Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13]1
Reactant: N#Cc1ccc(F)cc1
Reactant: OCC1CCCNC1
Product: N#Cc1ccc(N2CCCC(CO)C2)cc1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 4-fluorobenzonitrile and 3-hydroxymethylpiperidine.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Yield: 47.6 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.490 g, 1.08 mmol) was dissolved in a mixed solution of acetonitrile (15 ml) and water (3 ml) and after adding thereto CAN (1.48 g, 2.71 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.217 g, 0.514 mmol, 48%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12]([CH3:15])([CH3:14])[N:11]=[C:10]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:25])C.OO.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:13][C:12]([CH3:15])([CH3:14])[N+:11]([O-:25])=[C:10]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C2OC(C)(C)N=C2c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: OO
Solvent: CC(=O)O
Product: CN(C)c1ccc(C2OC(C)(C)[N+]([O-])=C2c2ccccc2)cc1

Procedure:
A solution of 70.2 g of 5-[p-(dimethylamino)-phenyl]-2,2-dimethyl-4-phenyl-3-oxazoline in 300 ml of glacial acetic acid was added while stirring to a mixture, cooled to 0° C., of 30 ml of acetic anhydride and 90 m. of 30% hydrogen peroxide. The mixture was then stirred at room temperature for an additional 2.5 hours, treated while cooling with sodium hydroxide (342 g of sodium hydroxide in 2 liters of water) and sufficient sodium carbonate was added until carbon dioxide no longer evolved. Then, the mixture was evaporated almost to dryness on a rotary evaporator in a water-jet vacuum at 60° C., and the residue was extracted with 2.5 liters of dichloromethane. The dichloromethane solution was dried over sodium sulfate, filtered and evaporated in a water-jet vacuum. The residue was chromatographed on silica gel, the elution being carried out firstly with acetone and subsequently with methanol. The fractions containing the product were combined and largely freed from solvent in a water-jet vacuum. There were thus obtained 52 g of a hygroscopic oil from which a part of the water was removed at room temperature and 0.1 Torr (4 hours). Crystallization was then carried out twice from acetone, the solution being decolorized with active carbon. The crystalline product was dried for 16 hours at 70° C. and 0.1 Torr, and there were obtained 40.8 g of 5-[p-(dimethylamino)phenyl]-2,2-dimethyl-4-phenyl-3-oxazoline N-oxide in the form of hygroscopic white crystals which decomposed during the melting from 130° C.
Reaction SMILES: O[CH2:2][CH:3]([CH:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]1[CH3:13])[C:4]#[N:5].N12CCCC=C1CCCCN2.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][CH:7]1[CH2:8][C:9]([CH3:12])([CH3:11])[CH2:10][CH:6]1[C:3](=[CH2:2])[C:4]#[N:5]
Reactant: CC1CC(C)(C)CC1C(C#N)CO
Agent: C1=C2CCCCNN2CCC1
Agent: CN(C)c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=C(C#N)C1CC(C)(C)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 3-hydroxy-2-(2,4,4-trimethylcyclopentyl)propanenitrile is placed in dichloromethane at 10° C. under an inert atmosphere. 2.2 eq. of DBU (diazabicyclo[5.4.0]undec-7-ene) and a few crystals of DMAP (4-dimethylaminopyridine) are added thereto, followed, dropwise, by 1.2 eq. of trifluoro-acetic anhydride. The reaction medium is stirred at ambient temperature overnight and is then poured onto water. The aqueous phase is extracted once with dichloromethane. The combined organic phases are washed with water. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1.C([Li])CCC>>[CH2:4]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)[C:3]#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)C1
Agent: [Li]CCCC
Product: C#CCC1CCN(C(=O)OC(C)(C)C)C1
Temperature: -80 °C

Procedure:
A flask was charged with tert-butyl 3-(3,3-dibromoprop-2-en-1-yl)pyrrolidine-1-carboxylate (155 g, 420. mmol) and (1,800 ml) and cooled to −80° C. A solution of butyllithium (370 ml, 2.20 equiv) was added dropwise such that the internal temperature was maintained at −80° C. After stirring for an addition hour at −80° C., the reaction mixture was quenched by the addition of 1,000 mL of saturated aqueous ammonium chloride. The resulting mixture was extracted with diethyl ether (3×1,000 mL). The combined organic layers were washed with brine (3×800 mL), then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford tert-butyl 3-(prop-2-ynyl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][C:25](Br)=[C:24]([CH3:29])[CH:23]=2)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:9]=1.[CH:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])[CH3:33].[F-].[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][C:25]([C:38]3[CH:39]=[CH:40][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:36][CH:37]=3)=[C:24]([CH3:29])[CH:23]=2)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CCCC(C)C)c2ccc(Br)c(C)c2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OC(CCCC(C)C)c2ccc(-c3ccc(C(C)C)cc3)c(C)c2)cc1
Temperature: 25 °C

Procedure:
3-{4-[1-(4-Bromo-3-methyl-phenyl)-5-methyl-hexyloxy]-benzoylamino}-propionic acid methyl ester (460 mg, 0.940 mmol) was dissolved in toluene (2.5 mL), followed by palladium tetrakis triphenylphosphine (46 mg, 0.0395 mmol), 4-isopropyl-phenyl boronic acid (308 mg, 1.88 mmol), and potassium fluoride (109 mg, 1.88 mmol). The reaction was purged with nitrogen and heated to reflux, then the water (2.5 mL) was added. The reaction was monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction was diluted with EtOAc and then celite added, followed by water. This mixture was then filtered through a pad of celite. The solution was separated in a separatory funnel, then the organic layer was washed with 0.1N sodium hydroxide, water, and brine. The organic layer was dried over anhydrous sodium sulfate, then concentrated. The product was purified by flash column chromatography (444 mg, 0.800 mmol).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[OH:8])(=[O:3])[CH3:2].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1.O>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[O:8][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(O)c1ccc(Br)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Yield: 95.8 %

Procedure:
A solution of 3-(5-bromothiophen-2-yl)-3-hydroxypropyl acetate (1.92 g, 6.9 mmol, 1.0 equiv.), TBDMSCl (1.24 g, 8.3 mmol, 1.2 eq) and 1H-imidazol (1.4 g, 20.7 mmol, 3.0 eq) in CH2Cl2 (50 mL) was stirred for 4 h at 60° C. Water was added and the reaction was extracted with EtOAc (3×200 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EA=100:1 as eluant) to produce 3-(5-bromothiophen-2-yl)-3-(tert-butyldimethylsilyloxy)propyl acetate (2.6 g, 97.6%) as yellow oil. LC-MS (m/z): 393.1 [M+H]+;
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:26][C:27]1([C:32]2([CH:35]=O)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29][O:28]1>>[CH:35]([C:32]1([C:27]2([CH3:26])[O:28][CH2:29][CH2:30][O:31]2)[CH2:33][CH2:34]1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCC=CC1(C2(C)OCCO2)CC1

Procedure:
2.07 g of pentyltriphenylphosphonium bromide and 600 mg of aldehyde 7 are reacted analogously to 193., and 567 g of title substance 200 is obtained as a colorless oil (8:1 E,Z-mixture that cannot be separated).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32]([C:34](=[O:36])[CH3:35])=[CH:33][C:12]=3[N:11]=2)=[C:6]([F:37])[CH:5]=1.C1COCC1.[OH-].[Na+].Cl>CO>[C:34]([C:32]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[C:16]([C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=4[F:37])=[N:11][C:12]=2[CH:33]=1)=[CH:17][C:18]1[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[C:23]=1[CH:24]=3)(=[O:36])[CH3:35]
Reactant: COC(=O)c1ccc(C2=Nc3cc(C(C)=O)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccc2c(c1)N=C(c1ccc(C(=O)O)cc1F)c1cc3c(cc1N2C)C(C)(C)CCC3(C)C
Reaction time: 12 h

Procedure:
A solution of 4-(2-acetyl-5,7,7,10,10-pentamethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl)-3-fluorobenzoic acid methyl ester (19) (R4=CH3, Z=3-F, 0.25 mmol) in the mixture of THF (2.5 mL) and MeOH (0.14 mL) is treated with 1N NaOH (0.41 mL) and the mixture is stirred for 12 h. The mixture is poured into 1N HCl and extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting solids are collected by filtration and washed with Et2O to give the acid (20) (R4=CH3, Z=3-F) as yellow solid: 1H-NMR (DMSO-d6) δ: 1.00 (6H, s), 1.26 (6H, s), 1.53-1.62 (4H, m), 2.55 (3H, s), 3.29 (3H, s), 6.75 (1H, s), 7.03 (1H, s), 7.18 (1H, d), 7.71 (1H, d), 7.75 (1H, d), 7.81 (1H, dd), 7.90-7.98 (2H, m), 13.47 (1H, br).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][CH:6]=1)=[O:4].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][N:7]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[CH:13]=2)[CH:6]=1)=[O:4]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: COC(=O)c1c[nH]cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)cc1C
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (139 mg) of 4-methylpyrrole-3-carboxylic acid methyl ester, 1.1 mmol (195 mg) 4-chloro-2-methyl-quinoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 mL of dry DMF. The mixture is stirred for 60 h at 80° C. under Argon, allowed to cool to room temperature, and diluted with water (20 mL). Part of the product precipitates and is filtered off. The filtrate is extracted twice with ethyl acetate (20 mL portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 4-methyl-1-(2-methyl-quinolin-4-yl)-1H-pyrrole-3-carboxylic acid methyl ester (MS molpeak 281 (M+) H, electrospray ionisation)) as an off-white foam after freeze-drying.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: COC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1ccccc1C(C)(C)C
Temperature: -30 °C
Yield: 92.9 %

Procedure:
A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with 2-tert-Butylaniline (109 g, 114 mL, 732 mmoles), triethylamine (81.4 g, 112 mL, 804 mmoles, 1.1 equiv.) and toluene (600 mL). The resulting mixture was stirred at a moderate speed at −30° C. An additon funnel was charged with Methyl chlorooxoacetate (100 g, 816 mmoles, 1.11 equiv.) with toluene (200 mL), and the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C. After addition, the reaction was warmed to room temperature for an hour, quenched with water, then partitioned between EtOAc/water. The aqueous phase was extracted with EtOAc (200 mL), and the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL), then dried the organic over MgSO4. The organic phase was concentrated by rotary evaporation, yielding the title compound as a pale yellow solid [Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate, 160 g, 93.1%]. MP 61.7–63.6° C. IR (KBr) 3409, 2954, 1736, 1724, 1530, 1299, 1166, 766 cm−1; 1H NMR (300 MHz, CDCl3): δ(ppm): 9.20 (br, 1H), 7.97 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.43 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.31–7.16 (m, 2H), 4.00 (s, 3H), 1.47(s, 9H). The product thus obtained can be used directly for the subsequent reaction.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH2:10]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH2:11][CH3:12]>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH2:10][CH2:11][CH3:12])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: CCCc1ncc[nH]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Solvent: C1CCOC1
Product: CCCc1nccn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 10.85 g of imidazole-4-sulfonylchloride and 180 ml of THF. This solution was treated with a solution of 15.4 g 2-n-propylimidazole in 100 ml of THF. The reaction mixture was stirred at room temperature overnight and then refluxed 48 hours. The clear solution was concentrated to an oil and dissolved in water. The opaque solution deposited crystals on standing which were filtered, washed and dried. Recrystallization from ethyl acetate gave 10.61 g of white crystals of 1-(4-imidazolylsulfonyl)-2-n-propylimidazole with mp 163°-4°, λmaxnujol 3.18 (NH), 7.32 (SO2N) and 8.52 μ (SO2N). NMR (DMSO, d6): 660-730 Hz, m, 1H; 496 Hz, d, J = 1.5 Hz, 1H; 477 Hz, d, J = 1.5 Hz, 1H; 447 Hz, d, J = 2 Hz, 1H; 415 Hz, d, J = 2 Hz, 1H; 174 Hz, t, J = 7 Hz, 2H; 82-118 Hz, sextet, J = 7 Hz, 2H; 51 Hz, t, J = 7 Hz, 3H.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>CCN(CC)CC.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.[Cu]I>[F:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:7]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#C[Si](C)(C)C
Temperature: 50 °C
Yield: 62.4 %

Procedure:
Ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (1.00 g, 3.27 mmol), PdCl2(PPh3)2 (115 mg, 0.16 mmol), CuI (44 mg, 0.23 mmol), and trimethylsilylacetylene (0.7 mL, 4.9 mmol) were dissolved in Et3N (5 mL). The mixture was immediately degassed by vacuum, and the flask was charged with N2. The mixture was heated overnight at 50° C. Water was added and then the solution was extracted with EtOAc (3×). The organic was washed with NH4Cl, brine and dried (MgSO4). The solvent was removed and then the residue was purified by silica gel column chromatography to obtain ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.66 g, 62% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: BrCCBr
Reactant: Oc1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(OCCBr)c1Cl
Yield: 60.2 %

Procedure:
To a mixture of 2,3-dichlorophenol (20 g, 0.123 mol) and 1,2-dibromoethane (30.5 g, 0.162 mol) was added a sodium hydroxide solution (5 g, 0.125 mol in 125 ml of water), and the mixture was heated under reflux for 8 h. The mixture was allowed to cool and extracted with chloroform (2×100 ml). The combined extracts were washed with 1N aqueous sodium hydroxide solution (100 ml), dried, filtered and concentrated in vacuo. The residue was distilled at 106° C./0.3 mm of mercury to afford on cooling to room temperature the title compound as a yellow solid (20 g, 60%).
Reaction SMILES: Cl.[C:2]([NH:6][C:7]1[C:12](/[CH:13]=[CH:14]/OCC)=[CH:11][N:10]=[C:9]([Cl:18])[N:8]=1)([CH3:5])([CH3:4])[CH3:3]>C(O)(C)C>[C:2]([N:6]1[C:7]2[N:8]=[C:9]([Cl:18])[N:10]=[CH:11][C:12]=2[CH:13]=[CH:14]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCO/C=C/c1cnc(Cl)nc1NC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)n1ccc2cnc(Cl)nc21
Yield: 85 %

Procedure:
Concentrated HCl (25 mL) was added to N-tert-butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyrimidin-4-amine (5.3 g, 20.72 mmol) (see Preparation 61) in isopropanol (210 mL) and the mixture was heated at reflux for 4 hours. The reaction mixture was then evaporated in vacuo and the residue was basified with saturated aqueous NaHCO3 and extracted with EtOAc (200 mL). The organic extract was dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (gradient of hexane:EtOAc 93:7 to 90:10) to afford the title compound as a yellow oil in 85% yield, 3.7 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=O)=[O:9])[CH:5]=[CH:6][CH:7]=1>CN(C)C=O.O.C(OCC)(=O)C.[Zn]>[OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:9])[CH2:10][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc(O)c1)c1cccc(O)c1
Yield: 31.1 %

Procedure:
A mixture of 3,3'-dihydroxybenzil (3.0 g.) and powdered zinc (5.0 g.) in N,N-dimethylformamide (25 ml.) and water (10 ml.) was stirred and heated under reflux for 6 hours. The cooled mixture was filtered through Celite and the filtrate was evaporated under oil pump vacuum to give a syrup. The syrup was dissolved in ethyl acetate and the solution was washed consecutively with dilute hydrochloric acid and saturated brine (thrice). The dried (MgSO4) solution was evaporated to smaller volume and benzene was added. A by-product (0.45 g., m.p. 225°-228°) crystallized on standing. The mother liquor was evaporated to a syrup which was crystallized by seeding from ethyl acetate benzene to give the title product (0.88 g., m.p. 151°-154°) which was shown to be identical with material produced from the two stage reduction (1, Sn/HCl; 2, Zn/chromic sulfate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][C:16]3[CH:32]=[CH:31][C:19]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]([O:33][CH3:34])[CH:17]=3)=[O:14])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:36][CH2:37]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]3[C:13](=[O:14])[N:15]([C:16]4[CH:32]=[CH:31][C:19]([O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[C:18]([O:33][CH3:34])[CH:17]=4)[CH2:37][CH2:36][N:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCNC(=O)OC(C)(C)C
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCCNC(=O)OC(C)(C)C

Procedure:
Following the procedure described in step D of Example 1, the above product of step B (55 mg) was alkylated with 1,2-dibromoethane to yield 7 mg of the title compound. MS (ESI) 456 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(=O)OCC>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (680 mg, 3.7 mmol), 2-(1-piperazinyl)benzonitrile (823 mg, 4.4 mmol), and D1 EA (1.3 mL, 7.4 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H) 3.23 (m, 4H) 4.09 (s, 2H) 7.13 (m, 1H) 7.21 (d, J=8.14 Hz, 1H) 7.59 (m, 2H) 7.71 (dd, J=7.80, 1.70 Hz, 1H) 8.34 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 336 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[O:9].[Cl-].[Cl-].[Mg+2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>C1COCC1.C(OCC)C>[Br:13][C:14]1[C:15]([OH:20])=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH:8]=[O:9]
Reactant: Oc1ccccc1Br
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Triethylamine (72 ml, 520 mmol) was added over 10 minutes to a suspension of paraformaldehyde (23.4 g, 780 mmol) and dry magnesium dichloride (49.5 g, 520 mmol, Aldrich; CAS 7786-30-3) in THF (1 liter) under nitrogen at room temperature. The resulting mixture was stirred for 20 min, then 2-bromophenol (45 g, 260 mmol) was added over 5 minutes via syringe. The resulting mixture was stirred under gentle reflux for 6 h then cooled to room temperature. The solution was left over the weekend and then diluted with diethylether (500 ml). The organic phase was washed with a 2N hydrochloric acid (500 ml) and the two phases were separated. The insoluble material was filtered off and the organic phase was washed twice with 2N hydrochloric acid (500 ml) then five times with water (100 ml), dried over magnesium sulphate and concentrated in vacuo to give the title compound as a colourless solid (46.5 g). MS (ES) C7H579BrO2 requires 200 found 199 [M−H]+.