Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH3:15][N:16]1[C:29]2[CH:28]=[C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:26]=[CH:25][C:24]=2[S:23](=[O:37])(=[O:36])[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2.I[CH2:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O1CCCC1>[CH3:15][N:16]1[C:29]2[CH:28]=[C:27]([CH:30]([CH2:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:26]=[CH:25][C:24]=2[S:23](=[O:36])(=[O:37])[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Reactant: ICC1CCOCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCOCC1)c1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.66 ml of 1,1,1,3,3,3-hexamethyldisilazane are dissolved in 20 ml of tetrahydrofuran. With ice cooling, 2.90 ml of n-butyllithium (2.5 M in n-hexane) are added dropwise, and the mixture is stirred at 0° C. for another 30 minutes. At −78° C., this solution is then added dropwise to a stirred solution of 2.0 g of ethyl (10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acetate in 100 ml of tetrahydrofuran. The reaction mixture is stirred at −78° C. for 20 minutes, and 2.0 g of 4-(iodomethyl)tetrahydro-2H-pyran are then added dropwise. The cooling bath is removed and the mixture is allowed to slowly warm to room temperature. The reaction mixture is stirred at room temperature overnight. 10 ml of water are then added, the tetrahydrofuran is removed under reduced pressure and the residue is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate (100%:0%)=>n-heptane:ethyl acetate (0%:100%). This gives 2.0 g of ethyl 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionate as a colorless solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CC(C)=O>[CH2:17]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1)[CH:16]=[CH2:15]
Reactant: Oc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=CCOc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reaction time: 72 h

Procedure:
10.6 g of trans-4-(4-hydroxycyclohexyl)phenol (55.13 mmol, 14 eq.) are dissolved in 150 mL of a 2/1 mixture of DMF and acetone, to which are added with stirring 4.8 mL of allyl bromide (55.13 mmol, 14 eq.), followed by 11.43 g (82.7, 1.5 eq.) of potassium carbonate. After 3 days, the reaction medium is poured into 300 mL of water, filtered, washed with water and dried to give 12.6 g of trans-4-(4-allyloxyphenyl)cyclohexanol.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.[C:13](=[O:15])=[O:14]>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:13]([OH:15])=[O:14])=[CH:5][CH:6]=1
Reactant: O=C=O
Reactant: Brc1ccc(Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
THF (50 mL) was added via cannula to a flame-dried 100 mL Schlenk flask. 2,5-dibromothiophene (10 mmol, 2.42 g) was added via syringe. Reaction vessel was cooled to −78° C. and n-butyllithium (1.61M solution in hexanes, 11 mmol, 6.8 mL) was added dropwise over 5 minutes. The solution was allowed to stir at −78° C. for 1 hr. Dry ice (approx. 50 g) was added to the reaction mixture, and was allowed to stir and return to room temperature for 18 hrs. under nitrogen. The light gray suspension was filtered and the white solid was stirred in 2M HCl for 1 hr. The suspension was filtered to yield a white solid (5.7 mmol, 1.2 g, 57%). 1H NMR (400 MHz, CDCl3) δ: 11.45 (br s, 1H), 7.64 (d, 1H, J=4.0 Hz), 7.11 (dd, 1H, J=4.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Cl)[CH:20]=1.CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: ClCc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCc3cccnc3)c12
Yield: 90 %

Procedure:
To a round bottom flask with stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), 3-picolyl chloride (1.1 equiv.) potassium carbonate (5 equiv.) and 10 mL DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of solvent afforded 3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carboxylic acid t-butyl ester as a thick oil in 90% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2)[CH3:2].[F:13][C@@H:14]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@H:15]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[OH-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:13][C@@H:14]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][OH:21])[O:16][C@H:15]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2]
Reactant: CCOc1ncnc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Temperature: 37 °C

Procedure:
6-Ethoxypurine (Sigma Chemical Company; 0.2 g, 1.2 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.4 g, 1.6 mmoles) which may be prepared according to J. F. Codington et al. (J. Org. Chem. 29:558, 1964) were suspended in 20 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. The pH of the suspension was adjusted to 7.0 with KOH and thymidine phosphorylase (2,000 I.U.) and purine nucleoside phosphorylase (5,540 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) were added and the suspension stirred at 37° C. On day 5, and additional 2,000 I.U. thymidine phosphorylase and 2,770 I.U. of purine nucleoside phosphorylase were added. On day 9, 0.2 g 6-ethoxypurine was added. The pH of the reaction was adjusted to 7.0 with KOH and 2,000 I.U. thymidine phosphorylase and 5,540 I.U. purine nucleoside phosphorylase were added. On day 28, the suspension was filtered. The filtrate was applied to a 2.5×8.5 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing with water, the product was eluted with methanol/water (3/7). Product containing fractions were combined and the solvent removed under vacuum. The product contained in the residue was further purified by chromatography on a 2.5×90 cm column of Biogel P-2 (Bio-Rad) with water/methanol (8/2) as the solvent followed by chromatography on a 2.5×50 cm silica gel column with acetonitrile/water (49/1) as the solvent. Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound which analyzed as a 0.5 hydrate.
Reaction SMILES: C([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15](C)[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.O[C:25]1C=CC(C#N)=C(C)C=1>>[OH:12][CH2:11][C:10]([NH:9][CH2:8][C@H:7]([OH:14])[CH2:6][O:5][C:4]1[CH:3]=[CH:18][C:17]([C:19](=[NH:22])[NH:20][OH:21])=[C:16]([CH3:25])[CH:15]=1)=[O:13]
Reactant: Cc1cc(O)ccc1C#N
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: Cc1cc(OC[C@@H](O)CNC(=O)CO)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (1.0 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 4-hydroxy-2-methyl-benzonitrile. LC-MS: tR=0.35 min, [M+H]+=297.99.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 5 h
Yield: 85 %

Procedure:
tert-Butyl 4-hydroxymethylpiperidine-1-carboxylate (prepared by referring to Japanese Patent Unexamined Publication No. 11-217377, 12.12 g, 56.30 mmol) was dissolved in dichloromethane (26 ml), and the solution was added with p-toluenesulfonyl chloride (10.73 g, 56.30 mmol) and triethylamine (8.63 mmol, 61.9 mmol) at room temperature, and then stirred at the same temperature for 5 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water and saturated brine, and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The residue was recrystallized from hexane (100 ml) to obtain the title compound as colorless solid (14.13 g, yield: 85%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (88 mg, 76%), MS (ISP) m/z=387.4 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and propionic acid.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][CH:12]=[C:11]2[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>C(O)(=O)C>[C:26]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH3:6])=[C:16]([Cl:17])[CH:15]=2)[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:12]1)(=[O:28])[CH3:27]
Reactant: COc1cc2c(CCNC(C)=O)c[nH]c2cc1Cl
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2c(CCNC(C)=O)cn(C(C)=O)c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To 30 ml. of N,N-dimethylformamide were added 210.7 mg. (0.79 mmole) of N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide (prepared as in Example 1) followed by 20.8 mg. of sodium hydride. The resulting mixture was stirred at room temperature for about one hour, and 68.2 mg. (0.06 ml.) of acetyl chloride were added. The mixture was stirred for an additional hour and then was poured into ice water containing a small amount of acetic acid. The resulting mixture was extracted with chloroform, and the extract was washed twice with saturation aqueous sodium chloride solution. The chloroform extract was dried over sodium sulfate and was concentrated in a rotary evaporator. The residue was recrystallized from benzene-ether and was vacuum-dried to obtain 108 mg. (40.8%) of the title compound, m.p. 178°-181° C.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].Br[CH2:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1>C(O)C>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:8][C:9]1[CH:13]=[CH:12][S:11][N:10]=1
Reactant: NCCS
Reactant: BrCc1ccsn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1ccsn1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g) to sodium (0.83 g) dissolved in ethanol (50 ml) with stirring at 0° under a nitrogen atmosphere. After stirring for 2 hours at 0° 3-bromomethylisothiazole (3.2 g) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, dried and concentrated to yield the amine base as an oil (1.56 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.Cl>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][C:11]=4[F:27])=[C:22]([CH2:23][CH2:24][CH3:25])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 22 h
Yield: 83.7 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (408 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (125 g) were dissolved in N,N-diethylaniline (1.5 L) at 160° C. (internal temperature). A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (38 mL) in N,N-diethylaniline (400 mL) was added dropwise over 30 min, and the mixture was stirred at 180° C. (internal temperature) for 22 hr. The reaction mixture was cooled to room temperature, and ethyl acetate (1 L) and 3M hydrochloric acid (1 L) were added. The mixture was transferred into a separatory funnel with ethyl acetate (2 L) and 3M hydrochlorid acid (1 L). The organic layer was successively washed with 3M hydrochloric acid (2 L) twice and brine (2 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound as a brown solid (246 g, 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: O=C1Cc2cccc(Br)c2N1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Cc2cccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)c2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.3 %

Procedure:
7-bromoindolin-2-one (25.4 mg, 0.120 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (89.5 mg, 0.236 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.4 mg), and K2CO3 (2 M in water, 0.34 ml, 0.68 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.2 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (20 ml, 5 ml, 2×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA). The fractions with product were purified on silica gel (3:2 hexanes/EtOAc->EtOAc->4:1 EtOAc/MeOH) to afford title compound (11.2 mg, 24%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: CC(C)C(NC1C=CC=C(C2CCNCC2)C=1)=O.Cl.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH:34]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCOCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1

Procedure:
4-(4-Nitrophenyl)-1,2,3,6-tetrahydropyridine was prepared by a similar procedure to that used for the preparation of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide using HCl gas and tert-Butyl 4-(4-Nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room temperature. The reaction mixture was concentrated in vacuo to give the crude product (69.8 mg) which used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:37][O:38][C:39](=[O:44])[C@H:40]([CH2:42][OH:43])[NH2:41].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:41][C@@H:40]([CH2:42][OH:43])[C:39]([O:38][CH3:37])=[O:44])=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 21 h
Yield: 73.6 %

Procedure:
A suspension of 14.1 g (0.0484 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 150 ml of dimethylformamide was treated portionwise with 8.24 g (0.0508 mol). of carbonyidiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 65° for 3 hrs. After cooling to 0-5° the white suspension obtained was treated with 8.28 g (0.0532 mol) of L-serine methyl ester hydrochloride and with 7.452 ml (0.0532 mol) of triethylamine and stirred at room temperature for 21 hrs. The white suspension was suction filtered and the filtrate was completely freed from the solvents. The orange oily residue was partitioned between ethyl acetate and water, extracted, chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent and recrystallized from hot ethyl acetate; the mother liquor was then digested with diethyl ether. There were obtained a total of 14.0 g (74%) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-ylcarbonylamino)-3-hydroxy-propionate as white crystals; m.p. 178-180°. [α]D20 =+1.2° (CH2Cl2, c=1%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:20]=1.I[CH3:22].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:20]=1
Reactant: CC1CN(c2ccccc2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(c2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To an ice cooled mixture of 0.46 g (0.0016 mole) of (rac)-2-chloro-7-methyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-51), 0.15 mL (0.00239 mole) of iodomethane and 10 mL of dimethylformamide was added 0.10 g (0.00239 mole) of a 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours, and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (100:0-60:40) to give 0.30 g of (rac)-2-chloro-5,7-dimethyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-51) as white powder. HRMS (ES+) m/z Calcd for C15H15CLN4O+H [(M+H)+]: 303.1007. Found: 303.1006.
Reaction SMILES: [Br-].[O:2]=[C:3]1[N:8]2[CH:9]=[N+:10]([CH2:12][CH2:13][CH3:14])[CH:11]=[C:7]2[CH2:6][CH2:5][NH:4]1.[F:15][C:16]1[CH:17]=[C:18]([C:26]2[S:30][C:29]([NH2:31])=[N:28][C:27]=2[CH3:32])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:24])=[O:23].CCN(CC)CC>CCOC(C)=O>[F:15][C:16]1[CH:17]=[C:18]([C:26]2[S:30][C:29]([NH:31][C:3]([NH:4][CH2:5][CH2:6][C:7]3[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH3:14])[CH:11]=3)=[O:2])=[N:28][C:27]=2[CH3:32])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: CCC[n+]1cc2n(c1)C(=O)NCC2
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCn1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(F)c3)s2)c1
Temperature: 120 °C
Yield: 23.4 %

Procedure:
A stirred mixture of 5-oxo-2-propyl-5,6,7,8-tetrahydro-imidazo[1,5-c]pyrimidin-2-ium bromide (Intermediate DA) (0.214 g, 0.83 mmol) and 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Intermediate AA) (0.15 g, 0.55 mmol) and Et3N (0.48 ml, 3.3 mmol) is heated at 120° C. for 2 days. After cooling to room temperature the mixture is diluted with EtOAc (50 ml) and washed water followed by brine. The organic extract is dried (MgSO4) and the solvent is removed to give a solid. Purification by chromatography oh silica eluting with DCM:MeOH (95:5) affords the titled compound (0.06 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.I[CH3:21]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:21])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)c1nc(Cl)ccc1[N+](=O)[O-]
Yield: 65 %

Procedure:
In accordance with the same procedures as in Step 2 of Preparation 4, except for using (6-chloro-3-nitropyridin-2-yl)-(4-fluorobenzyl)-amine prepared in Step 1 and iodomethane, the titled compound was obtained as yellow solid. (Yield: 65%)