Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([CH2:9][CH2:10][CH2:11][CH:12]=O)=[N:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][C@@H:27]1[C@H:31]2[O:32][C:33]([CH3:36])([CH3:35])[O:34][C@H:30]2[C@H:29]([N:37]2[C:41]3[N:42]=[CH:43][N:44]=[C:45]([NH:46][CH:47]4[CH2:49][CH2:48]4)[C:40]=3[CH:39]=[CH:38]2)[CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:25][CH2:26][C@@H:27]3[C@H:31]4[O:32][C:33]([CH3:35])([CH3:36])[O:34][C@H:30]4[C@H:29]([N:37]4[C:41]5[N:42]=[CH:43][N:44]=[C:45]([NH:46][CH:47]6[CH2:49][CH2:48]6)[C:40]=5[CH:39]=[CH:38]4)[CH2:28]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reactant: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(Cl)c(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(Cl)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
4-(5,6-Dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butanal (0.310 g, 0.801 mmol) and 7-[(3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.262 g, 0.763 mmol) were dissolved in DCE (17 ml) at r.t. under N2 and left for 15 mins. Sodium triacetoxyborohydride (0.226 g, 1.07 mmol) was added and the reaction left overnight. The reaction was quenched by the addition of sat. Na2CO3 solution (20 ml) and DCM (20 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM to 10% MeOH:90% DCM as eluent to give the product as a white foam (0.222 g, 41%): MS (ESI+) for C35H49Cl2N7O3Si m/z 714.4 [M+H]+; LC purity 99% (ret. time, 1.73 min); 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.00 (d, J=3.63 Hz, 1H), 6.64 (br. s., 1H), 5.62 (br. s., 1H), 5.42 (s, 2H), 4.91-5.03 (m, 2H), 4.55 (t, J=6.23 Hz, 1H), 3.45-3.59 (m, 2H), 2.90-3.02 (m, 3H), 2.82-2.89 (m, 1H), 2.69-2.81 (m, 3H), 2.45 (dt, J=12.61, 6.46 Hz, 1H), 2.35 (tt, J=12.41, 6.27 Hz, 1H), 2.16 (q, J=11.98 Hz, 1H), 1.97 (dt, J=15.41, 7.66 Hz, 2H), 1.69 (quin, J=7.37 Hz, 2H), 1.57 (s, 3H), 1.30 (s, 3H), 0.85-0.99 (m, 4H), 0.64-0.76 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=2)[CH:2]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)=[O:30])[CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29](=[O:30])[C:31]3[CH:38]=[CH:37][C:34]([C:35]4[NH:16][C:9]5[CH:8]=[C:7]([C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:12]=[CH:11][C:10]=5[N:13]=4)=[CH:33][CH:32]=3)[CH:26]=2)[CH:21]=[CH:20]1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Product: O=C(Nc1ccc2cc[nH]c2c1)c1ccc(-c2nc3ccc(-c4cccnc4)cc3[nH]2)cc1

Procedure:
Compound 650 was prepared according to the procedure similar to that described in Scheme III from 1-(3-pyridinyl)-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C27H19N5O: 430.16; found: 429.96.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C(O)C>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Cl)C#N
Solvent: CCO
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 77 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and absolute ethanol (125 ml) is stirred at about 77° C. for 24 hours. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as ethanol are distilled off (distillate 100 ml) by raising the external temperature to about 130° C. After cooling to 70° C., water (100 ml) is allowed to run in dropwise at 70-60° C. The mixture is seeded, cooled to about 20° C. and the suspension is stirred at about 20° C. for about 1 hour. The product is isolated by filtration and washed with cyclohexane (100 ml) and then with water (100 ml). The product is dried in vacuo at about 60° C. Yield: 17.73 g=40.3% (pale beige powder).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20].N#N.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)cc1C2
Agent: N#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC12CCC(=O)C=C1c1cc(F)c(NC(C)=O)cc1C2
Reaction time: 4.5 h
Yield: 85.1 %

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.12 g, 4.1 mmol) in anhydrous CH2Cl2 (13.7 mL) was purged with N2, cooled in an ice bath, and treated with pyridine (0.33 mL, 4.1 mmol) followed by acetyl chloride (0.65 mL, 9 mmol). After stirring at 0–5° C. for 4.5 hours, the reaction mixture was partitioned between water and EtOAc. The organic portion was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to provide 7-(acetylamino)-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.1 g) as an orange foam. This material was used without further purification.
Reaction SMILES: CC1C(CN2CC(C3C=C(F)C=C(F)C=3F)CC2=O)=C(C)N(S(C2C=CC(C)=CC=2)(=O)=O)N=1.Cl.[NH2:35][CH2:36][CH:37]([C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([F:51])[C:45]=1[F:52])[CH2:38][C:39]([O:41]CC)=O.[Br:53][C:54]1[CH:55]=[N:56][N:57]([CH3:61])[C:58]=1[CH:59]=O>>[Br:53][C:54]1[CH:55]=[N:56][N:57]([CH3:61])[C:58]=1[CH2:59][N:35]1[CH2:36][CH:37]([C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[C:46]([F:51])[C:45]=2[F:52])[CH2:38][C:39]1=[O:41]
Reactant: Cn1ncc(Br)c1C=O
Reactant: CCOC(=O)CC(CN)c1cc(F)cc(F)c1F
Agent: Cc1ccc(S(=O)(=O)n2nc(C)c(CN3CC(c4cc(F)cc(F)c4F)CC3=O)c2C)cc1
Agent: Cl
Product: Cn1ncc(Br)c1CN1CC(c2cc(F)cc(F)c2F)CC1=O

Procedure:
1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 182 is prepared as for compound x61 starting from ethyl 4-amino-3-(2,3,5-trifluorophenyl)butanoate hydrochloride x60 and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde x65.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][CH2:42][CH2:43][Cl:44]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:40][CH2:41][CH2:42][CH2:43][Cl:44])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(O)c(C#N)cc34)cc2)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Reaction time: 0.83 h

Procedure:
N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (200 mg), potassium carbonate (65 mg) and 1-bromo-4-chlorobutane (81 μl) were suspended in dimethylformamide (3 ml), and the suspension was heated and stirred for 1 hour and 50 minutes. The reaction solution was poured into saturated brine and extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, it was passed through NH silica (Fuji Silysia Chemical) and washed in ethyl acetate, and the filtrate was concentrated. The obtained solid was washed with ether and dried to obtain 110 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:46]([NH:45][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:47])[CH:29]=3
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 28 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 28% yield. LCMS for C25H22ClN6O (M+H)+: m/z=457.2. 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 9.28 (s, 1H), 8.69 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.90 (m, 1H), 7.40 (m, 2H), 7.31 (m, 1H), 7.22 (m, 3H), 7.06 (dd, 1H), 7.01 (m, 1H), 6.89 (m, 2H), 6.78 (m, 1H), 2.80 (m, 4H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CI>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([CH3:1])([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)C1(C)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (3.1 mL, 22 mmol) in tetrahydrofuran (60 mL) cooled at −78° C. was added n-butyllithium (2.5N solution in hexanes, 8.9 mL, 22 mmol) dropwise over 5 minutes and the mixture was stirred for 30 minutes at −78° C. A solution of tert-butyl 1-benzylpiperidine-4-carboxylate (5.0 g, 20 mmol) in tetrahydrofuran (40 mL) was then added to the reaction mixture dropwise over 10 min and the temperature was maintained at −78° C. for 30 minutes before methyl iodide (1.3 mL, 21 mmol) was added in one portion. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction was quenched with water (100 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic portions were dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 0-100% ethyl acetate in heptanes) to afford the title compound as a colorless oil, which was used in the next step without any further purification (5.3 g, 90%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:23]2[N:24]=[CH:25][NH:26][C:27](=[S:28])[C:22]=2[CH:21]=[CH:20]1)(=O)C.[Na]>CO>[C@@H:6]1([N:19]2[C:23]3[N:24]=[CH:25][NH:26][C:27](=[S:28])[C:22]=3[CH:21]=[CH:20]2)[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(=S)[nH]cnc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2ccc3c(=S)[nH]cnc32)[C@@H](O)[C@@H]1O

Procedure:
A solution of 3.0 g of 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one, eight ml of acetic anhydride, 150 ml of pyridine, and 50 mg of p-dimethylaminopyridine is stirred at room temperature for 24 hours, evaporated in vacuo, co-evaporated with xylenes, and distributed between ethyl acetate and water. The ethyl acetate layer is washed with saturated NaHCO3 and dried with MgSO4. Removal of the ethyl acetate provides 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. This is dissolved in 150 ml of dry pyridine, treated with 8.8 g of phosphorus pentasulfide, and heated under reflux for 5 hours. The pyridine is removed in vacuo and the residue is treated with water. The precipitate is filtered, washed with water, and recrystallized from ethanol to afford 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-3,7-dihydro-4H-pyrrolo-[2,3-d]pyrimidine-4-thione. A solution of 5.0 g of 7-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-4-thione, 200 ml of methanol, and 54 mg of sodium methalate is heated under reflux for 2 hours and treated with IRC-50 ion exchange resin. The filtrate is evaporated in vacuo and the resulting residue is recrystallized from ethanol-water to provide 7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]-pyrimidine-4-thione.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([NH:27][C:28]3[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:24]=[CH:25][CH:26]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CN(C=O)C>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:31]=[CH:30][N:29]=[C:28]([NH:27][C:23]2[CH:22]=[C:21]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH:26]=[CH:25][CH:24]=2)[N:33]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)cc1
Temperature: 85 °C

Procedure:
Ethyl 4-bromobenzoate (73.2 mg, 0.301 mmol) was added to a mixture of N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.274 mmol), PdCl2(dppf)-CH2Cl2 adduct (22.4 mg, 0.027 mmol), DMF (5.5 mL), and aqueous K2CO3 (2 M, 0.411 mL, 0.822 mmol) and the reaction mixture was evacuated and back flushed with Argon. The reaction mixture was heated in the microwave reactor for 2 hours at 85° C. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to afford ethyl 3′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-carboxylate as an off-white solid. MS ESI calc'd. for C20H17F3N3O2[M+H]+ 388, found 388. 1H NMR (500 MHz, CDCl3): δ 8.67 (d, J=4.9 Hz, 1H); 7.96 (s, 1H); 7.61 (t, J=6.2 Hz, 3H); 7.55 (s, 1H); 7.47-7.40 (m, 1H); 7.40 (d, J=7.9 Hz, 2H); 7.35 (d, J=7.7 Hz, 1H); 7.06 (d, J=4.9 Hz, 1H); 4.22 (q, J=7.1 Hz, 2H); 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:34])=[C:12]([CH:19](C(OC(C)(C)C)=O)[C:20]([O:22]C(C)(C)C)=[O:21])[CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:34])=[C:12]([CH2:19][C:20]([OH:22])=[O:21])[CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C

Procedure:
The crude bis(1,1-dimethylethyl) {3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4-nitrophenyl}propanedioate was dissolved in CH2Cl2 (100 mL) and TFA (50 mL) and heated to 40° C. for 3 h. The reaction mixture was cooled to RT and concentrated. Water (200 mL) and EtOAc (100 mL) were added, the layers were separated and the aqueous layer extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to give the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.17 (br s, 1H), 8.01 (dd, 1H), 7.58 (dd, 1H), 7.50 (s, 1H), 7.23 (s, 1H), 7.15 (s, 1H), 3.84 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH3:25].Cl>ClCCCl>[Cl:23][C:22]1[C:17]([Cl:16])=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][C:21]=1[C:4]([C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])=[O:5]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2c(F)cccc2F)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 24.6 g of 2,6-difluorobenzoylchloride in 100 ml of 1,2-dichloroethane, 18.5 g of AlCl3 is added in portions over a 30 minute period. A solution of 22.5 g of 2,3-dichloroanisole in 100 ml of 1,2-dichloroethane is added thereto. The mixture is stirred for one hour and poured over 100 ml concentrated HCl and ice. The organic layer is separated and the aqueous layer extracted with CHCl3. The organic extract is washed with water, dried (Na2SO4) and evaporated to give an oil which crystallizes from hexane to yield solid 2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone which upon recrystallization from ether has an mp 94°-96° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.[C:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.O>[C:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:29](=[O:31])[CH2:28][C:27](=[O:32])[NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:25][CH:24]=2)[CH2:60][CH2:59]1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
HOBt (570 mg, 4.2 mmol) and DIPEA (541 mg, 4.2 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (1 g, 3.5 mmol) in DMF (10 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (810 mg, 4.2 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (720 mg, 3.86 mmol) were added. The resulting reaction mixture was stirred at room temperature overnight. Water was then added and the resulting precipitate was filtered and dried to afford 1.4 g (93%) of 4-[2-(biphenyl-4-ylcarbamoyl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR: (CDCl3): δ 8.6 (s, 1H), 7.9 (m, 2H), 7.7 (m, 2H), 7.65 (m, 1H), 7.5 (m, 3H), 7.4 (s, 1H), 4.1 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>ClCCl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:17](=[O:20])[CH:18]=[CH2:19])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOC(=O)C(=C)C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
5.0 g of hydroxyethyl methacrylate was weighed into a 250 ml r.b. flask fitted with stirrer, thermometer and nitrogen blanket. 3.88 g of triethylamine was then added followed by 80 ml of dichloromethane. The mixture was cooled and 4.15 g of acryloylchloride was added dropwise. The reaction mixture turned yellow and after 10 min a precipitate formed. Stirring was continued for 90 minutes. The precipitated material (TMEDA.HCl) was then filtered off and the organic solution extracted with sodium bicarbonate solution. The solution was then dried over anhydrous magnesium sulphate and after filtration the solvent evaporated to give a pale yellow oil (yield˜90%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.Cl>CN(C)C=O.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
2.7 g (67.5 mmol) of powdered NaOH are introduced into 10.8 g (675 mmol) of diethyl malonate in 30 ml of dimethylformamide at room temperature, with cooling, a solution of 5 g (31 mmol) of 2-chloro-5-nitropyridine in dimethylformamide is then added dropwise and the mixture is stirred at room temperature until the reaction is complete. For working up, the mixture is poured onto 500 ml of water and acidified with concentrated HCl and the precipitate is filtered off with suction and rinsed with petroleum ether.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH2:8][CH2:9]I.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.O>CN(C=O)C.C(OCC)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:9][CH2:8][F:7])=[CH:14][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: FCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 72.5 %

Procedure:
After adding 7.34 g of potassium carbonate and 8.31 g of 1-fluoro-2-iodoethane to a solution of 4.5 g of 4-fluorophenol in 50 ml of DMF, the mixture was stirred at room temperature for 27 hours. Water was added to the reaction mixture, and extraction was performed with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.6 g) as a colorless liquid.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:6]=2[N:7]=1)[CH3:2].[OH-].[Na+].I[CH3:16]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:16])[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(O)cccc2o1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(OC)cccc2o1
Reaction time: 8 h

Procedure:
2-Ethyl-4-hydroxybenzoxazole (4.17 g) was dissolved in tetrahydrofuran (73 ml) at room temperature. Tetrabutylammonium iodide (0.4 g) was added, followed by a solution of sodium hydroxide (3.89 g) in water (40 ml). The mixture was stirred for 10 minutes before addition of iodomethane (3.13 ml). Stirring was then continued overnight. The crude mixture was evaporated onto silica, and purified by flash chromatography eluting with 25% then 50% ethyl acetate in hexane to give the title compound as a straw coloured liquid (3.05 g).