Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2.O.N.[ClH:15]>CN1CCCC1=O.CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[Cl:15][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=2
Reactant: Cl
Reactant: Oc1ccc2ncc(Br)cc2c1
Agent: N
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCCCCC
Product: Oc1ccc2ncc(Cl)cc2c1
Temperature: 150 °C

Procedure:
3-Bromo-6-hydroxyquinoline (2.75 g) and cuprous chloride (9 g) in dry N-methylpyrrolidin-2-one (25 ml) were stirred and heated at 150° C. under an atmosphere of nitrogen for 2 hours. The dark red suspension was cooled to ambient temperature, poured into water then treated with sufficient aqueous ammonia to dissolve the solid material. The blue solution was taken to pH 5-6 with hydrochloric acid (2M) then ethyl acetate was added. The mixture was filtered and the insoluble solids washed with ethyl acetate. The organic component of the filtrate was separated and the aqueous phase was further extracted with ethyl acetate. The ethyl acetate fractions were combined, washed with brine, dried over magnesium sulphate then evaporated under reduced pressure to give a solid. The solid was fractionated by chromatography (silica; hexane/ethyl acetate, 2:1 by volume) to give 3-chloro-6-hydroxyquinoline as a pale yellow solid, 0.95 g. (M+ 179, 1×Cl). 1H NMR (CDCl3) δ: 7.06(1H, d); 7.35(1H, dd); 7.91(1H, d); 7.96(1H, d); 8.59(1H, d); 9.55(1H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(Sc2ccccc2)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Yield: 74.1 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 6.07 g (25.6 mmol) 3-chloro-4-thiophenoxyaniline was heated to reflux under N2. Removed heat at about 8 hours, made basic with saturated sodium bicarbonate, stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Dissolved nearly completely in 400 ml ethyl acetate, stirred with Darco and filtered. Stripped solvent and boiled in hexane to remove last of the excess aniline. Dried in vacuo, giving 6.90 g of red solid: mass spectrum (electrospray m/e): M+H=433.1, 435.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:32][O:33][C:34]([C:36]1([NH2:45])[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35].C(Cl)CCl>CN(C=O)C>[CH3:32][O:33][C:34]([C:36]1([NH:45][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH:4]=2)[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(CCOc2cc(C(=O)O)ccc2Br)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)C1(NC(=O)c2ccc(Br)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reaction time: 8 h
Yield: 90.3 %

Procedure:
The compound of step 2 (0.410 g, 1.22 mmol) was dissolved in DMF (5 ml), EDIA (0.790 g, 6.12 mmol), HOBT (33 mg, 0.244 mmol), and 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (0.246 g, 1.47 mmol) were added, the mixture was cooled in an ice bath and EDC (352 mg, 1.84 mmol) was added. The mixture was stirred overnight. The volatiles were evaporated in vacuo, the mixture was partitioned between 2 N hydrochloric acid and EA, the organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to give 0.56 g of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:30])[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 4 h

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.32 g, 2.98 mmol) in dry N, N-dimethylformamide (6 mL) was heated to 60° C. Portions (ca. 1 mmol each) of N-bromosuccinimide (1.59 g, 8.93 mmol) were added over 5 hours. Heating was continued for an additional 4 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Title compound eluted with 1:1 hexane-ethylacetate as a tan powder (1.1 g, 69%), 1H-NMR identical with recrystallized sample. Such a sample was recrystallized from ethanol-water to a white powder, m.p. 156°-159° C.; 1H-NMR (DMSO-d6) δ: 8.34, 7.97 (both s, 1 each, 2 benzimidazole CH), 5.6 (m, 1, OCH), 5.3 (m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.4-4.2 (m, 2, OCH2), 2.7- 2.5 (m, 1, CH), 2.4-2.0 (m) overlapping 2.1 and 2.07 (both s, total 8, CH2 and 2CH3CO), 1.92 (s, 3, CH3CO); mass spectrum (CI): 527 (6.6), 525 (45), 523 (100), 521 (65, M+1), 257 (48, M-B).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:3]=[C:2]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)c(N3CCCCC3)nc2n1
Product: Clc1nc2c(N3CCCCC3)nc(N3CCNCC3)nc2nc1N1CCCCC1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4,7-dipiperidino-pteridine and piperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:21]1[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)CCN2C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-fluoroindoline (1.0 g, 7.30 mmol) and N-Boc-4-piperidone (1.60 g, 7.50 mmol) in tetrahydrofuran (10.0 mL) was added sodium triacetoxyborohydride (1.80 g, 7.50 mmol). After stirring for 3 hours at room temperature, to the mixture were added saturated sodium bicarbonate water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (chloroform/methanol=98/2 to 90/10) to give a Boc derivative of the title compound. MS (ESI+) 321 (M++1, 100%)
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[S:6][C:5]=1C(O)=O)[CH:2]=[CH2:3]>N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]>[CH2:1]([C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[S:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1c(C(=O)O)sc2c1c(=O)n(C)c(=O)n2C
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: C=CCc1csc2c1c(=O)n(C)c(=O)n2C
Temperature: 235 °C

Procedure:
Copper powder (231 mg, 3.642 g atom) was added to a suspension of Step 7 intermediate (3.4 g, 12.142 mmol) in quinoline (60 ml) and the resulting mixture was stirred and heated at 235° C. for 3 h under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 1 N HCl and water. The combined organic layers were dried and concentrated. The purification of crude product by silica gel column chromatography by using 5% ethyl acetate in petroleum ether gave 2.17 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 3.41 (s, 3H), 3.55 (s, 3H), 3.71 (s, 2H), 5.09-5.15 (m, 2H), 5.97-6.10 (m, 1H), 6.50 (s, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>C(OCC)(=O)C.O.[Cu](I)I.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>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cccc(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)c1
Temperature: 60 °C
Yield: 100.7 %

Procedure:
A solution of (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate (25 mg, 0.05 mmol) and 3-ethynyltoluene (6 mg, 0.055 mmol) in ethyl acetate (0.5 mL) and H2O (50 μL) was purged with argon. Triethylamine (15 μL, 0.1 mmol), copper iodide (0.5 mg, 0.05 eq) and Bis(triphenylphosphine)palladium(II) dichloride (0.9 mg, 0.025 eq) were added and the solution was heated to 60° C. for 2 h. The mixture was cooled and purified by silica gel chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) to give the title compound as a green oil (25 mg, 92%). MS ESI 497.3 [M+H]+, calcd for [C26H28N2O4S+H]+ 497.15.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.[OH:23]O>C(O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]([OH:23])=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(C=O)ccc21
Reactant: OO
Solvent: O=CO
Product: Cn1c(COc2ccc(C#N)cc2)nc2nc(C(=O)O)ccc21

Procedure:
1.25 g (4.3 mMol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-imidazo[4,5-b]pyridine-5-carbaldehyde were dissolved in 10 ml formic acid and mixed at 0° C. with 1.0 ml hydrogen peroxide (33% strength). After 12 hours at 40° C. the white precipitate formed was suction filtered, washed with water and dried at 40° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1.CCCCCCC.[F:21][C:22]1[CH:23]=[C:24]([O:29]C)C=C[C:27]=1[F:28].CN(C)C=O>C1COCC1.O.C(O)(=O)C>[F:21][C:22]1[C:27]([F:28])=[CH:10][CH:9]=[C:13]([O:12][CH3:11])[C:23]=1[CH:24]=[O:29]
Reactant: COc1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A solution of lithium diisopropylamide, 2M in THF/n-heptane (171 mL, 341 mmol) was further diluted with dry THF (250 mL) and cooled under nitrogen to −75° C. 3,4-Difluoroanisole (46.8 g, 325 mmol) in dry THF (100 mL) was added dropwise and the mixture stirred at −75° C. for 1 h. Dry N,N-dimethylformamide (27.6 mL, 358 mmol) was added dropwise and the mixture stirred for 10 mins at −70° C. Acetic acid (30 mL) and water (400 mL) were added, warming the temperature to 10° C. Extracted into diethyl ether (2×300 mL). Combined extracts were washed with water (250 mL), aqueous hydrochloric acid (0.2 N, 400 mL) and brine (2×250 mL), dried (MgSO4) and the solvent evaporated in vacuo to give a red/orange oil which crystallised. Purification was by recrystallisation from diethyl ether/petroleum ether 40–60 to give (53.0 g, 95%) of solid; δH (300 MHz, CDCl3) 10.40 (1H, s, CHO), 7.37 (1H, q, ArH), 6.71 (1H, m, ArH), and 3.93 (3H, s OCH3).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][N:15]=1.N12CCCN=C1CCCCC2>N1C(C)=CC=CC=1C>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([N:10]2[CH2:9][CH2:8][N:7]3[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]3[CH2:11]2)=[N:15]1
Reactant: Clc1noc2ccccc12
Reactant: OCC1CCC2CNCCN2C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1cccc(C)n1
Product: OCC1CCC2CN(c3noc4ccccc34)CCN2C1
Temperature: 145 °C
Yield: 41.6 %

Procedure:
A mixture consisting of racemic (7S*,9aS*)-7-(hydroxymethyl)perhydro-1H-pyrido[1,2-a]pyrazine (see Example 27; 500 mg, 2.93 mmol), 3-chloro-1,2-benzisoxazole (890 mg, 5.86 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU, 446 mg, 0.438 ml, 2.93 mmol) in 2,6-lutidine (0.5 ml) was stirred and heated at 145° C. for 18 hours. The solvent was removed in vacuo, and the tarry residue was thoroughly extracted with methylene chloride (150 ml). Insolubles were filtered and the solvent was removed in vacuo to afford a dark brown residue. Flash chromatography of the entire sample (20 g silica gel, 32-63 mesh; eluting with ethyl acetate/methanol=95:5 in volume) afforded 350 mg (41.7%) of the title compound (in which the 7- and 9a-hydrogen substituents remain cis) as a colorless amorphous solid. HRMS m/z 287.1639 (M, C16H21N3O2). 13CNMR (CDCl3) delta 164.0, 161.0, 129.5, 122.3, 122.1, 116.1, 110.5, 67.5, 60.2, 58.2, 54.2, 53.7, 48.3, 34.4, 26.9, 26.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13](=O)[NH:14][CH:15]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:13]1[CH:12]=[N:11][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][N:14]=1
Reactant: COc1ccc(F)c(-c2c[nH]c(=O)cn2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(F)c(-c2cnc(Cl)cn2)c1

Procedure:
A solution of 5-(2-fluoro-5-methoxyphenyl)-pyrazin-2-one in POCl3 was heated at 100° C.-110° C. in a sealed tube for 16 h. After evaporating the remaining POCl3 under reduced pressure, the brown residue was taken up in EtOAc and washed (3×) with saturated aqueous NaHCO3 solution. The EtOAc solution was then dried (Na2SO4) and concentrated under reduced pressure leaving a brown oil. The oil was filtered through a pad of silica gel (30% EtOAc/hexanes eluent) and the solvents were again evaporated under reduced pressure. The oil was taken up in CH2Cl2, heated for 5 min. with decolorizing charcoal and filtered through celite. Evaporation of the solvent afforded 2-chloro-5-(2-fluoro-5-methoxyphenyl) pyrazine as a light-brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:12].Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[CH2:9][CH2:8][C:7]2=[O:12])[CH2:24][CH2:23]1
Reactant: O=C1CCC(=O)N1CCCCCl
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCCN2C(=O)CCC2=O)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Scheme-III: A mixture of 1-chloro-4-(2,5-dioxopyrrolidin-1-yl)butane (11.0 g, 58.04 mmol), 1-[2-methoxyphenyl)piperazine hydrochloride (12.99 g, 56.85 mmol), potassium carbonate (16.02 g, 116.09 mmol) and potassium iodide (0.577 g, 3.48 mmol) in N,N-dimethylformamide (45 ml) was stirred at 100° C. for 18 hours. N,N-dimethylformamide was evaporated at reduced pressure and the residue was taken up in water (100 ml) and extracted with chloroform (2×100 ml). The extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(2-methoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butane as an oil which was purified by column chromatography over silica gel (230-400 mesh) using chloroform-methanol (98:2) as eluent; yield 18.00 g, (92%), oil. Hydrochloride salt was prepared by the method described above; mp 218-220° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH3:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH2:9]([N:16]1[C:20]([Br:1])=[CH:19][N:18]=[C:17]1[CH3:21])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ncc(Br)n1Cc1ccccc1
Reaction time: 6 h
Yield: 84.1 %

Procedure:
Add N-bromosuccinimide (7.85 g, 44 mmol) to a solution of 1-benzyl-2-methyl-1H-imidazole (8.0 g, 46 mmol) in chloroform (200 mL) and stir for 6 hours. Wash reaction with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dry over magnesium sulfate, and filter through 2″ pad of silica gel. Concentrate filtrate reduced pressure. Suspend residue in diethyl ether (600 mL), heat to reflux and filter hot Concentrate ether filtrate under reduced pressure to give 9.3 g (37 mmol) of the desired compound as a tan solid.
Reaction SMILES: [O:1]=[P:2]12[O:13][P:11]3([O:14][P:4]([O:6][P:7]([O:10]3)([O:9]1)=[O:8])(=[O:5])[O:3]2)=[O:12].[Al+3].[Cl-:16].[Cl-:17].[Cl-].O=P(Cl)(Cl)Cl.P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.O=POP=O.[C:39](=[O:41])=[O:40]>>[O:5]=[P:4]12[O:3][P:2]3([O:9][P:7]([O:10][P:11]([O:13]3)([O:14]1)=[O:12])(=[O:8])[O:6]2)=[O:1].[C:39](=[O:41])=[O:40].[Cl:16][Cl:17]
Reactant: [Cl-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClP(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: ClCl

Procedure:
A process of anhydrous carbo-chlorination of AlPO4 comprising the steps of introducing AlPO4 -containing material into a reactor zone; introducing chlorine and carbonaceous material into said reactor zone; heating the reactor zone to a temperature of from 600°-1200°C to form aluminum chlorides, phosphorous oxides, phosphorous chlorides, phosphorous oxychlorides and carbon oxides; separating the reaction products into three fractions by condensation, the first fraction being P2O5, the second fraction being AlCl3 and AlCl3 . POCl3, and the third fraction being PCl3, PCl5, P2O3, CO and CO2 ; and passing said fraction, which is gaseous, into an oxidizer to produce P2O5, CO2 and Cl2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[C:15]([NH:22][CH2:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([O-:29])=[O:28])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(CC)CC)C>C(OCC)(=O)C>[C:15]([NH:22][CH2:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([O:29][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[O:28])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)[O-]
Reactant: O=C(CCCBr)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCC(=O)OCc1ccccc1
Yield: 47.6 %

Procedure:
This compound was prepared from benzyl 4-bromobutanoate (7.2 g; 28.0 mmol), 5-(Boc-amino)-4-oxopentanoate (6.7 g; 29.0 mmol), triethylamine (2.95 mmol), and ethyl acetate (100 mL) as described in Example 1a. The crude product was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2) (750 mL) collecting 6×100 mL fractions. After evaporation of fractions 3 and 4, 5.43 g (46%) product was obtained (yellow oil).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:18])[C:14]=1[N+:15]([O-:17])=[O:16])[CH:10]=O.[Cl-].[NH4+].[CH2:21]1C[O:24][CH2:23][CH2:22]1>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:21][CH2:22][CH2:23][OH:24])[CH:12]=[C:13]([CH3:18])[C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(C=O)cc(C)c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: Cc1cc(C=CCCO)cc(C)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3-(hydroxypropyl)triphenylphosphonium bromide (10.5 g) in dry THF (100 ml) at 0°, under nitrogen was added n-butyllithium (1.8 M in hexane, 30 ml). The stirring was continued at 0° for 30 min then a solution of 3,5-dimethyl-4-nitrobenzaldehyde (4.5 g) in dry THF (50 ml) was added over 10 min. The mixture was stirred at -10° for 1 h and at 0° for 1 h, saturated ammonium chloride (50 ml) was added and the mixture was extracted with EA (3×50 ml) the organic extracts were washed with water, brine, dried, concentrated and purified by [FCS] eluting with cyclohexane/EA 4:1 to give the title compound (1.05 g). T.l.c. (cyclohexane/EA 4:1) Rf 0.08.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18](O)=[CH:19][CH:20]=2)C[CH2:14]1>CN(C=O)C>[NH:3]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a solution of CDI in 25 mL anhydrous DMF was added 1 (0.76 g, 1.72 mmol), see Example 4, in one portion. The mixture was allowed to stir at room temperature for 15 minutes, then at 80° C. for 2 hours. The solution was then cooled to room temperature, the 5-indanol added, and stirring continued for 16 hours. The reaction was quenched by pouring into 200 mL H2O, and the resulting yellow precipitate filtered and air dried. Column chromatography (30% EtOAc/Hex→50% EtOAc/Hex) yielded 0.24 g (25%) of 2, mp 258°-260° C.
Reaction SMILES: [BH4-].[Na+].C(O)(C(F)(F)F)=O.[CH3:10][N:11]([CH3:28])[CH2:12][CH2:13][C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[C:23](=O)[CH2:24][O:25][CH3:26].[NH4+].[OH-]>ClCCl>[CH3:26][O:25][CH2:24][CH2:23][C:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[S:18][C:14]=1[CH2:13][CH2:12][N:11]([CH3:10])[CH3:28]
Reactant: COCC(=O)c1c(CCN(C)C)sc2ccccc12
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCc1c(CCN(C)C)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (16 mg, 0.42 mmol) was added to a cooled (0° C.) solution of TFA (0.6 mL). The mixture was stirred for 30 min at room temperature. A solution of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-2-methoxy-ethanone (10 mg, 0.036 mmol) in dichloromethane ((0.6 mL) was added and the mixture was heated at reflux for 1 hour. An additional batch of sodium borohydride (10 mg) was added and the reaction was stirred overnight at rt. Diluted NH4OH was added until the pH of the mixture was approximately 9. The product was extracted with dichloromethane, the organic layer was concentrated and purified by mass triggered preparative HPLC to afford {2-[3-(2-methoxy-ethyl)-benzo[b]thiophen-2-yl]-ethyl}-dimethyl-amine (Compound 22-2). (MH+=263.9, tR=4.07, Method 2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[C:23]4[CH2:22][C:21]([O:24]CC)=[CH:20][CH2:19][C:18]=4[CH:17]=[CH:16][CH:15]=3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(Br)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(-c4ccc(Br)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 8B for the product of Example 1H.