Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[NH:3]1[CH2:6][CH:5]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]4[N:16]([C:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][C:31]=5[F:32])[N:28]=[CH:27][CH:26]=[CH:25]6)=[CH:19][N:20]=4)[N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C=O.[BH3-][C:36]#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:32][C:31]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[CH2:21][C:18]1[N:16]2[N:17]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([CH:5]4[CH2:4][N:3]([CH3:36])[CH2:6]4)[CH:11]=3)[CH:13]=[CH:14][C:15]2=[N:20][CH:19]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CNC4)c3)nn12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CN1CC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask was charged with MeOH (1 mL). 6-[6-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-7-fluoro-quinoline (Stage 146.1, 26 mg, 0.065 mmol), formaldehyde (9.7 μL, 0.130 mmol) and NaBH3CN (20 mg, 0.325 mmol) were then added. The pH was adjusted to 5-6 with a drop of acetic acid and the RM was stirred at rt for 2 h. The mixture was then diluted with DCM, washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100)). The residue crystallized in DCM. The solid was filtered off, and dissolved in EtOAc. The solution was washed again with NaHCO3, dried over Na2SO4, filtered and concentrated to afford the title compound as a foam (tR 2.93 min (conditions 3), MH+=414.1, 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.60 (s, 1H); 8.35 (m, 1H); 8.09 (m, 3H); 7.77 (m, 1H); 7.58 (m, 2H); 7.47 (m, 1H); 5.01 (m, 1H); 4.55 (s, 2H); 3.71 (m, 2H); 3.40 (m, 2H); 2.34 (s, 3H))
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][C:11]([S:13][CH2:14][CH:15]1[S:19][CH:18]([CH2:20][O:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)[CH2:17][S:16]1)=[O:12].O.C1(C)C=CC=CC=1>CC(C)=O>[C:11]([S:13][CH2:14][CH:15]1[S:19][CH:18]([CH2:20][O:21][C:22](=[O:26])[CH:23]=[CH2:24])[CH2:17][S:16]1)(=[O:12])[CH:10]=[CH2:9]
Reactant: O=C(CCCl)OCC1CSC(CSC(=O)CCCl)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OCC1CSC(CSC(=O)C=C)S1
Yield: 76.8 %

Procedure:
Next, 40.0 g (0.39 mol) of triethylamine was added dropwise to a solution of 50.0 g (0.13 mol) of 2-(3-chloropropionylthiomethyl)-4-(3-chloropropionyloxymethyl)-1,3-dithiolan prepared above dissolved in 195 g of acetone at 2 to 5° C. in 1 hour. They were allowed to react at the same temperature for 1.5 hours, with stirring, to which 520 g of water was added. The resultant mixture was treated with 520 g of toluene to extract the reaction product. The extract organic phase (toluene solution) was washed with water until the aqueous phase turned neutral. Then, the organic phase was separated out, incorporated with 0.12 g of 4-methoxyphenol as a polymerization inhibitor, and distilled under a vacuum to be concentrated while removing toluene, to obtain a lightly yellowish, transparent liquid as a crude product. The crude product thus prepared was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate mixture), to obtain 29.0 g of 2-acryloylthiomethyl-4-acryloyloxymethyl-1,3-dithiolan, which was a colorless, transparent liquid, in a yield of 77%.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 2.58 g, 14.2 mmol) and triethylamine (1.43 g, 14.2 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1.63 g, 14.2 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 3.15 g (85%). 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 5.56 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (Cl) 261 (MH+); [α]D+53.8 (c, 1.1, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1cc(N)n[nH]1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and a Dean-Stark trap was charged with 287b (11.0 g, 1.0 eq., 64.7 mmol), hexane-2,5-dione (11.1 g, 1.5 eq., 97.2 mmol), p-toluenesulfonic acid monohydrate (558 mg, 0.05 eq., 3.24 mmol), and toluene (100 mL). The reaction mixture was refluxed overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 1:2 petroleum ether/ethyl acetate to afford 287c (10.4 g, 65%) as white solid. MS-ESI: [M+H]+ 249.0
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[O:38][CH3:39]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) in acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 l). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118-119° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44]>>[CH2:35]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[CH:12]=1)=[O:7])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reactant: CN(C)CCCBr
Product: CCCCN(CCCC)C(=O)c1cn(CCCN(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Yield: 78.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 266A, methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (200 mg, 0.38 mmol) and 3-bromo-N,N-dimethylpropan-1-amine (77 mg, 0.46 mmol) were converted to the title compound (180 mg, 78%). MS(ESI+) m/z 602.6 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH3:32][C:33]1[C:34]([C:49]2[S:53][C:52]3[CH:54]=[CH:55][CH:56]=[C:57]([C:58]([NH2:60])=[O:59])[C:51]=3[CH:50]=2)=[N:35][C:36]([NH:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:37][CH:38]=1>>[ClH:3].[ClH:1].[CH3:32][C:33]1[C:34]([C:49]2[S:53][C:52]3[CH:54]=[CH:55][CH:56]=[C:57]([C:58]([NH2:60])=[O:59])[C:51]=3[CH:50]=2)=[N:35][C:36]([NH:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][N:46]([CH3:4])[CH2:45][CH2:44]2)=[N:37][CH:38]=1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(N)=O)cccc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2c(C(N)=O)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide and isolated as a yellow solid. ES+(m/z) 424 [M(free base)+H].
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])C.Cl>CO>[C:6]([OH:20])(=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19]
Reactant: CCOCCCCCSCCCCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCCCCCSCCCCC(=O)O
Reaction time: 7 h

Procedure:
NaOH (1M, 24 mL, 24 mmol) was added to a solution of the above ethyl-6-thia-12-oxatetradecanoate, (6.8 mmol) in MeOH (20 mL). After stirring for 7 h, the reaction mixture was acidified with 10% HCl (pH 1) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water (50 mL), brine (50 mL), and dried (Na2SO4). The crude product was recrystallized from hexane to afford the title compound, 6-thia-12-oxatetradecanoic acid; yield 82%; bp 144°-146° C./0.01 torr; IR(neat): 3000 (broad) and 1730 cm-1 ; NMR: 1.23 (3H, t, J=7.3 Hz), 1.46 (2H, quint, J=6.9 Hz), 1.55-1.69 (6H, m), 1.74 (2H, quint, J=7.3 Hz), 2.37 (2H, t, J=7.6 Hz), 2.51 (2H, t, J=7 Hz), 2.53 (2H, t, J=7 Hz)m 3,42 (2H, t, J=6.9 Hz), 3.48 (2H, q, J=7.3 Hz), and 10.6 ppm (1H, br s); Found: C, 58.07, H, 9.78%. Calcd for C13H26SO2 : C, 58.03, H, 9.74%.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[C:25]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3ccccc23)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
A microwave vessel was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.008 mmol), 2-naphthylboronic acid (225 mg, 1.310 mmol), tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.076 mmol), sodium carbonate (534 mg, 5.04 mmol), toluene (8.06 mL), and water (2.02 mL). The mixture was heated at 100° C. for 2 h, then cooled to rt and partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), and concentrated. The resulting crude material was purified by flash chromatography, eluting with a gradient of 0-6% EtOAc in hexane to give 4-chloro-5,7-difluoro-3-methyl-2-(naphthalen-1-yl)quinoline. Mass Spectrum (ESI) m/e=340.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([NH:9][C@H:10]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[O:8])=[CH:4][C:3]=1[C:32]1[N:36]([CH3:37])[N:35]=[CH:34][C:33]=1[Cl:38].NN>CO>[NH2:21][CH2:20][C@@H:10]([NH:9][C:7]([C:5]1[O:6][C:2]([Cl:1])=[C:3]([C:32]2[N:36]([CH3:37])[N:35]=[CH:34][C:33]=2[Cl:38])[CH:4]=1)=[O:8])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)c(F)c2)CN2C(=O)c3ccccc3C2=O)oc1Cl
Agent: NN
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2ccc(F)c(F)c2)oc1Cl
Reaction time: 12 h

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-(3,4-difluorophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-furancarboxamide (304 mg, 0.54 mmol) in methanol (5 ml) at 25° C. was added hydrazine (0.08 ml, 2.7 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of the title compound as a yellow solid: LC-MS (ES) m/z 430(M+H)+, 1H NMR (400 MHz, MeOD) δ ppm 2.91-3.05 (m, 2H) 3.17-3.28 (m, 2H) 3.81 (s, 3H) 4.57 (d, J=9.60 Hz, 1H) 7.12 (br. s., 1H) 7.18-7.28 (m., 2H) 7.36-7.39 (m, 1H) 7.58 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]#[N:11].BrBr.BrC1C=CN=C(OC)C=1C#N.[I:25]I>>[I:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]#[N:11]
Reactant: II
Reactant: COc1nccc(Cl)c1C#N
Agent: BrBr
Agent: COc1nccc(Br)c1C#N
Product: COc1nccc(I)c1C#N

Procedure:
Thus, 2-chloro-3-cyanopyridine (A18) provided 2-methoxy-3-cyanopyridine (A19) upon treatment with sodium methoxide in methanol. Lithiation of the 2-methoxy-3-cyanopyridine (A19) with LDA gave the intermediate carbanion derivative 4-lithio-2-methoxy-3-cyanopyridine (A21), which upon treatment with hexachloroethane provided the 4-chloro-2-methoxy-3-cyanopyridine (A20). Analogously, reaction with bromine provides the 4-bromo-2-methoxy-3-cyanopyridine (A22) and reaction with iodine provides the 4-iodo-2-methoxy-3-cyanopyridine (A23). All 4-halo-2-methoxy-3-cyanopyridines are highly valuable intermediates, especially for the synthesis of kinase inhibitors. Reduction of the 4-halo-2-methoxy-3-cyanopyridines, for example with DIBAL (diisobutylaluminum hydride) in solvents such as toluene, dichloromethane, or tetrahydrofuran at temperatures ranging from −80° C. to about 80° C., preferably at 20° C. provides after standard workup the 4-halo-2-methoxypyridine-3-carboxaldehydes. The 4-halo-2-methoxypyridine-3-carboxaldehydes are highly valuable synthetic intermediates. 4-chloro-2-methoxy-3-pyridinecarboxaldehyde (A9) was prepared in this manner.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)=[CH:9]2)=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2C=C(c3c[nH]cn3)c3ccccc32)cc1
Solvent: CCO
Product: Fc1ccc(C2CC(c3c[nH]cn3)c3ccccc32)cc1

Procedure:
The mixture of the isomers of 4-[3-(4-fluorophenyl)-3H-inden-1-yl]-1H-imidazole was hydrogenated in ethanol using 10% palladium on charcoal as a catalyst. The mixture was filtered through Celite, and the solvent was evaporated. The crude 4-[3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]-1H-imidazole which was the mixture of the cis and trans diastereomers (the ratio 95.5:4.5) was purified by flash chromatography (elution with a dichloromethane-methanol gradient).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH:19]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:19][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH:3]1[CH:10]=[CH:11][CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(=O)C=CC1=C(C)CCCC1(C)C
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Product: CCCCCC(O)C=CC1C(C)(C)CCCC1(C)O

Procedure:
The entitled compound was obtained from 1-(2,6,6-trimethylcyclohex-1-enyl)oct-1-en-3-one in the same manner as in Example 1-(4), (5), and (6).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: OCC1CCc2ccccc2C1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 124.9 %

Procedure:
A solution of 2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene (2.28 g, 14.0 mmol) in 100 ml of CH2Cl2 was treated with PBr3 (1.28 g, 4.73 mmol) at 0° C. The mixture was stirred at room temperature for 72 hours then poured onto 100 g of ice. The organic layer was isolated, washed with 10% K2CO4 aqueous solution, H2O , sat'd brine, and then dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, EtOAc:hexane, 1:10) to give a colorless oil (1.33 g, 41.6%); 1H NMR (CDCl3, 300 MHz) δ 1.55 (m, 1H), 2.11 (m, 1H), 2.11 (m, 2H), 2.58 (dd, J1 =16.2 Hz, J2 =10.2 Hz, 1H), 2.80-3.10 (m, 3H), 3.45 (d, J=6.3 Hz, 2H), 7.10 (m, 4H).
Reaction SMILES: C([O-])(=O)CCC.[Na+].C([N-]C(C)C)(C)C.[Li+].[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1COCC1.C(C1C=CC=CC=1)C.[Cl:36][C:37]1[CH:44]=CC=C[C:38]=1[CH2:39]Cl.O=S(Cl)Cl>C1COCC1>[CH2:17]([C:18]1[CH2:39][C:38]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:44][C:37]=2[Cl:36])[CH3:16]
Reactant: CCCCCCC
Reactant: ClCc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: CCCC(=O)[O-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CCC1=Cc2cccc(Cl)c2C1
Reaction time: 24 h

Procedure:
A 12L round-bottom flask was equipped with a mechanical stirrer, thermometer and reflux condenser. 385 g sodium butanoate (3.5 mol) and 2L THF were added to form a slurry. 2.625L lithium diisopropylamide, 2M in heptane/THF/ethyl-benzene (5.25 mol, 50% excess) were added at ambient temperature, and then stirred for 24 hours. Then 705 g 2-chlorobenzyl chloride (4.375 mol, 25% excess) was added, and the reaction stirred for another 24 hours. Once completed, the reaction was quenched by adding 1500 mL H2O, and the solution allowed to separate. The aqueous layer, pH=13, was separated and neutralized by addition of 12N HCl to obtain pH=7.0, at which point a phase separation occurs. 2-(2-chlorobenzyl) butanoic acid was concentrated in the organic layer. Synthesis of 2-ethyl-7-chloroindene was completed by the same sequence of reactions and method as described in Example 1, beginning with the addition of SOCl2. See FIGS. 1 and 3. The product, 2-ethyl-7-chloroindene, was obtained by distillation at 110-114° C. under 1-3 mm Hg. Yield was 205 g (33% overall) of a clear, colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]2[CH2:10][N:9]([O:11][CH2:12][C:13]3C=C[CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:20]1C=CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH:1]1([CH2:6][C@@H:7]2[CH2:10][N:9]([O:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:20]3)[C:8]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=COCCC1
Reactant: O=C1[C@H](CC2CCCC2)CN1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: O=C1[C@H](CC2CCCC2)CN1OC1CCCCO1
Yield: 100 %

Procedure:
(3R)-3-(Cyclopentylmethyl)-1-[(phenylmethyl)oxy]-2-azetidinone (100 g, 386 mmol) was dissolved in ethanol (1.2 L), and the solution was degassed. Pd on C (10%, dry, 8 g) was added and the suspension was purged with hydrogen and stirred under a hydrogen atmosphere (balloon) until the reaction was complete by LC-MS (approximately 6 h). The suspension was then sparged with nitrogen, filtered through Celite, and evaporated to dryness. The resulting solid was redissolved in CH2Cl2 (1 L) and dihydropyran (70 mL, 767 mmol) was added, followed by pyridinium p-toluenesulfonate (PPTS, 5%, 4.85 g). The reaction mixture was stirred 3 days at room temperature, then concentrated and chromatographed on silica gel using 10-20% ethyl acetate in hexanes to provide (3R)-3-(cyclopentylmethyl)-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone as a colorless liquid (100%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])C.CC[O-].[Na+].Cl.CCOC(C)=O>CCO.[Cl-].[Na+].O>[O:3]=[C:4]1[CH2:5][N:6]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:7][CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CCCC(=O)N(CCC(=O)OCC)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C=CCCC(=O)N1CC(=O)C(C(=O)OCC)C1

Procedure:
To the product of Step B, 1-b, (7.06 g, 24.7 mmol) in EtOH (40 mL) was added NaOEt (20.3 mL, 54.4 mmol, 21 wt in EtOH). The reaction was heated to reflux for 3 h and then cooled before the addition of aq HCl (28 mL, 2 M) followed by dilution with EtOAc and brine. The solution was extracted three times with EtOAc and dried (Na2SO4) to afford the title compound, 1-1, which was used without further purification to prepare Intermediate 4. HPLC/MS: 240.1 (M+1); Rt=2.22 min.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([Br:16])=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7](=[O:17])[C:6]1=[O:18])([OH:3])=[O:2].[N+:19](C1C=C(C=CC=1)N)([O-:21])=[O:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([CH2:4][N:5]1[C:14]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[C:11]([Br:16])=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7](=[O:17])[C:6]1=[O:18])([OH:3])=[O:2]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Br)c(Br)cc21
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 28 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-carboxymethyl-6,7-dibromo-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.260 mmol) and m-nitroaniline (40 mg, 0.29 mmol) in dry DMF (2 mL) under N2 at 28° C., DCC (60 mg, 0.29 mmol) was added in one portion. The solution was stirred for 4 h at 28° C. The insoluble solid was filtered and washed with DMF (1 mL). The clear filtrate was then poured into water (30 mL). The precipitated solid was filtered and dried under vacuum (water aspirator) to obtain 65 mg crude product as a yellow powder. The product was purified by Soxhlet extraction in boiling ethanol (20 mL), keeping the oil bath temperature at 120° C., for 4 h. The insoluble material (in the thimble) was dried under vacuum to obtain 30 mg pure (1H NMR) N-(N'-(m-nitrophenyl)carboxamidyl)-methyl-6,7-dibromo-1,4-dihydroquinox-aline-2,3-dione as a white solid (some of the product also ends up being extracted by hot ethanol which accounts for the low yield of pure product). M.p.>300° C. (decomposes). 1H NMR: δ4.98 (s, 1H), 7.45 (s, 1H), 7.61 (d of d seen as a t, J=8.1 Hz) 7.79 (s, 1H), 7.86 (d, 1H, J=9 Hz), 7.91 (d, 1H, J=8.4 Hz), 8.54 (s, 1H), 10.76 (s, 1H), 12.28 (s, 1H). IR (KBr, cm-1): 3444, 3289, 1707, 1686, 1672, 1602. HRMS: Calculated for C16H10BF2N4O5, 495.9018; Observed, 495.9008.