Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.C(OCC)C>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)c(F)cc1Cl
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
1-Bromo-4-chloro-2,5-difluorobenzene (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to −10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at −10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to −10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3% yield) that was used without further purification: 1H NMR (CDCl3): δ 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:27]2[CH:28]=[CH:23][N:24]=[C:25]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[N:26]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Clc1ccnc(N2CCCC2)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(N4CCCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide and 4-chloro-2-pyrrolidin-1-ylpyrimidine as the starting materials.
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[C:18]([O:22][C:23]([NH:25][C@H:26]([C:37](O)=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:37](=[O:38])[C@H:26]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NCCCCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCCCCCCO

Procedure:
N-Methylmorpholine (2.2 mL, 19.7 mmol) was added dropwise at room temperature to 7-amino-1-heptanol hydrochloride salt (3.3 g, 19.7 mmol), in 50 mL of dry DMF under argon with stirring. After stirring for 5 minutes the following were added: N-t-butoxycarbonyl-L-tryptophan, (5 g, 16.45 mmol), 1-hydroxybenzotriazole, (2.52 g, 16.45 mmol) and EDCI hydrochloride (4.73 g, 24.7 mmol). The mixture was stirred for 2 hours and then the DMF removed under reduced pressure. The residue was taken up in cold 2.5% HCl (100 mL) and ethyl acetate (3×100 mL) and transferred to a separatory funnel. The organic phase was isolated and washed consecutively with cold 2.5% HCl (100 mL) and then brine (100 mL). The ethyl acetate phase was dried (MgSO4), filtered and concentrated to obtain N-t-butoxycarbonyl-L-tryptophan-(7-hydroxyheptyl)amide; IR (neat): 3300, 2921, 1685, 1645, 1490, 1356, 1157 cm-1 ; 1H NMR (80 MHz, CDCl3): δ 0.98-1.62 (m, 10H, --(CH2)5 --), 1.45 (s, 9H, t-butyl), 2.86-3.32 (m, 4H,CH--CH2, HN--CH2), 3.68 (t, 2H, J=5.6 Hz, --CH2OH), 4.22-4.55 (m, 1H, CH), 5.12-5.32 (broad d, 1H, NH--CH), 5.65-5.9 (broad t, 1H, NH--CH2), 6.98-7.92 (m, 5H, ArH), 8.63 (broad 8, indole NH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[C:13](=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 95.6 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (500 mg, 2.99 mmol) and potassium carbonate (0.42 g, 3.0 mmol) were dissolved in 6.0 mL of N,N-dimethylormamide. After addition of iodemethane (0.38 mL, 6.0 mmol) at room temperature, the mixture was stirred for 5 h at the same temperature. The reaction mixture was diluted with ethyl acetate and water, and separated. The organic layer was washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/1) to obtain the title compound as a pale yellow powder (518 mg, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:23]3[CH2:24][CH2:25][NH:20][CH:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COC(=O)C1CNCCN1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 81.6 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (2.14 g) in dichloromethane (20 ml) is added dropwise, taking 40 minutes while stirring at 0° C., to a mixture of methyl piperazine-2-carboxylate hydrochloride (1.75 g), triethylamine (3.2 g) and dichloromethane (40 ml). The reaction mixture is poured into ice-water and shaken. The organic layer is separated and subjected to distillation under reduced pressure. The residue is dissolved in 1N-HCl (20 ml) and washed with ethyl acetate. The aqueous layer is separated and then neutralized with sodium hydrogencarbonate, followed by extraction with dichloromethane. The organic layer is dried, and the solvent is distilled off. Crystals obtained from the residue are recrystallized from ethyl acetate - hexane to afford methyl 4-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine-2carboxylate as colorless needles (2.45 g), m.p. 103-104° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH2:24][OH:25])=[CH:20][N:19]=1)=[O:22])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Product: CC(C)(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 51 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.22 mmol) was converted, using tert-butylamine instead of S-(+)-1-amino-2-propanol, to the title compound (45 mg, 51%), which was obtained as a colourless gum. MS: m/e=400.2 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@H:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[NH:31]([C:48]([O:50][CH2:51][CH:52]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58]2[C:53]1=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[C@H:32]([C:45](O)=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:31]([C:48]([O:50][CH2:51][CH:52]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:58]2[C:53]1=[CH:54][CH:55]=[CH:56][CH:57]=2)=[O:49])[C@H:32]([C:45]([NH:10][C@H:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of diisopropylethyl amine (1.19 mL, 3.43 mmol) in DCM (50 mL), was added Lys(Z)OMe (1.13 g, 3.43 mmol). To this solution was added FmocTyr(tBu)OH (1.50 g, 3.26 mmol), then HOBt (0.463 g, 3.43 mmol), and finally EDC.HCl (0.6571 g, 3.43 mmol). This solution was allowed to stir for 8 h at which time the organic solution was washed with 1N HCl (2×20 mL), then saturated NaHCO3 (2×20 mL), and finally H2O (2×20 mL). The organic layer was concentrated in vacuo to yield a white solid (2.34 g, 97.5% yield): 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=7.53, 2H), 7.55 (m, 2H), 7.40 (t, J=7.45, 2H), 7.38-7.29 (m, 7H), 7.08 (m, 2H), 6.88 (d, J=8.25, 2H), 6.43 (br s, 1H), 5.52 (br s, 1H), 5.15-5.07 (br m, 3H), 4.50 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 4.18 (t, J=6.92, 1H), 3.70 (s, 3H), 3.18-2.95 (m, 4H), 1.85-1.35 (m, 4H), 1.30 (s, 10H), 1.20 (br s, 2H); 13C NMR (125 MHz, CDCl3) δ 163.0, 154.6, 143.9-143.8 (3), 141.46, 136.6, 130.0, 128.7, 128.2, 127.9, 127.3, 125.2, 124.5, 120.2 (2), 67.13, 66.8, 53.6, 52.6, 47.3, 41.0, 37.8, 32.6, 29.4, 29.0 (3), 22.17; HRMS (FAB) m/z calcd for C43H49N3O8 (M+H)+ 736.3598, found 736.3623.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:20])=[N:11][N:12]3[C:17](O)=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].O=P(Cl)(Cl)[Cl:30]>>[CH3:1][N:2]([CH3:21])[C:3]1[N:4]=[CH:5][C:6]([C:9]2[C:10]([CH3:20])=[N:11][N:12]3[C:17]([Cl:30])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:7][CH:8]=1
Reactant: Cc1cc(O)n2nc(C)c(-c3ccc(N(C)C)nc3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)n2nc(C)c(-c3ccc(N(C)C)nc3)c2n1

Procedure:
Intermediate 8 was dissolved in POCl3 (2 ml) and refluxed for 2 hours. The reaction mixture was cooled and poured onto ice. The solution was made basic (pH =9) by addition of solid sodium carbonate and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated, yielding 3-[6-(dimethylamino)-3-pyridinyl]-2,5-dimethyl-7-chloro-pyrazolo[2,3-a]pyrimidine (intermediate 9).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:30][S:29]1.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([CH2:54][N:55]2[CH2:57][CH:56]2[CH3:58])[C:51](O)=[O:52])=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([CH2:54][N:55]2[CH2:57][CH:56]2[CH3:58])[C:51]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[S:29][CH2:30][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:52])=[CH:46][CH:45]=1
Reactant: CC1CN1CC(C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC1CN1CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
HBTU (37 mg, 0.097 mmol) was added to a solution of the (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (30 mg, 0.097 mmol) and 2-(4-chlorophenyl)-3-(2-methylaziridin-1-yl)propanoic acid (47 mg, 0.097 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was subject to column chromatography, eluting with EA-DCM/MeOH (20:1-10:1). The product was treated with HCl (4M, 2 mL) afforded 2-(4-chlorophenyl)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-(2-methylaziridin-1-yl)propan-1-one as the HCl salt (1 mg, 2%). LC/MS (APCI+) m/z 458.1.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[OH-].[Na+]>ClCCCl>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Glacial acetic acid (1.3 mL, 22.7 mmol) and sodium triacetoxyborohydride (6.73 g, 31.7 mmol) were added to a solution of 5-aminoindole (3 g, 22.7 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.52 g, 22.7 mmol) in 1,2-dichloroethane (100 mL). The reaction mixture was stirred for 4 hours at room temperature; an aqueous solution of NaOH (1 M, 100 mL) was then added. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure to give 6.9 g (96% yield) of 4-(1H-indol-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a black foam; this material was used without further purifications for the next step.
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Na+]>>[CH2:15]([O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OC1CCCCCCCCCCC1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCOC1CCCCCCCCCCC1
Reaction time: 0 h

Procedure:
Cyclododecanol (20.0 g, 0.11 tool), 1-bromohexane (120.0 g, 0.727 mol), and 60% sodium hydride in mineral oil (5.6 g, 0.14 mol) prepared as in Example 1 were refluxed for 2 hours. A 28.4 g sample (96%) was isolated as in Example 1. GC showed 99% one component; bp 109°-111° C. at 0.03 min. IR (neat, cm-1) 28 38, 2868, 1470, 1452, 1354, 1100 (C-O-C); 13C NMR (ppm, CDC13) 76.90 (α-ring carbon), 68.64 (α-chain carbon), 31.81, 30.31, 2 9.06, 26.00, 24.78, 24.31, 23.29, 22.71, 20.78, 14.10; MS, m/z (relative intensity) 268 (M+,1.1), 225(0.03), 211(0.2), 197(1.0), 183(0.4), 138(2.4), 124(3.6), 111(4.5), 110(6.4), 97(2.0), 96(19.9), 83(15.4), 82(46.5), 69(16.1), 68(17.1), 55(34.2), 54(6.2), 43(100.0), 41(40.3), 39(14.8). Anal calcd for C18H36O:C,80.53; H,13.52. Found: C, 80.77; H, 13.33.
Reaction SMILES: C([N:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2C=CC=CC=2C=O)[CH2:25][CH2:24]1.CN(C)C=O>C(OCC)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:4][C:5](=[O:13])[CH:6]=[CH:7][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:22]=2[N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1
Reactant: CC(=O)N(Cc1ccc(Cl)cc1)C(=O)Cc1ccccc1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccccc2C=CC(=O)NCc2ccc(Cl)cc2)CC1

Procedure:
In a flame-dried 25 mL 3-neck round bottom flask equipped with a magnetic stir bar, 83 mg (2.07 mmol of a 60% oil dispersion) of sodium hydride was washed with hexane and covered with 1.0 mL of anhydrous N,N-dimethylformamide (DMF). To this was added 156 mg (0.517 mmol) of N-acetyl-N-(4-chlorobenzyl)phenylacetamide (prepared as above) and 84 mg (0.414 mmol) of 2-(4-methylpiperazin-1-yl)benzaldehyde with an additional 1 mL of DMF. The brown reaction mixture was stirred at 250C for 48 hours, diluted with ethyl acetate, washed with 1N lithium chloride (LiCl) followed by saturated aqueous sodium chloride. The organic layer was dried over calcium sulfate (CaSO4) and concentrated to an oil which was crystallized from about 1 mL of boiling ethyl acetate to give the title product as colorless crystals, 20 mg, m.p. 193-194° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (67.0 g, 0.389 mol) was dissolved in anhydrous methanol (600 ml) and 0.5 M NaOMe in MeOH (800 mL) was added slowly to the mixture (temperature rises to ca. 30° C.). The reaction mixture was stirred at room temperature overnight. The solution was concentrated and the residue was transferred to a separatory funnel containing water (2 L). The aqueous layer was extracted with CH2Cl2 (2×2 L). The combined organic layers were dried over MgSO4, filtered and concentrated to give 2-methoxy-3-methyl-5-nitropyridine (63.0 g, 97% yield) as a white solid which was dried under vacuum: 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 4.06 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.83, 141.91, 139.37, 132.92, 121.77, 54.83, 15.84; An analytical sample was recrystallized from hexane to give white needles, mp 95-96. 5° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[CH:17]12[CH2:23][CH:20]([CH:21]=[CH:22]1)[CH:19]1[C:24]([O:26][C:27](=O)[CH:18]21)=[O:25]>C1(C)C=CC=CC=1>[C:7]([CH:2]([N:1]1[C:24](=[O:25])[CH:19]2[CH:18]([CH:17]3[CH2:23][CH:20]2[CH:21]=[CH:22]3)[C:27]1=[O:26])[CH:3]([CH3:4])[CH2:5][CH3:6])([OH:9])=[O:8]
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Reactant: CCC(C)C(N)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)C(C(=O)O)N1C(=O)C2C3C=CC(C3)C2C1=O
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a suspension of (dl)-isoleucine (2.03 g, 15.5 mmol) in toluene (40 mL) was added triethylamine (2.4 mL, 17.2 mmol). The mixture was heated to reflux temperature and bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic anhydride (2.53 g, 15.5 mmol) was added. The reaction mixture was kept at reflux temperature and allowed to react for 4 hrs. After cooling to room temperature, the solvent was evaporated and the residue dissolved in H2O. The aqueous solution was washed with EtOAc, acidified with conc. HCl until pH=1, and extracted with EtOAc. The organic phase was washed with 5% HCl and brine and dried over Na2SO4. Removal of the solvent gave a white solid (3.72 g) which was recrystallized from EtOAc/hexane to yield the pure product as colorless crystals: mp=109° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=O)[CH2:3][CH:4]=O.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:9])[CH:6]=[CH:7][N:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:4]=[CH:3]1
Reactant: COC(=O)CCCN
Reactant: CC(C)(CC=O)CC=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCN1C=CC(C)(C)C=C1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
Under nitrogen, 5.89 g (0.046 mole) of 3,3-dimethylglutaraldehyde, 7.03 g (0.0457 mole) of methyl 4-aminobutanoate hydrochloride (the compound of Example 9a), and 9 g of 5A molecular sieves were combined in 425 ml of chloroform at room temperature. 7.0 ml (0.05 mole) of triethylamine were added to the reaction mixture before it was warmed to reflux. After 21 hours the reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated in vacuo. The residue was suspended in about 300 ml of ethyl ether and filtered. The filtrate was evaporated in vacuo to yield 8.56 g of crude product. The crude product was distilled to yield 2.5 g of the title compound as a clear liquid, bp 95° C./0.2 mm Hg.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Br:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>[OH-].[Na+]>[Br:9][CH2:10][CH2:11][C:12]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:13]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)CCBr
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)CCBr
Reaction time: 1.5 h

Procedure:
L-proline (5.75 g.) is dissolved in N sodium hydroxide with stirring in an ice bath. To this 50 ml. of N sodium hydroxide is added followed immediately by 3-bromopropanoyl chloride (8.5 g.). The pH is about 8 and the bath is removed. After 1.5 hours an additional 2.5 ml. of 2 N sodium hydroxide is added to bring the pH to 7. The reaction mixture is extracted twice with ether, the aqueous portion is acidified with concentrated hydrochloric acid and extracted into ethyl acetate. Yield 7.7 g. The 1-(3-bromo-1-oxopropyl)-L-proline is converted with dicyclohexylamine in ethyl acetate to the dicyclohexylamine salt, m.p. 284°-286°. This salt is then converted to the free acid with 10% potassium bisulfate in ethyl acetate. This product is recrystallized from ethyl acetate:hexane and recrystallized from ethyl acetate, m.p. 83°-85°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1>[CH3:19][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2cc(-c3ccccc3)[nH]c2c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 6-nitro-2-phenyl-1H-indole (106 mg, 0.44 mmol) and 18-Crown-6 (130 mg, 0.49 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature was added potassium tert-butoxide (55 mg, 0.49 mmol) followed by methyl iodide (31 μL, 0.49 mmol). The solution was stirred at room temperature for 30 min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 110 mg (98%) of the title compound.
Reaction SMILES: ClC1C=CC(CC(O)=O)=CC=1OC1C=C[C:16]([S:19](C)(=[O:21])=[O:20])=[CH:15]C=1C#N.N[C:26]1[CH:27]=[CH:28][C:29]([Cl:34])=[C:30]([CH:33]=1)[C:31]#[N:32].C(SSCC)C>>[Cl:34][C:29]1[CH:28]=[CH:27][C:26]([S:19]([CH2:16][CH3:15])(=[O:21])=[O:20])=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: N#Cc1cc(N)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(C#N)c1
Solvent: CCSSCC
Product: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The subtitle compound was prepared by the methods of example 2 steps (i) and (ii) using 5-amino-2-chlorobenzonitrile and diethyldisulfide.