Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][NH2:19])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33])(=O)C.C1C[O:37][CH2:36][CH2:35]1>>[C:36]([C:28]1[CH:27]=[C:26]([NH:31][C:32]([NH:19][CH2:18][C@@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C@H:10]2[CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[CH2:8][CH2:9]2)=[O:33])[CH:25]=[CH:30][CH:29]=1)(=[O:37])[CH3:35]
Reactant: NC[C@@H]1CCCN1[C@H]1CC[C@@H](Cc2ccc(F)cc2)CC1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccccc1N=C=O
Product: CC(=O)c1cccc(NC(=O)NC[C@@H]2CCCN2[C@H]2CC[C@@H](Cc3ccc(F)cc3)CC2)c1
Reaction time: 4 h

Procedure:
To a stirring solution of {(2S)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidinyl}methanamine (58 mg, 2 mmol) in 2 ml of THF at 25° C. under N2 was added 3 acetylphenyl isocyanate (32 mg, 2 mmol Aldrich). Worked up after 4 hours by stripping off the THF then purifying over silica gel in 100% ethyl acetate followed by 4:1 chloroform/methanol. Obtained 11 mg of a white foam as product. MS (ESI) detects 452 (M+H).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:26][C:27]([CH:29]([N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:30])=[O:28]>C1COCC1>[CH3:5][O:4][C:1](=[O:3])[CH2:2][CH2:26][C:27](=[O:28])[C@@H:29]([N:31]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH3:30]
Reactant: CC(C(=O)CBr)N(Cc1ccccc1)Cc1ccccc1
Reactant: COC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Methyl acetate (1.0 mmol, 0.08 mL) was added dropwise to a solution of LDA (1.05 mmol) in 2.0 mL THF at -78° C., and the resulting solution was stirred for 45 minutes. Hexamethyl phosphoric triamide (1.0 mmol, 0.18 mL) was then added, and after 15 minutes a solution of α-(N,N-dibenzylamino)ethyl bromomethyl ketone (crude from the previous reaction, assumed to be 1.0 mmol) in 2.0 mL was added via syringe. The resulting solution was stirred at -78° C. for 45 minutes and then quenched with saturated solution of NaHCO3. After a work-up as described in Example 8, 0.39 g of crude product was obtained. The product was further purified by column chromatography on silica gel with 8:1 hexanes-ethyl acetate as the solvent system (Rf=0.33) to yield 0.21 g (62%) of methyl-(5S)-5-(N,N-dibenzylamino)-4-oxo-hexanoate as a colorless viscous oil. Analytical data: 1H NMR (300.15 MHz) δ0.95 (d, J=6.6 Hz, 3H), 2.62-2.30 (m, 4H), 3.36 (q, J=6.2 Hz, 1H), 3.60 (ABq, δA =3.41, δB =3.82, J=13.5 HZ, 4H), 3.49 (S, 3H), 7.23-7.37 (m, 10H); 13C NMR 5.1, 38.9, 48.8, 51.4, 54.4, 57.5, 126.9, 128.2, 128.8, 129.2, 139.4, 170.4, 208.2.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[S:7][CH:8]=[C:9](Br)[N:10]=1)(=[O:3])[CH3:2].C[Sn](C)C.C[Sn](C)C.N1(C2SC=[C:29]([Sn:31](C)([CH3:33])[CH3:32])N=2)CCCCC1>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>[C:1]([O:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([Sn:31]([CH3:33])([CH3:32])[CH3:29])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(Br)cs1
Reactant: C[Sn](C)(C)c1csc(N2CCCCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: CC(=O)OCc1nc([Sn](C)(C)C)cs1

Procedure:
2-Acetoxymethyl-4-bromothiazole (387) was taken up in degassed toluene (0.1 M), and was then treated hexamethylditin (10 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) at 80° C. for 3 h according to the procedure described for the synthesis of 2-piperidinyl-4-(trimethylstannyl)thiazole (373), to yield, after flash column chromatography (silica gel, 5% NEt, in hexanes), 2-dacetoxymethyl-4-(trimethylstannyl)thiazole (388; 100%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1C(N)=O.C([O:33][C:34](=[O:50])C1C=CC=C(B2OC(C)(C)C(C)(C)O2)C=1)C>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>[N:27]1[C:28]2[C:23](=[CH:22][C:21]([CH2:20][C:17]3[N:15]4[N:16]=[C:11]([C:9]5[CH:10]=[C:2]([CH:3]=[CH:7][CH:8]=5)[C:34]([OH:50])=[O:33])[CH:12]=[CH:13][C:14]4=[N:19][CH:18]=3)=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: NC(=O)c1ccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)c1

Procedure:
The title compound was prepared in analogy to the compound of Example 15 starting with 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid ethyl ester, using PdCl2(dppf)/CH2Cl2 (1/1) as catalyst and with an additional ester deprotection step afterwards (tR 3.14 min (conditions 11), MH+=380.9).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[CH2:6]1.S(Cl)([Cl:14])=O.C1COCC1.ClCCl>ClC(Cl)C>[Cl:14][CH2:2][CH2:3][NH:4][CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[CH2:6]1
Reactant: O=S1(=O)CCC(NCCO)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: O=S1(=O)CCC(NCCCl)C1
Temperature: 78 °C
Yield: 80.2 %

Procedure:
A mixture of 3-((2-hydroxyethyl)amino)tetrahydrothiophene 1,1-dioxide (260 mg, 1.451 mmol) and sulfurous dichloride (863 mg, 7.25 mmol) in dichloroethane (3 mL) was heated up at 78° C. for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to provide the black oil. To this black oil was added THF (5 mL) and dichloromethane (5 mL), grey-white solid was observed. The solid was filtered and collected to provide the desired product as a grey solid (230 mg, 80%). LCMS: m/e 198.1 (M+H)+, 0.60 min (method 6).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[N:20]1(CCO)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82]([OH:86])[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([O:86][CH2:1][CH2:2][CH:25]3[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]3)[CH:81]=2)=[N:60][CH:59]=[N:58]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: c1cc(OCCC2CCCCN2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.7 %

Procedure:
Triphenylphosphine (0.210 g, 0.801 mmol), tetrahydrofuran (0.62 mL), 1-piperidineethanol (0.683 mL, 5.14 mmol) and diethylazodicarboxylate (0.806 mL, 5.12 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.654 g, 1.08 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. Purification by preparative HPLC (5–70% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.248 g, 59% yield). 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.35 (s, 1H), 8.09 (m, 1H), 7.64 (m, 2H), 7.56 (s, 1H), 7.50 (m, 1H), 7.04 (m, 1H), 4.26 (s, 2H), 2.87 (s, 2H), 2.62 (s, 4H), 1.65 (s, 4H), 1.50 (s, 2H). ES-MS (m/z) 389 [M+1]+
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[C:13]4[N:14]([CH:25]=[CH:26][N:27]=4)[CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1.CN(C=O)C.C(OCC)C>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[N:17]=[C:12]([N:8]4[CH:9]=[CH:10][N:11]=[C:7]4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:13]4[N:14]([CH:25]=[CH:26][N:27]=4)[CH:15]=3)[CH:19]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: Nc1cccc(-c2cn3ccnc3c(-n3ccnc3-c3ccccc3)n2)c1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1)Nc1cccc(-c2cn3ccnc3c(-n3ccnc3-c3ccccc3)n2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Solid 3-[8-(2-Phenyl-imidazol-1-yl)-imidazo[1,2-a]Pyrazin-6-yl]-phenylamine (50 mg) (7) is added to an anhydrous 0.2 M solution of (4-Chloro-phenyl)-acetyl chloride in toluene (0.7 mL) at room temperature, and 0.25 ml of anhydrous DMF is subsequently added to solubilize the reagents. The reaction is warmed to 50° C. and stirred under N2 for 3 hours. The reaction is cooled to room temperature. Diethyl ether (15 ml) is then added slowly and the resulting tan solid 2-(4-Chloro-phenyl)-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-acetamide (60 mg) (8) is filtered and washed with diethyl ether and dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])=[O:15])[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([O:20][CH2:31][CH3:32])=[O:19])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
A solution of 8.41 g (0.025 mole) of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzoic acid, described in Example I, in 300 cm3 of ethyl alcohol containing 0.4cm3 of 98% sulfuric acid is heated for 14 hours at reflux. The solution is then concentrated under reduced pressure and the resulting crude ester is dissolved in 300 cm3 of ethyl ether. The ether solution is washed with sodium bicarbonate and then with water, dried on sodium sulfate and evaporated to dryness. After drying, 7.9 g of ethyl 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzoate are obtained in the form of a colorless oil which slowly crystallizes at ambient temperature to give a white solid whose melting point is 58°-59° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([C:27]3[C:32]4[O:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:31]=4[CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:20][C:21]1[CH:22]=[N:23][C:24]([C:27]3[C:32]4[O:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:31]=4[CH:30]=[CH:29][CH:28]=3)=[CH:25][CH:26]=1)[CH:11]=[C:10]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:40])=[O:4]
Reactant: COC(=O)CCC(=O)c1cn(Cc2ccc(-c3cccc4c3oc3ccccc34)nc2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC(=O)c1cn(Cc2ccc(-c3cccc4c3oc3ccccc34)nc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 98.2 %

Procedure:
2N Sodium hydroxide solution (1.45 mL, 2.9 mmol) was added dropwise to a stirred solution of methyl-4-[5-chloro-1-(6-dibenzofuran-4-yl-pyridin-3-ylmethyl)-1H-indol-3-yl]-4-oxo-butyrate (500 mg, 0.95 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a white solid (475 mg, 98%): Rf: 0.35 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.82 (1H, d, J=2 Hz, ArH), 8.76 (1H, s, ArH), 8.31 (1H, d, J=8 Hz, ArH), 8.18 (4H, m, ArH), 7.88 (1H, dd, J=8, 2 Hz, ArH), 7.72 (2H, d, J=9 Hz, ArH), 7.50 (2H, q, J=6 Hz, ArH), 7.40 (1H, t, J=7 Hz, ArH), 7.27 (1H, dd, J=8, 2 Hz, ArH), 5.65 (2H, s, CH2N), 3.16 (2H, t, J=7 Hz, CH2CO), 2.59 (2H, t, J=7 Hz, CH2CO); ESI-LCMS e/z calculated for C30H21ClN2O4 508.950, found 509 [M+H (35Cl)]+, 511 [M+H (37Cl)]+, 531 [M+Na (35Cl)]+, 533 [M+Na (37Cl)]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH:29]1[C:33](B(O)O)=[CH:32][CH:31]=[N:30]1.C(=O)(O)[O-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:31]5[NH:30][N:29]=[CH:33][CH:32]=5)[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccn[nH]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)cc(Cl)nn23)ccc1C(=O)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2cnc3c(NCC(C)C)cc(-c4ccn[nH]4)nn23)ccc1C(=O)NC1CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a mixture of 125 mg (314 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 111 mg (942 μmol) 1H-pyrazol-5-yl boronic acid, 44 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.63 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then the mixture was filtered and concentrated and purified by chromatography to give 41 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>CN(C)C=O.O>[CH2:18]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: O=C1NC(=O)C2CC12
Reactant: C=CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCCCN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4dione (0.3 g) and 7-octenyl bromide (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: O([CH2:9][C:10]1[CH:14]=[CH:13][O:12][C:11]=1[CH2:15][CH2:16]O)[Si](C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[CH2:32]([NH2:35])[CH:33]=[CH2:34]>ClCCl.C(OCC)(=O)C>[CH2:32]([N:35]1[CH2:16][CH2:15][C:11]2[O:12][CH:13]=[CH:14][C:10]=2[CH2:9]1)[CH:33]=[CH2:34]
Reactant: C=CCN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccoc1CCO
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN1CCc2occc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude 2-(3-hydroxymethylfuran-2-yl)ethanol and 1.74 ml (9.96 mmol) of N,N-diisopropylethylamine in 50 ml of dichloromethane, 0.71 ml (9.13 mmol) of methanesulfonyl chloride was added dropwise under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and then saturated sodium chloride. After which it was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 50 ml of ethanol, 0.36 g (6.22 mmol) of allylamine and 2.38 ml (13.7 mmol) of N,N-diisopropylethylamine were added, followed by overnight stirring at 80° C. The solvent was distilled off under reduced pressure from the reaction mixture; the resulting crude product was purified by silica gel column chromatog-raphy (hexane/ethyl acetate=9/1 to 6/1) to yield 5-allyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
To a solution of Example 76 (0.160 g, 0.304 mmoles) in dichloromethane (25 ml), BBr3 (1M in dichloromethane, 1.6 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.080 g, 51% yield). MP: 271-273° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.17(s,1H), 8.06(s, 1H), 8.05(dd, J=7.9,1.4 Hz, 1H), 7.86(dt, J=8.5,1.5 Hz, 1H), 7.68(d, J=8.3 Hz, 1H),7.53(t, J=7.9 Hz, 1H), 7.28(br s,1H), 7.05(dt, J=6.8,2.0 Hz, 1H), 6.91(br s, 2H), 6.86(s,1H), 6.79(d, J=9.4 Hz, 1H), 6.66(td, J=10.3, 2.1 Hz, 1H),6.05(q, J=6.7 Hz, 1H),1.88(d, J=7.1 Hz, 3H). Mass: 511.80(M+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.[Cl:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>C1COCC1.CCOC(C)=O>[Cl:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:37][S:34]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[CH2:29][CH2:30]1)(=[O:35])=[O:36]
Reactant: O=C(Cl)CCCCCl
Reactant: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: O=C(CCCCCl)CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of LDA (51 mmol, prepared by slow addition of n-butyl lithium (20.4 ml, 2.5M in hexane, 51 mmol) to a solution of diisopropylamine (5.16 g, 51 mmol) in THF (30 ml) at −78° C.) at −78° C. was added a solution of 1-(4-fluorophenyl)4-(methanesulfonyl)-piperazine (6 g, 23.2 mmol) in THF (150 ml). The mixture was stirred for 1 h at −78° C. A solution of 5-chlorovaleryl chloride (4 g, 25.8 mmol) in THF (20 ml) was added dropwise. The mixture was stirred at −78° C. for 1 h and at room temperature for 18 h. The solution was diluted with EtOAc and washed with sat. NH4Cl and brine and dried over MgSO4. Chromatography of the residue on silica gel (eluant: EtOAc—CH2Cl2— petroleum ether (15:35:50)) afforded 1-(6-chloro-2-hexanone-1-sulfonyl)-4-(4-fluorophenyl)piperazine (5.22 g, 60%) as white crystals: MS (ESI): 399 (MNa+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 77.5 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.3 mmol) was added to a solution of 4-cyanophenol (5.0 g, 42.3 mmol), and K2CO3 (14.6 g, 0.10 mol) in DMF (50 mL). The mixture was heated at 80° C. for 15 hr. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, brine, and dried over sodium sulfate. The organic phase was filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with (hexanes/ethyl acetate 4:1) to give the product (9.0 g, 77.8%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:16])([CH:13]([CH3:15])[CH3:14])[CH:8]2[OH:12])=[CH:4][C:3]=1[O:17][CH2:18][C:19]([NH2:21])=[O:20].[C:22](OCC)(=[O:28])[C:23](OCC)=[O:24].CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:16])([CH:13]([CH3:14])[CH3:15])[CH:8]2[OH:12])=[CH:4][C:3]=1[O:17][C:18]1[C:19](=[O:20])[NH:21][C:23](=[O:24])[C:22]=1[OH:28]
Reactant: CC(C)C1(C)Cc2cc(OCC(N)=O)c(Cl)c(Cl)c2C1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)C1(C)Cc2cc(OC3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1O

Procedure:
When [6,7-dichloro-1-hydroxy-2-methyl-2-(i-propyl)-indan-5-yl]oxyacetamide is utilized as starting material in the reaction with diethyl oxalate/potassium t-butoxide there is obtained 4-[6,7-dichloro-1-hydroxy-2-methyl-2-(i-propyl)indan-5-yloxy]-3-hydroxy-3-pyrroline-2,5-dione. Where [6,7-dichloro-2-ethyl-1-hydroxy-2-(n-propyl)indan-5-yl]oxyacetamide is utilized as starting material in this reaction there is obtained 4-[6,7-dichloro-2-ethyl-1-hydroxy-2-(n-propyl)indan-5-yloxy]-3-hydroxy-3-pyrroline-2,5-dione.