2O (50 mL), dried over MgSO4 and concentrated to give a yellow oil. Purification by silica gel chromatography (100:1 CH2Cl2/MeOH) afforded 630 mg (91%) of N-(4-iodophenyl)-2-morpholin-4-ylacetamide as a waxy tan solid. This product was converted to analogues in a similar manner as Example 14.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1>C1C=CC=CC=1>[Br-:20].[CH2:29]([O:28][C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)=[O:27])[CH3:30]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A mixture of 16 g of triphenylphosphine, 13.35 g of ethyl 4-bromomethylbenzoate and 50 ml of benzene was stirred at room temperature for 2 days. The precipitate was filtered off, and dried in vacuo to give 20.8 g of (4-ethoxycarbonylbenzyl)triphenylphosphonium bromide.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(O)(=O)C[C:12](CC(O)=O)(C(O)=O)[OH:13]>C(OC=O)C.C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH:12]=[O:13])[C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC1(C)CCC(=O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC=O
Solvent: O
Product: CC1(C)CCC(=O)C(C=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of K. tert.-butylate (24.5 g, 109 mmol, 50% solution in tert.-butanol) in THF (700 mL) ethylformate (120 mL, 123 mmol) is slowly added. The mixture is stirred at rt for 30 min before a solution of 4,4-dimethyl-cyclohexanone (50 g, 396 mmol) in ethylformate (50 mL) and THF (70 mL) is added over a period of 20 min. Upon complete addition, stirring is continued at 15-20° C. for 30 min. The orange suspension is poured onto 10% aq. citric acid solution (200 mL) and brine (200 mL) and extracted with EA (2×200 mL). The organic extracts are washed with 0.2 N aq. NaOH and brine, dried over Na2SO4 and evaporated to dryness to give 5,5-dimethyl-2-oxo-cyclohexanecarbaldehyde (52 g) as a yellow oil; LC-MS: tR=0.89 min, [M+1+CH3CN]+=196.15.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-:23].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.[OH-].[Na+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([I:23])=[CH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [I-]
Reactant: COc1ccc(C#Cc2ccncc2)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(I)=Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of acetylene from step 1 (8.79 g, 30 mmol) in dichloromethane (600 mL) at room temperature there was added a solid mixture of sodium iodide (18 g, 120 mmol) and p-toluenesulfonic acid monohydrate (11.4 g, 60 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with aqueous 1N NaOH (600 mL) and stirred vigorously for 15 min. The organic phase was collected and washed 3 times with water, dried and evaporated to a residue which was stirred in a 2:1 mixture of hexane and ether (100 mL) for 2 h and filtered to afford the desired vinyl iodide (8.46 g, 67%) as a beige solid, assayed by NMR to be a 4:1 mixture of Z and E isomers.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:23]([N:5]1[C:6]2[CH:7]=[C:8]([I:15])[CH:9]=[CH:10][C:11]=2[C:12]2[C:4]1=[CH:3][C:2]([I:1])=[CH:14][CH:13]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Ic1ccc2c(c1)[nH]c1cc(I)ccc12
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCn1c2cc(I)ccc2c2ccc(I)cc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of compound 5 (3.00 g) in 30 mL of anhydrous DMF was added 660 mg (4.78 mmol, Aldrich Co.) of anhydrous K2CO3. The solution was stirred at 80° C. for 2 h under argon after 0.93 g (4.82 mmol) of bromooctane was added. The mixture was stirred at 80° C. for 24 h and then quenched with 30 mL of water. The aqueous layer was extracted three times with 50 mL of diethyl ether. The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel, hexanes as eluent) followed by recristallization in methanol to give 1.55 g of the title product as a white solid. M.P. 82-84° C. (Global yield for the last two steps: 38%).