Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C(OC(C)C)C(OC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([O:56][CH3:57])[C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:51][C:46]=2[N:45]=[C:44]2[N:58](CC=C)[NH:59][C:60]([CH3:61])=[C:43]2[N:42]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([O:56][CH3:57])[C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[CH:51][C:46]=2[N:45]=[C:44]2[NH:58][NH:59][C:60]([CH3:61])=[C:43]2[N:42]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC)c(OC(C)C)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1OC(C)C
Product: COc1cc2c(cc1OC(C)C)N=C1NNC(C)=C1N=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-8-(1-methylethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVii) was prepared by reacting 0.0023 moles of (2-amino-5-methoxy-4-(1-methylethoxy)phenyl)-(2-chlorophenyl)-methanone (Xii) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-8-(1-methylethoxy)-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVii) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=397.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].Cl[C:13]1[S:17][N:16]=[C:15]([S:18][CH3:19])[N:14]=1.[Cl-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][C:13]1[S:17][N:16]=[C:15]([S:18][CH3:19])[N:14]=1
Reactant: OCc1ccccc1Cl
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
Into 2 ml of N,N-dimethylformamide was dissolved 215 mg of 2-chlorobenzyl alcohol, 59 mg of sodium hydride (60% in oil) was added thereto under ice-cooling. After stirring for 30 minutes, a solution of 250 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole in 2 ml of N,N-dimethylformamide was added dropwise into the mixture and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 2 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 188 mg of 5-(2-chlorobenzyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (2)).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:7]=1[N+:13]([O-:15])=[O:14]>>[N:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[N+:13]([O-:15])=[O:14])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1cccc(F)c1[N+](=O)[O-]

Procedure:
reacting sodium azide with 1,3-difluoro-2-nitrobenzene to form 1-azido-3-fluoro-2-nitrobenzene; and
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li+].[CH3:10][CH:11]([N-]C(C)C)[CH3:12].C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH2:12]([C:7]1[C:6]([Br:8])=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])[CH:11]=[CH2:10]
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1c(Br)cncc1Br
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A THF (100 mL) solution of 3,5-dibromopyridine (5 g, 21.1 mmol) at −78° C. was added via cannula to a solution of LDA (22.2 mmol) in THF (700 mL) at −78° C. keeping the temperature <60° C. After stirring for 10 min. at −78° C., allyl bromide (2.56 mL, 29.5 mmol) was added via syringe and the reaction mixture was stirred for 2 hr at −78° C. Saturated NH4Cl (100 mL) was added slowly to quench the reaction. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration in vacuo gave the title compound as an oil which was purified by chromatography on silica gel with hexane:ethyl acetate 9:1.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][C:11]=1[CH3:20].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:5]1[CH2:6][CH2:7][O:8][C@H:3]([CH3:2])[CH2:4]1)[NH2:16]
Reactant: C[C@@H]1CNCCO1
Reactant: CC(=O)Nc1ccc(Br)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: Cc1cc(N)ccc1N1CCO[C@H](C)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Under N2 atmosphere, to a mixture of (R)-2-methylmorpholine HCl salt (1.1 g, 8 mmol), N-(4-bromo-3-methylphenyl)acetamide (1.7 g, 7.45 mmol), Pd2 dba3 (92 mg, 0.1 mmol) and 2-(di-t-butylphosphino)biphenyl (72 mg, 0.24 mmol) was added LiHMDS (28 mmol, 28 mL, 1 M in THF). The resulting mixture was stirred at 65° C. overnight. THF was removed under reduced pressure. The residue was treated with HCl (1N), basified with NaHCO3, and then extracted with EtOAc. The combined organics was washed with brine and dried over Na2SO4. The crude was purified by flash chromatography on silica gel (40-100% EtOAc in hexanes) to afford the product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:20]1[S:24][N:23]=[CH:22][N:21]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[C:31]1([C@@H:37](O)[CH2:38][CH2:39][OH:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:20]1[S:24][N:23]=[CH:22][N:21]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]([C@@H:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:38][CH2:39][OH:40])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8]
Reactant: OCC[C@H](O)c1ccccc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)oc(=O)n3[C@H](CCO)c2ccccc2)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Accordingly, the compound of Formula 37-1 (N-(2,4-dimethoxybenzyl)-3-[(1R)-3-hydroxy-1-phenylpropyl]-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydro-1,3-benzoxazole-6-sulfonamide) was prepared from a solution provided by dissolving 200 mg of the compound of Formula 1-5 (0.429 mmol, prepared as described above) and (S)-1-phenylpropane-1,3-diol (65.3 mg, 0.429 mmol) (0.429 mmol) in 2 mL of THF. This solution was cooled to 0° C. and treated with triphenylphosphine (0.225 g, 0.858 mmol) followed by DEAD (0.136 mL, 0.858 mmol). After stirring at 0° C. for 120 min, the reaction mixture was diluted with EtOAc (50 mL) and saturated sodium bicarbonate (5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by normal phase chromatography (10-80% EtOAc in hexane) yielded the compound of Formula 37-1 as a yellow oil which was used as isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc(F)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 81.3 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.15 g of 3-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.23 g of 4-(3-fluorophenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (61)), m.p.: 60.1° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][N:6]([C:8](=[O:16])[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1.[CH3:25][NH2:26]>C(Cl)Cl.CO>[CH3:24][C:2]1([CH3:1])[CH2:7][N:6]([C:8](=[O:16])[CH:9]([NH:26][CH3:25])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1
Reactant: CN
Reactant: CCOC(=O)C=CC(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CC(NC)C(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 36.6 %

Procedure:
In 3 ml of methylene chloride was dissolved 0.5 g of ethyl 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)-4-oxo-2-butenoate followed by addition of 0.116 g of methylamine in methanol. The mixture was stirred at room temperature for 4 days, at the end of which time the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crude crystals were washed with ethanol-hexane to give 0.2 g of ethyl 4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)-3-methylamino-4-oxobutanoate.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([C@H:20]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:45][CH2:44][CH2:43][NH:42][C:41]3=[O:46])[CH2:36][CH2:35]2)[CH2:21][N:22]([CH3:31])[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:17][C:18]=1[Cl:19]>ClCCl>[C:23]([N:22]([CH3:31])[CH2:21][C@H:20]([C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)[CH2:32][CH2:33][N+:34]1([O-:6])[CH2:35][CH2:36][CH:37]([N:40]2[CH2:45][CH2:44][CH2:43][NH:42][C:41]2=[O:46])[CH2:38][CH2:39]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(C[C@@H](CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C[C@@H](CC[N+]1([O-])CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 61 %

Procedure:
3-Chloroperoxybenzoic acid (0.700 g) in dichloromethane (16 mL) was added dropwise to a solution of (S)-N-[2-(3,4-dichlorophenyl) -4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide (1.31 g) in dichloromethane (12 mL) at 0° C. After being stirred for 1 hour, the reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried, and evaporated. The crude product was chromatographed, with dichloromethane:methanol (gradient 98:2, 70:30) as eluent. The purified product (0.592 g) and p-toluenesulfonic acid monohydrate (0.232 g) were dissolved in dichloromethane:methanol and evaporated to give the title compound as a white solid (0.824 g); MS: m/z=533(M+1); Analysis for C27H34C12N4O3.1.10 C7H8O3.1.10 H2O: Calculated: C, 56.11; H, 6.10; N, 7.54; Found: C, 55.85; H, 5.96; N, 7.33.
Reaction SMILES: CCCCCC.[N+]([O-])(OCCC(C)C)=O.[S:16]1[CH:20]=[CH:19][C:18]2[CH:21]=[C:22]([S:25][CH:26]([N+:30]([O-:32])=[O:31])C([O-])=O)[CH:23]=[CH:24][C:17]1=2.[Li+].Cl.C(=O)=O>O1CCCC1.O>[N+:30]([CH2:26][S:25][C:22]1[CH:23]=[CH:24][C:17]2[S:16][CH:20]=[CH:19][C:18]=2[CH:21]=1)([O-:32])=[O:31]
Reactant: O=C([O-])C(Sc1ccc2sccc2c1)[N+](=O)[O-]
Agent: CC(C)CCO[N+](=O)[O-]
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=[N+]([O-])CSc1ccc2sccc2c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A 1.55 M solution of butylithium in hexane (6.2 ml, 10 mmol) was added to a stirred solution of A (1.1 g, 5 mmol) in anhydrous tetrahydrofuran (30 ml) maintained at -40° C. under an atmosphere of argon. When the addition was complete, the mixture was stirred for 1 hour at -5° C. Isoamyl nitrate (2 ml, 15 mmol) was then added dropwise to the stirred mixture at -5° C. The reaction mixture was then stirred for a further 2 hours at -5° to 0° C. The mixture (containing lithium 2-(benzo[b]thien-5-ylthio)-2-nitroacetate) was acidified to pH 2 by addition of 2 M hydrochloric acid and was then left for 30 minutes at ambient temperature, after which time evolution of carbon dioxide (produced by decarboxylation of 2-(benzo[b]thien-5-ylthio)-2-nitroacetic acid) had ceased. Water (50 ml) was then added and the mixture was extracted with ethyl acetate. The combined extracts were washed successively with a saturated solution of sodium hydrogen carbonate, then with brine, dried (Na2SO4), and the solvent removed by evaporation. The residual oil was purified by flash chromatography using 75:25 v/v hexane/toluene as eluant to give 5-(nitromethylthio)benzo[b]thiophene as a yellow oil; NMR (90 MHz): 5.5 (s,2H), 7.2-8.0 (m,5H); m/e (electron impact); 225 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:20])[CH2:15][CH2:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(CO)NC(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Yield: 81.1 %

Procedure:
A solution of [4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetic acid (Example 44, 0.300 g, 1.03 mmol), 2-amino-2-methylpropan-1-ol (0.111 g, 1.24 mmol), EDCI (0.238 g, 1.24 mmol) and HOBt (0.168 g, 1.24 mmol) in acetonitrile (5 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=80:20 to 40:60) to provide 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-N-(2-hydroxy-1,1-dimethylethyl)-2-oxoacetamide (0.302 g, 81%) as a white amorphous.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[C:6]([NH:13][CH2:14][C:15](O)=[O:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[C:9]([O:8][C:6](=[O:7])[NH:13][CH2:14][C:15](=[O:16])[N:3]1[CH2:4][CH2:5][S:1][CH2:2]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C1CSCN1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCSC1

Procedure:
Thiazolidine (85 mmol) and Boc-glycine (57 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 60 hour reaction time) and the product used without purification. Yield 12.7 g, 90%.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([S:12](Cl)(=[O:14])=[O:13])[CH2:3][CH2:2]1.[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1>>[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37][S:12]([N:4]3[CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[O:1][CH2:2][CH2:3]3)(=[O:14])=[O:13])[C:28]([N:30]3[CH2:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH2:35]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: O=S(=O)(Cl)N1CCOc2ccccc2C1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Product: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)N2CCOc3ccccc3C2)CC1

Procedure:
This compound was prepared from 200 mg of 2,3-dihydro-5H-benzo[f][1,4]oxazepine-4-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 80 mg (oil), (+)-FAB-MS: 530 (MH+).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][C:27]1[C:28]([C:34]([NH:36][CH3:37])=[O:35])=[N:29][C:30](Br)=[CH:31][N:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:36][CH3:37])=[O:35])=[N:29][C:30]([C:15]2[CH:14]=[N:13][CH:12]=[C:11]([C:9]([NH:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:10])[CH:16]=2)=[CH:31][N:32]=1
Reactant: CC1(C)OB(c2cncc(C(=O)NCc3ccccc3)c2)OC1(C)C
Reactant: CNC(=O)c1nc(Br)cnc1N
Product: CNC(=O)c1nc(-c2cncc(C(=O)NCc3ccccc3)c2)cnc1N
Yield: 38 %

Procedure:
3-amino-N-methyl-6-(5-{[(phenylmethyl)amino]carbonyl}pyridin-3-yl)pyrazine-2-carboxamide was synthesized according to the procedure described above from N-(phenylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxamide and 3-amino-6-bromo-N-methyl-2-pyrazincarboxamide. Yield 38%. 1H NMR (400 MHz, d6-DMSO): 9.58 (d, 1H), 9.36 (t, 1H), 9.02 (m, 3H), 8.86 (t, 1H), 7.34 (m, 4H), 7.24 (m, 1H), 4.50 (d, 2H), 2.83 (d, 3H); MS (EI) for C19H18N6O2: 363 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)CCc1ccc(N)c(F)c1
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCC)cc1F

Procedure:
In a manner directly analogous to that described in Example 9, ethyl 3-fluoro-4-aminohydrocinnamate is alkylated with hexadecyl bromide to form ethyl 3-fluoro-4-(hexadecylamino)-hydrocinnamate. Subsequently, in a manner directly analogous to that described in Example 10, ethyl 3-fluoro-4-(hexadecylamino)hydrocinnamate is hydrolyzed to 3-fluoro-4-(hexadecylamino)-hydrocinnamic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C1C(=O)N([Br:21])C(=O)C1.OS(O)(=O)=O>O>[Br:21][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc2c(c1Br)CCCC2=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a suspension of 6-methoxy-1-tetralone (2.0 g, 11.4 mmol) and NBS (2.0 g, 11.4 mmol) in H2O (30 mL) was added conc. H2SO4 (1.2 mL, 22.7 mmol) at rt. The reaction was stirred at 60° C. for 3 h. The mixture was filtered, and concentrated. Purification by prep-HPLC gave 1.2 g (41%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.13-2.18 (2H, m), 2.61 (2H, t, J=6.0 Hz), 3.03 (2H, t, J=6.0 Hz), 3.97 (3H, s), 6.88 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.8 Hz). [M+H] Calc'd for C11H11BrO2, 255, 257. Found, 255, 257.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:17]=2)[O:12][C:11]=1[C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:8]>C1COCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[C:18]3[C:10]([N:9]4[CH2:4][CH2:5][CH2:6][C:7]4=[O:8])=[C:11]([C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])[O:12][C:13]3=[N:14][C:15]=2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N1CCCC1=O
Temperature: 60 °C

Procedure:
To a magnetically stirred suspension of 7 mg (0.173 mmol) of sodium hydride in 1 mL THF was slowly added 0.100 g (0.173 mmol) of the product of Example 47 dissolved in 1 mL of THF. After 15 min the addition was complete and the reaction mixture was stirred and heated to 60° C. for 3.5 h. The reaction was then cooled to room temperature, and partitioned between saturated aq. NaHCO3 and EtOAc. The organic product was extracted into EtOAc, separated, dried (Na2SO4) filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 541.0 (M+1), 542.9 (M+3); Rt=4.60 min.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[CH:10][C:11]3[C:16]([C:7]2=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1/[CH:23]=[CH:24]/[C:25](OCC)=[O:26])=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH:1]([C:4]1[N:8]2[N:9]=[CH:10][C:11]3[C:16]([C:7]2=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[CH2:23]/[CH:24]=[CH:25]/[OH:26])=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1c(C/C=C/O)c(-c2ccccc2)c2c3ccccc3cnn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
A stirred solution of ethyl (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)propenoate (0.86 g) in dry tetrahydrofuran (25 ml) at 0° C. under an atmosphere of argon was treated dropwise with a solution of diisobutyl aluminium hydride in tetrahydrofuran (1M; 6.7 ml). The reaction mixture was stirred at 0° C. for 1 hour and then it was quenched by dropwise treatment with saturated aqueous sodium sulphate solution (25 ml). The resulting mixture was partitioned between water (100 ml) and diethyl ether (100 ml), and the organic layer was separated. The aqueous layer was extracted with diethyl ether (2×100 ml) and the combined organic layers were dried over magnesium sulphate and evaporated, to give (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)propen-1-ol (0.96 g), in the form of a yellow oil. [NMR (in a mixture of CDCl3 and D2O ): 1.54 (6H, d, J=7 Hz), 3.82 (1H, septet, J=7 Hz), 4.15 (2H, dd, J=7 Hz, 1 Hz), 5.55 (1H, dt, J=16 Hz, 7 Hz), 6.62 (1H, dt, J=16 Hz, 1 Hz), 7.21-7.32 (3H, m), 7.35-7.62 (6H, m), 8.23 (1H, s)].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH2:31])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OC)cc3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 1.33 mmol) was reacted with the product from Example 50b (326 mg, 1.33 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (392 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.85 (m, 2H) 2.34 (s, 3H) 3.00 (t, J=7.54 Hz, 2H) 3.72 (s, 3H) 6.27 (d, J=6.99 Hz, 1H) 6.84 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.27 (m, 4H) 7.83 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 9.02 (d, J=8.46 Hz, 1H) 11.06 (br. s., 1H) 14.37 (br. s., 1H); MS (ESI+) m/z 416 (M+H)+.