Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.Cl.[CH3:18][NH:19][O:20][CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7]([N:19]([O:20][CH3:21])[CH3:18])=[O:8]
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)sc1Cl
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a stirred solution of 2,5-dichloro-3-thiophenecarbonylchloride (1.08 g, 5.0 mmol) and pyridine (2 mL) in CH2Cl2 (10 mL) was added N,O-dimethylhydroxylamine hydrochloride (490 mg, 5.0 mmol) at room temperature, and the mixture was stirred for 18 hours. CH2Cl2 (10 mL) was added to the mixture. The combined organic layers were washed with 1N HCl solution, saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo to give light yellow oil (1.09 g, 91% yield). The compound was used for next reaction without purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH2:3][CH3:4].[C:10]1(=O)[O:14][CH2:13][CH2:12][CH2:11]1>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][C:13]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCCO1
Reactant: CCCCOCCCN
Product: CCCCOCCCN1CCCC1=O
Temperature: 275 °C

Procedure:
360 grams of butoxypropylamine (2.75 moles) and 250 grams of butyrolactone (3.0 moles) were charged to a 1-liter stainless steel autoclave. After purging, the mixture was heated to 275° C. for six hours. The reactor was then cooled and the product discharged. The product was distilled with a simple Vigreux column, initially at atmospheric pressure to remove by-product water and then under vacuum (<1 mm) to recover the product. Butoxypropyl Pyrrolidone distills at about 135° C. to 145° C. under these conditions. The recovery was 391.2 grams of>98% pure Butoxypropyl Pyrrolidone.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.CCCCCC>[NH2:4][C:3]1[C:19]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([CH3:21])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CC(N)c1ccccc1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1

Procedure:
Starting from 2-amino-2-phenylacetonitrile and benzoylacetone, the open-chain intermediate compound is obtained, melting at 134°-135° C. (from diethyl ether/hexane). The title compound is obtained in a 60% overall yield. M.P. 285°-290° C. (from methanol/diethyl ether). The free base melts at 203°-5° C. (from methanol).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[CH2:18]([C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.C1(C)C=CC=CC=1>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([N:17]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:31]3)[C:5]=2[CH:4]=1
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 67.9 %

Procedure:
Heat a suspension of 2-methyl-4H-3-thia4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride (466 mg, 1.75 mmol) and 2-(S)-phenethyl-piperazine (1.0 g, 5.3 mmol) in DMSO (2.5 mL) and toluene (10 mL) at reflux for 48 hours. Evaporate the toluene under vacuo and pour the resulting solution into water (10 mL). Purify the resulting brown solid by flash chromatography eluting with methylene chloride/methanol (95:5) to give 2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene as a yellow solid (478 mg, 65%): mp 75–84° C.; 1H NMR(CDCl3): δ1.76 (m, 2H), 2.31 (s, 3H), 2.60 (dd, 1H), 2.71 (m, 2H), 2.80 (m, 1H), 2.92 (m, 2H), 3.04 (m, 1H), 3.96 (m, 1H), 4.12 (m, 1H), 4.91 (s, 1H), 6.29 (s, 1H), 6.60 (d, 1H), 6.89 (t, 1H), 6.96 (t, 1H), 7.03 (d, 1H), 7.15–7.30 (m, 5H); MS (APCI) m/z (rel intensity) 403 (100).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:19]2[CH2:20][CH2:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(N2CCC(c3ccccc3)CC2)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (4 g, 14.605 mmol), 4-phenylpiperidine (3.532 g, 21.907 mmol) and DIPEA (5.088 ml, 29.209 mmol) in CH3CN (150 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution). The resulting mixture was extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH/EtOAc gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D14 (2.32 g, 52%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.O1CCOCC1>[ClH:27].[ClH:27].[N:11]1([C:15]2[CH:16]=[C:17]([CH2:25][CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cc(N2CCCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(6-Ethylquinolin-8-yl)[1,4]-diazepan-1-carboxylic acid tert-butyl ester (1.0 g, 1.0 equiv) was dissolved in MeOH (5 mL) and 1.0 M HCl in 1,4-dioxane (10 mL) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was concentrated to dryness to afford the title compound (1.0 g). MS (ES) m/z 256.1 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:26][CH2:25][CH2:24][C@@H:20]1[C:21]([OH:23])=[O:22]>CN(C)C(=O)C.O.[Cu]I>[CH2:8]([O:7][C:5]([C:4]1[CH:3]=[C:2]([N:19]2[CH2:26][CH2:25][CH2:24][C@@H:20]2[C:21]([OH:23])=[O:22])[CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: O=C(O)[C@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)O)c1
Temperature: 25 °C
Yield: 19.2 %

Procedure:
Add ethyl 3-iodobenzoate (1.5 mL, 8.9 mmol), potassium carbonate (1.3 g, 9.4 mmol) and copper (I) iodide (0.17 g, 0.89 mmol) to a solution of D-proline (1.00 g, 8.69 mmol) in N,N-dimethylacetamide (20 mL). Bubble Argon through the mixture for 30 min then heat the reaction to 90° C. for 15 hours. Cool the mixture to room temperature, dilute with water, and filter to remove insoluble material. Wash the filtrate with diethyl ether and adjust the pH of the aqueous phase to slightly acidic by the addition of a 2 N solution of hydrochloric acid. Extract the mixture with methylene chloride and wash the combined organic phase with brine. Dry over anhydrous sodium sulfate and concentrate under reduced pressure to provide an oil. Re-dissolve the material in methylene chloride and concentrate under a stream of nitrogen to provide 0.44 g (19.2%) of (R)-1-(3-ethoxycarbonyl-phenyl)-pyrrolidine-2-carboxylic acid as an oil.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[SH:64][C:65]1[N:70]([CH3:71])[C:69](=[O:72])[C:68]([OH:73])=[N:67][N:66]=1.O>CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:64][C:65]4[N:70]([CH3:71])[C:69](=[O:72])[C:68]([OH:73])=[N:67][N:66]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cn1c(S)nnc(O)c1=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC(F)F)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)nnc(O)c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
To a mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (1.5 g) and sodium iodide (769 mg) in N,N-dimethylformamide was added 3-mercapto-4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine (816 mg). After being stirred for 45 minutes at room temperature, the reaction mixture was poured into water. The resulting precipitates were collected by filtration and dissolved in ethyl acetate. The solution was washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried and evaporated under reduced pressure. The residue was triturated in diisopropyl ether and collected by filtration to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.25 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][CH:13]=1.[C:26](#N)C.O>>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][O:11][C:12]1[N:16]([C:17]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][N:18]=2)[N:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)c(F)c1F
Reactant: CC#N
Solvent: O
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)c(F)c2F)c1

Procedure:
The title compound was prepared from 2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 94) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 2.31 (3H, s), 3.96 (3H, s), 5.27 (2H, s), 5.80 (1H, d, J=6.4 Hz), 6.94-6.97 (1H, m), 7.13-7.17 (1H, m), 7.58 (1H, s), 7.76 (1H, d, J=4.0 Hz), 8.30 (1H, s), 8.69 (1H, d, J=2.4 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.485 min. [M+H] Calc'd for C18H15F2N3O3, 360; Found, 360.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].F[C:10]1[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][CH:2]1[N:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:15]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: CC1NCCNC1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(=O)NCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 140 °C
Yield: 24.5 %

Procedure:
A mixture of 3-methyl-2-ketopiperazine (200 mg, 1.75 mmol), 5-fluoro-2-nitrobenzo-trifluoride (366 mg, 1.75 mmol), N,N-diisopropylethylamine and N,N-dimethylformamide (1 mL) was heated at 140° C. for 10 min under microwave irradiation, then partitioned between sat. aq. ammonium chloride solution and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 4:1) produced the title compound (130 mg, 24%). Yellow solid, MS: 304.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][C@H:13]2[C:31](O)=[O:32])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:61][O:62][C:63]1[CH:74]=[CH:73][CH:72]=[CH:71][C:64]=1[CH2:65][N:66]([CH3:70])[CH2:67][CH2:68][NH2:69]>>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][C@H:13]2[C:31]([NH:69][CH2:68][CH2:67][N:66]([CH3:70])[CH2:65][C:64]2[CH:71]=[CH:72][CH:73]=[CH:74][C:63]=2[O:62][CH3:61])=[O:32])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccccc1CN(C)CCN
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cc(Cl)cc(Cl)c2)[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cc(Cl)cc(Cl)c2)[C@H](C(=O)NCCN(C)Cc2ccccc2OC)C1
Yield: 89.5 %

Procedure:
According to the procedure of Example 1, Step E above, 46 mg (0.080 mmole) of (S)-1-[N-(3,5-dichlorophenyl)-N-phenylcarbamoyl]-4-(N,N-di-n-pentylcarbamoyl)piperazine-2-carboxylic acid, 12 mg (0.088 mole) of HOBt, 21 mg (0.112 mmole) of EDAC, and 31 mg (0.16 mmole) of N-(2-methoxybenzyl)-N-methylethylenediamine (from Example 1, Step E b) above) after purification by flash chromatography on 16 g of silica gel eluting with 100:5:CH2Cl2 :methanol: provided 54 mg (90%) of an oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[CH:21][C:16]=3[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]2=[O:31])=[C:10]([O:34][CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:46]=2N=N1.CCN(C(C)C)C(C)C.C(N)(CC)(C)C>C(Cl)Cl>[CH:25]1([N:15]2[C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=3[N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH2:3][CH3:46])=[CH:9][C:10]=3[O:34][CH3:35])[C:14]2=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)C)cc1OC
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CCC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 0.9 g of the compound obtained in Example 15 Step B, 0.9 g of BOP and 1 ml of DIPEA in 20 ml of DCM is added 1 g of tert-amylamine, and the mixture is left stirring for 3 hours at RT. The reaction mixture is washed with 1N HCl solution, with 1N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with DCM. 0.34 g of the expected product is obtained, mp=164° C.
Reaction SMILES: N(CCC1C=CC(F)=CC=1)=[N+]=[N-].[CH2:13]([N:20]=[N+:21]=[N-:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38]#[CH:39])=[N:35][C:34]=1[CH3:40])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([C:38]2[N:22]=[N:21][N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:39]=2)=[N:35][C:34]=1[CH3:40])=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C#Cc1nc(C)c(C(=O)NCc2ccccc2)s1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [N-]=[N+]=NCCc1ccc(F)cc1
Product: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 40 %

Procedure:
Following the procedure as described in Example 1, making variations as necessary to replace 1-(2-azidoethyl)-4-fluorobenzene with benzylazide to react with N-benzyl-2-ethynyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 40% yield: mp 108-109° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.49-7.18 (m, 10H), 6.35 (t, J=5.3 Hz, 1H), 5.51 (s, 2H), 4.56 (d, J=5.3 Hz, 2H), 2.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 157.9, 156.6, 142.9, 137.8, 133.7, 129.3, 129.1, 128.8, 128.5, 127.8, 127.7, 124.8, 121.5, 54.6, 44.2, 17.2; MS (ES+) m/z 390.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:42](Cl)([CH3:44])=[O:43]>C(Cl)Cl>[C:42]([O:1][CH2:2][C:3]1[C:11]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][C:9]2[N:8]3[CH2:16][CH2:17][N:18]([C:23]4[N:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[C:26]([C:33](=[O:35])[CH3:34])=[CH:25][N:24]=4)[CH:19]([CH:20]([CH3:22])[CH3:21])[C:7]3=[CH:6][C:5]=2[CH:4]=1)(=[O:43])[CH3:44]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2cc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(C)=O)c(C(F)(F)F)n1)C3C(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (132 mg, 0.26 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL) and AcCl (130 μL, 1.3 mmol). The mixture was stirred at rt for 10 h. The reaction was quenched with water (5 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (1/1) to give (2-(5-acetyl-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methyl acetate. LC-MS m/z 553 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=[O:8].[C:15](Cl)(Cl)=[O:16]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:14][C:15](=[O:16])[O:9][C:7](=[O:8])[C:6]2=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a mixture of 10.0 g (51.0 mmol) of 4,5-dimethoxyanthranilic acid in 80 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.0 g (97.2%) of the 4,5-dimethoxyisatoic anhydride as a gray solid. MS (Cl mode) m/z 206 (M-18, 100%), 224 (M+H, 51%).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)C.[BH4-].[Na+]>O>[I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)/C=C/I
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)/C=C/I
Reaction time: 2 h

Procedure:
A solution of 78.2 g (0.310 moles) of 1-iodo-trans-1-octen-3-one (Example 724) in 150 ml. of absolute ethanol is added dropwise over 2 hours to a slurry of 6.49 g. (0.172 moles) of sodium borohydride in 50 ml. of absolute ethanol cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours with ice cooling and is then poured into 1 1. of water. The mixture is extracted into benzene and the organic phase is washed with saturated brine, dried (Na2SO4) and evaporated. The resulting oil is dissolved into 400 ml. of absolute ethanol and treated with 5 mole percent of p-carboxyphenylhydrazine at 70° C. for 1.5 hours to remove residual ketone. The mixture is cooled and evaporated and the residue is dissolved into 400 ml. of ether and is filtered. The filtrate is washed with dilute sodium bicarbonate solution and saturated brine, dried (Na2SO4), and evaporated to an oil. This oil is chromatographyed upon 2 Kg. of Florisil® packed in hexane and the product is obtained upon elution with benzene Distillation of the product yields a colorless oil, b.p. 74°-76° C. (0.005 tor.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:22][CH:21]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: OB(O)c1ccc(-c2ccccc2)nc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
2-Iodo-1-nitrobenzene (6.88 g, 27.64 mmol), 6-phenyl-3-pyridinylboronic acid (5.5 g, 27.64 mmol), potassium phosphate (17.6 g, 82.91 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.451 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.55 mmol) were to toluene (150 mL) and water (12 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 5.02 g of the title compound.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][N:4]2[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[N:2]1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+].[NH4+]>CCOCC>[C:12]1([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:3]2[N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][N:2]=2)[OH:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C1=NCC2CCCCN12)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(C1=NCC2CCCCN12)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The oil from Example 2 was dissolved in dried ether (25 ml.) and immediately added to phenylmagnesium bromide (prepared from 1.23g. magnesium and 8.00g. bromobenzene) in 150ml. dried ether. The mixture was stirred at room temperature for 16 hours. It was then poured on to a mixture of ammonium chloride (2.7g.) and ice and basified with ammonium solution. The solid remaining in the mixture was removed by filtration, and the ether layer was combined with chloroform extracts of the aqueous layer, dried over magnesium sulphate and evaporated to a residue. This residue and that from chloroform washings of the solid remaining after the Grignard reaction was crystallised from ethanol to give the title compound (0.56g.), m.p. 131°-3°C.