Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[N:4]=1>C(Cl)Cl.O=[Mn]=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][CH:17]=2)[N:4]=1
Reactant: OCc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Yield: 75.5 %

Procedure:
A solution of [4-(3, 5-bis-trifluoromethyl-pyrazol-1-yl)-phenyl]-methanol (2 g) and MnO2 (excess) in DCM (30 mL) was stirred at room temperature for 24 hours. Solid materials were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2, 4:1 hexane/EtOAc) to give 4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (1.5 g, 76% yield) as a colorless syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[C:7](=[N:8][NH:9][CH:10]=3)[C:6]=2[CH:15]=1.Cl[C:17]1[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][N:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[C:7](=[N:8][N:9]([C:17]4[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][N:18]=4)[CH:10]=3)[C:6]=2[CH:15]=1
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Reactant: CC(C)n1ncnc1Cl
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Yield: 58.9 %

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared from 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (450 mg, 1.7 mmol) and 5-chloro-1-isopropyl-1H-[1,2,4]triazole (369 mg, 2.55 mmol) to give 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a white solid (375 mg, 59%). LCMS RT=5.05 min M+H+=374/376
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11](O)=[O:12].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[F:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([Cl:21])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1OC1CCCC1F
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC1CCCC1F
Temperature: 60 °C

Procedure:
A suspension of 3-(2-fluorocyclopentyloxy)-4-methoxybenzoic acid (0.48 g) in toluene (20 mL) is treated with thionyl chloride (0.34 g) and then is heated at 60° C. for 3 hours, and cooled and evaporated to give 3-(2-fluorocyclopentyl-oxy)-4-methoxybenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1.[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:17])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ccc(Br)o2)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 1.96 g (8.46 mmol) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyrimidine-5-carbonitrile in 8 ml DMF was added dropwise a solution of 1.58 g (8.88 mmol) N-bromosuccinimide in 7 ml DMF and stirring continued at room temperature for 1 hour. The reaction mixture was then poured into 500 ml ice-water and the resulting precipitate collected by filtration and washed with water and then ether to afford 2.50 g (95%) 2-amino-4-(5-bromo-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a light brown crystalline solid. ES-MS m/e (%): 311 ([M{81Br}-H]−, 100), 309 ([M{79Br}-H]−, 95).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.FC(F)(F)S(O[CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:6]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: FC(F)(F)Cn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.1 %

Procedure:
A 250 mL RB flask was charged with 4-bromo-1H-pyrazole (2.00 g, 13.6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.35 ml, 17.0 mmol), cesium carbonate (8.87 g, 27.2 mmol), and 1,4-dioxane (40.0 ml, 468 mmol), capped, and stirred at room temperature for 20 hours. The reaction mixture was filtered and the solid washed with dioxane; the filtrate was then concentrated to give 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.402 g, 77.1% yield) as a crude oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[N:17]([CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:18](=[O:21])[NH:19][N:20]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH:23]1([CH2:22][N:17]2[C:18](=[O:21])[NH:19][N:20]=[C:16]2[CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:29](=[O:31])[CH3:30])[CH:7]=[CH:6][CH:5]=3)[CH2:13][CH2:12]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(N2CCN(CCc3n[nH]c(=O)n3CC3CCCCC3)CC2)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(N2CCN(CCc3n[nH]c(=O)n3CC3CCCCC3)CC2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
A solution of 5-{2-[4-(3-aminophenyl)piperazin-1-yl]ethyl}-4-(cyclohexylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one D10 (0.13 g, 0.34 mmol) in pyridine (2 mL) was cooled to 0° C. and acetyl chloride (0.025 mL, 0.029 g, 0.36 mmol) was added. The reaction mixture was stirred at 0° C. for 18 hrs and then evaporated to dryness. The residue was purified by flash chromatography (Silica gel 60 Å, 45 μm, 10% methanol in dichloromethane) and afforded 0.015 g (10%) N-[3-(4-{2-[4-(cyclohexylmethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]ethyl}piperazin-1-yl)phenyl]acetamide E38 as an orange oil.
Reaction SMILES: [CH2:1](OC(C1OC2C=CC=C(C(=O)N)C=2C=1C)=O)C.[H-].[Na+].IC.[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:41])[NH:39][CH3:40])[C:31]=2[C:32]=1[CH3:33])=[O:27])[CH3:24]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[O:41])[N:39]([CH3:1])[CH3:40])[C:31]=2[C:32]=1[CH3:33])=[O:27])[CH3:24]
Reactant: CCOC(=O)c1oc2cccc(C(N)=O)c2c1C
Reactant: CCOC(=O)c1oc2cccc(C(=O)NC)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(C(=O)N(C)C)c2c1C
Temperature: 50 °C

Procedure:
To 200 mg of 4-carbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (0.81 mmol, 1 eq.) in 5 mL of DMF was added 50 mg of NaH (60% in mineral oil, 1.25 mmol, 1.5 eq) under nitrogen. After 30 min of reaction, iodomethane (0.053 mL, 0.85 mmol, 1 eq) was added to the reaction. The mixture was then heated to 50° C. for 12 h. After work up and column chromatography, a mixture of 3-methyl-4-methylcarbamoyl-benzofuran-2-carboxylic acid ethyl ester and 4-dimethylcarbamoyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained (76 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.8 (d, J=4.5 Hz, 6 H) 4.4 (q, J=7.2 Hz, 2 H) 7.3 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (dd, J=8.3, 7.3 Hz, 1 H) 7.8 (dd, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:32])[CH2:17][CH:18]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:32])[CH2:17][CH:18]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Yield: 95.2 %

Procedure:
To a solution of ethyl 4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (5.35 g, 12.4 mmol) in 85% ethanol (160 mL) was added iron powder (6.94 g) followed by a 2 N aqueous solution of hydrochloric acid (6.2 mL). The resulting mixture was refluxed for 2.5 h, filtered through a pad of Celite®, and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (4.74 g, 95%). LC-MS ret. time 3.22 min, m/z 402.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.18 (t, 3H), 1.83-2.10 (m, 2H), 2.65 (t, 2H), 3.03-3.12 (m, 2H), 3.41-3.48 (m, 1H), 4.12 (q, 2H), 6.70 (d, 2H), 7.19 (d, 4H), 7.25 (m, 1H), 7.38 (d, 2H), 7.53 (d, 2H), 7.89 (d, 2H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:9]1[C:14]([CH:15]=O)=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]([CH:29]([CH3:31])[CH3:30])[N:10]=1)([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:6]([C:9]1[C:14]([CH:15]=[CH2:1])=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]([CH:29]([CH3:31])[CH3:30])[N:10]=1)([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1c(C(C)C)nc(C(C)C)c(CCCCC)c1-c1ccc(F)cc1
Temperature: -78 °C
Yield: 66 %

Procedure:
Methyl triphenylphosphonium bromide was suspended in 15 mL of dry THF under argon and stirred at −78° C. Butyllithium (1.6M, 0.42 mL) was added dropwise over 2 min. and then the reaction mixture was allowed to stir at 0° C. for 1.5 hours. The solution was cooled again to −78° C., treated dropwise with a solution of 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) in 5 mL of dry THF, and then stirred at 0° C. for 2.5 hours. The reaction was quenched with water (10 mL) and the THF evaporated in vacuo. Diethyl ether was added and the mixture was washed with water (2×20 mL), brine (1×20 mL), and dried with MgSO4. Filtration, concentration and flash chromatography (30% CH2Cl2/hexanes) yielded a solid (0.132 g, 0.37 mmol, 66%). 1H NMR (300 MHz, CDCl3) δ 7.08 (m, J=1.1 Hz, 4 H), 6.34, 6.28 (d, J=11.4 Hz, J=11.4 Hz, 1 H), 5.19 (d, J=1.8 Hz, 1 H), 4.96 (d, J=1.8 Hz, 1 H), 3.39 (septet, J=6.6 Hz, 1 H), 3.24 (septet, J=6.6 Hz, 1 H), 2.30 (t, J=5.2 Hz, 2 H), 1.20 (m, J=2.2 Hz, 18 H), 0.979 (t, J=6.0 Hz, 3 H). FAB-MS: calcd for (C24H32FN) 353, found 354 (M+H). Anal. Calcd for C24H32FN: C, 81.54; H, 9.12; N, 3.96; F, 5.37. Found: C, 81.46; H, 9.06; N, 3.78; F, 5.59. mp 44-46° C. Rf=0.7 (30% CH2Cl2/hexanes).
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:8][CH2:7][C@@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:5]1[CH2:27][NH2:28])(=O)[CH3:2].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:22]([O:21][C:20](=[O:26])[NH:19][C@@H:6]1[CH2:7][CH2:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:10][N:4]2[C:1]([CH3:2])=[N:28][CH2:27][CH:5]12)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)N1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=NCC2[C@H](NC(=O)OC(C)(C)C)CC[C@@H](c3cccc(F)c3F)CN12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl [(3R,6S)-1-acetyl-2-(aminomethyl)-6-(2,3-difluorophenyl)azepan-3-yl]carbamate (22 mg, 0.055 mmol) in acetic acid (3 mL) was heated to 80° C. After 6 h, the reaction mixture was allowed to cool to ambient temperature. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. MS 380.1 (M+1).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:53]=[CH:52][N:13]([C@@H:14]2[O:28][C@H:17]([CH2:18][O:19]C(=O)C3C=CC=CC=3)[C@@H:16]([NH:29][C:30]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C@H:15]2[F:51])[C:12](=[O:54])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>N1C=CC=CC=1.CO.O>[C:1]([NH:9][C:10]1[CH:53]=[CH:52][N:13]([C@@H:14]2[O:28][C@H:17]([CH2:18][OH:19])[C@@H:16]([NH:29][C:30]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C@H:15]2[F:51])[C:12](=[O:54])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(N[C@H]2[C@@H](F)[C@H](n3ccc(NC(=O)c4ccccc4)nc3=O)O[C@@H]2COC(=O)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: COc1ccc(C(N[C@H]2[C@@H](F)[C@H](n3ccc(NC(=O)c4ccccc4)nc3=O)O[C@@H]2CO)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
N4 -benzoyl-2'-fluoro-3'-(4-methoxytrityl)amino-2',3'-dideoxycytidine 15 was prepared as follows: To 1.3 g (1.75 mmol) of 14 in 20 mL of 65/30/5 pyridine/methanol/water, cooled in an ice bath, was added 10 mL of cold 2M NaOH in 65/30/5 pyridine/methanol/water. The mixture was stirred cold for 20 min, then neutralized with pyridinium-H+ form Bio-Rad AG® 50W-X8 cation exchange resin. After 5 min, the resin was removed by filtration and washed with methanol. The combined filtrate and wash were concentrated in vacuo to an oil, which was dissolved in 100 mL ethyl acetate. The mixture was washed with 100 mL saturated aqueous NaHCO3 and with water (2×100 mL). After concentration in vacuo to a foam, the product was dissolved in 10 mL CH2Cl2 and pipetted into 75 mL rapidly stirred hexane/ether, 2/1. The product was collected by filtration and dried under vacuum, giving 1.13 g (102% yield) of product as a white powder. Mass-spectrometry, FAB+, M+Cs+, calculated: 753.1489, observed: 753.1499. 1H NMR δ 8.30 (br d, J=6.8 Hz, 1H), 7.89 (br d, J=6.7 Hz, 2H), 7.64 (dd, J=7.4, 7.4 Hz, 1H), 7.44-7.56 (mm, 9H), 7.22-7.32 (mm, 9H), 6.82 (d, J=8.8Hz, 2H), 5.80 (d, J=15.7Hz, 1H), 4.26 (mm, 2H), 4.13 (d, J=10.2 Hz, 1H), 3.81 (s, 3H), 3.26 (dddd, J=3.4, 10.7, 10.8, 26.5 Hz, 1H), 2.93 (dd, J =3.3, 50.5 Hz, 1H), 2.50 (dd, J=2.8, 11.0 Hz, 1H); 19F NMR δ -195.3 (m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[NH2:5].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24].CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:5][C:26]([NH:25][C:23](=[O:24])[C:22]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=2[F:20])=[O:27])[CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(NC(=O)NC(=O)c2c(F)cccc2F)c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Yield: 96.8 %

Procedure:
Into a magnetically stirred solution of 3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylaniline (1.5 grams, 4.73 mmol) prepared in Part B in toluene (15 milliliters) under nitrogen atmosphere was added neat 2,6-difluorobenzoyl isocyanate (1.3 grams, 7.10 mmol) and the mixture was refluxed for a period of 1 hour. The reaction mixture was allowed to cool and hexane (3 milliliters) was added to induce crystallization. The resultant precipitate was filtered and washed successively with hexane and toluene to give pure 1-[3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl) urea (2.29 grams, 4.58 mmol, 97%) as a white solid having a melting point of 188° C.-190° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[NH:8][CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20].[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=2[O:13][CH3:14])[C:5](=[O:20])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7]1
Reactant: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 50 °C
Yield: 80.5 %

Procedure:
A mixture of ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (1.00 g, 3.53 mmol), iodomehtane (0.450 mL, 7.23 mmol) and K2CO3 (976 mg, 7.06 mmol) in DMF (15 mL) was heated at 50° C. for 1 h. The mixture was concentrated in vacuo and dried under high vacuum. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with water and then dried to yield ethyl 1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (845 mg, 81%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:12]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:13]=3[S:14][C:15]=2C(O)=O)[CH2:7][CH2:6]1)=[O:4]>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.[Cu]>[CH3:1][O:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:12]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:13]=3[S:14][CH:15]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)N1CCC(c2c(C(=O)O)sc3cc(C(F)(F)F)ccc23)CC1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(c2csc3cc(C(F)(F)F)ccc23)CC1
Temperature: 200 °C
Yield: 82.4 %

Procedure:
A mixture of 4-(2-carboxy-6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (4.3 g, 11.1 mmol) and copper (705 mg, 11.1 mmol) in quinoline (28 mL) was heated at 200° C. for 45 minutes. Upon cooling to room temperature the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with 5% HCl (2×20 mL), water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The residue was separated via chromatography (30% EtOAc in heptane) yielding 3.14 g (82%) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24](C)(C)C[C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:46]([C:43]2[CH:44]=[CH:45][C:40]([N:31]3[N:30]=[C:29]([C:21]4[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[C:26]([O:25][CH3:24])[CH:22]=4)[C@@H:38]4[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]4)[C:32]3=[O:39])=[CH:41][CH:42]=2)=[O:47])[CH2:10][CH2:9]1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5c(Cl)cncc5Cl)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 1-(3,5-Dichloropyridin-4-yl)piperazine as described for compound 8. Crystallised as the free base from methanol. M.p. 137–139° C.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH2:14][C@H:10]([C:11]([OH:13])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][N:18]([CH3:17])[C:11]([C@H:10]1[CH2:14][CH2:15][CH2:16][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:13]
Reactant: CNCCOCCOCCOCCOCCOCCOCCOC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCCOCCOCCN(C)C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 212.5 %

Procedure:
To a solution of Boc-(S)-nipecotic acid (137 mg, 0.60 mmol), N-methyl-2,5,8,11,14,17,20-heptaoxadocosan-22-amine 135c.1 (310 mg, 0.88 mmol) and DIPEA (335 mg, 2.6 mmol) in DMF (3 mL) was added HATU (285 mg, 0.75 mmol). The reaction was stirred for 1 hour and then the DMF was removed under vacuum. The residue was added to saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated to give (S)-tert-butyl 3-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl(methyl)carbamoyl)piperidine-1-carboxylate (720 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]=1[CH3:9].[K].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>[Cl-].C[N+](C)(C)C>[CH2:11]([N:6]1[C:7](=[O:8])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]1=[O:5])[CH:13]1[O:15][CH2:14]1
Reactant: CC1=C(C)C(=O)NC1=O
Reactant: ClCC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K]
Product: CC1=C(C)C(=O)N(CC2CO2)C1=O

Procedure:
30 g (0.184 mol) of potassium dimethymaleimide are suspended in 175 g (1.89 mols) of epichlorohydrin. After adding 0.05 g of tetramethylammonium chloride, the mixture is heated, whilst stirring, and boiled under reflux for 18 hours and is then filtered. After removing the unconverted chlorohydrin by distillation under a waterpump vacuum, about 30 g of a viscous, pale brown liquid which has an epoxide content of 4.9 equivalents/kg (calculated: 5.5 equivalents/kg) remain. The NMR spectrum of the product corresponds to N-glycidyl-dimethylmaleimide of the formula ##STR31##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][NH:29][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[CH2:25][CH2:26]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 4-benzylpiperazin-1 ylethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. m/z (ES+)=398 [M+H]+; RT=2.75 min.
Reaction SMILES: [H-].[Na+].CCCCC.[C:8]([O:17]C)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>CO.O1CCCC1>[C:22]1([C:19](=[O:21])[CH2:20][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CCCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)CCCCC(=O)CC(=O)c1ccccc1

Procedure:
A dispersion of 16.9 G (0.4 mole) of 56% by weight sodium hydride in mineral oil is slurried with n-pentane under nitrogen, the supernatant liquid is removed by suction with a sintered glass tip tube. This process is repeated three times before 500 ml of dry tetrahydrofuran and 75.8 G (0.48 mole) of methyl isooctanoate are added. The resultant mixture is heated to reflux temperature with agitation. A total of 48 G (0.4 mole) of acetophenone is added to the above refluxing mixture over a 3 hour period of time. The system is maintained at reflux temperature for an additional one half hour after the acetophenone addition is completed. Approximately 20 ml of methanol is added to the above mixture at room temperature to destroy any unreacted sodium hydride. The reaction mixture is then poured into a vigorously stirred mixture of 75 ml of concentrated hydrochloric acid and 250 G of ice. When most of the ice has melted the solution is extracted twice with 242 ml of heptane per extraction. The combined heptane extracts are successively washed with water, 10% sodium carbonate solution and again with water. The heptane solution is dried with sodium sulfate, filtered, the volatiles removed at reduced pressure and the residue distilled to yield 1-phenylisodecane-1,3-dione.