Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[C:23]2[C:24]([O:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:30][O:29][C:24]1[C:23]([C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ncccc1-c1[nH]c2ccccc2c1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ncccc1-c1[nH]c2ccccc2c1C1CCNCC1
Temperature: 60 °C
Yield: 136 %

Procedure:
3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-(2-methoxy-pyridin-3-yl)-1H-indole (0.53 g, 1.34 mmol), 10% Pd/C (50 mg), and ammonium formate (0.85 g, 13.4 mmol) were combined in methanol (100 ml) and heated at 60° C. for 2 h. The reaction was cooled, filtered through celite, and the filter cake washed with methanol. The solvent was removed under reduced pressure to give the desired product as a yellow foamy solid (0.56 g, qunatitative) which could be used in the next reaction without any further purification or purified by reverse phase chromatography. M.p.=110-115° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.11 (s, 1H, indole-NH), 8.58 (brs, 1H, NHHCl), 8.48 (brs, 1H, NHHCl), 8.26 (dd, J1=2.0 Hz, J2=4.8 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.75 (dd, J1=2.0 Hz, J2=7.6 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.14 (dd, J1=5.2 Hz, J2=7.6 Hz, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 3.94 (s, 3H), 3.37 (m, 2H), 2.96 (m, 2H), 2.83 (m, 1H), 2.34 (m, 2H), 1.82 (m, 2H); LCMS: 308.65 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12](/[C:13](/Cl)=[N:14]\[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[C:27]#[CH:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[CH:28]=[C:27]([C:26]([O:30][CH2:31][CH3:32])=[O:29])[O:15][N:14]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O/N=C(/Cl)c1ccc(OCc2ccccc2)cc1
Reactant: C#CC(=O)OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Temperature: 80 °C

Procedure:
To (E)-4-(benzyloxy)-N-hydroxybenzimidoyl chloride (7.8 g) in Toluene (78 ml), Ethyl propiolate (7.25 ml) was added and stirred. To this, Et3N (4.58 ml) was added dropwise since reaction was exothermic and the reaction mixture was then heated to 80° C. for 2 hours. The reaction mixture was cooled, diluted with Ethyl acetate and washed successively with 0.1M Aqueous HCl, water and brine. Organic layer was collected and concentrated to obtain dark brown residue which was purified by column chromatography (silica gel, DCM) to obtain pale brown solid which was crystallized from DCM-Petroleum ether to obtain the title compound as off white solid. Yield: 2.83 g (29%); MS (ES+): m/z 324 (M+1); 1HNMR (CDCl3; 300 MHz): δ 7.8 (d, 2H), 7.36-7.47 (m, 5H), 7.28 (s, 1H), 7.1 (d, 2H), 5.14 (s, 2H), 4.48 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:15]#[N:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:25])[CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C
Temperature: 85 °C
Yield: 107.2 %

Procedure:
A solution of (E)-ethyl 3-(4-bromophenyl)-2-cyanoacrylate (59.4 g, 212 mmol) in toluene (420 mL) was added over 80 min at 0-5° C. to o-tolylmagnesium chloride solution (1 M in tetrahydrofuran, 276 mL, 276 mmol). The reaction mixture was heated at 85° C. for 1½ h, then poured upon ice water and partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (84.6 g), which was directly used in the next step. Light yellow oil, MS: 370.0 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=O>[Cl-].[Cl-].[Zn+2].C(OC(=O)C)(=O)C>[C:13]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][C:20](=[O:21])[CH3:19])/[CH:16]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2)(=[O:12])[CH3:14]
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(/C=C2\CCCc3cc(C)cnc32)cc1OC(C)=O

Procedure:
A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 ml), 3,4-dihydroxybenzaldehyde (20 g) and acetic anhydride (50 ml) was heated at 100° for 48 hours. Further acetic anhydride (50 ml) and ZnCl2 (1 g) were added and the mixture was heated at reflux for 16 hours. The solvent was removed by evaporation, the residue was neutralised (Na2CO3) in the presence of ethyl acetate and extracted with ethyl acetate. The ethyl acetate solution was extracted with 2N HCl and this extract was washed with ethyl acetate, basified (Na2CO3) and extracted with Et2O. The ether solution was dried (MgSO4) and evaporated and the residue triturated with hexane and recrystallised from di-isopropyl ether to give the title compound (22 g) m.p. 100°-1° C.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1>[C-:2]#[C-:3].[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCBr
Agent: C#CCCCCCCCC
Agent: [Mg]
Solvent: C1CCOC1
Product: [C-]#[C-]

Procedure:
19.35 g of magnesium (0.79 gramme-atom) and then 750 cm3 of anhydrous tetrahydrofuran (THF) are placed in a 2-liter round-bottomed flask equipped with a stirrer and an argon inlet. 90.25 g of ethyl bromide (1.15 equivalent) are then introduced dropwise so as to maintain the THF refluxing. When the addition is complete, this refluxing is maintained until the magnesium has been completely converted. 100 g of 1-decyne (0.72 mol) are then added dropwise at this temperature in the course of approximately half an hour, and the mixture is maintained refluxing for a further hour and a half after the addition is complete. 5.20 g of cuprous cyanide are then introduced and boiling is maintained for a further hour. To the 1-decyne acetylide thereby formed, 250 g of 1,4-dichloro-2-butyne, or 2.8 equivalents with respect to the decyne, are added at a temperature maintained at between 40° and 50° C. Boiling is maintained for 5 hours. The solvent is removed in a rotary evaporator. The oily mass obtained is cooled and stirred in the presence of 350 cm3 of water saturated with ammonium chloride, and then extracted 3 times with ether. The ether phase is washed twice with water, dried over magnesium sulphate and then concentrated at normal pressure, and the remaining ether is then removed under a pressure of 26.6×102Pa. The crude 1-chloro-2,5-tetradecadiyne is distilled at a temperature of between 118° C. and 125° C. under 2.6 Pa. In the final fractions at between 125° C. and 130° C. under 4 Pa, the remainder of the expected product is distilled mixed with 1-bromo-2,5-tetradecadiyne, which forms during the reaction by exchange of chlorine with bromine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](F)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:32]1[C:33](CC(C2SC=CC=2)=O)=[C:34]([CH:38]=[CH:39][C:40]=1F)[C:35](Cl)=[O:36]>>[CH2:15]1[C:26]2[C:27](=[CH:28][CH:29]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]6[CH:33]=[CH:32][CH:40]=[CH:39][CH:38]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:25]=2)[CH2:12][CH2:11][NH:10]1
Reactant: O=C(Cc1c(C(=O)Cl)ccc(F)c1Br)c1cccs1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared in a manner analogous to Example 66, using 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 3-bromofluoro-2-thiophenecarbonylmethylbenzoyl chloride. HRMS: calc. C28H19N6OSFBr calcd for C31H22F2N6O: 532.1823, found: 533.1921 (M+H)+ 585.0508 found 585.0515+).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[S:6][C@@H:5]2[C@H:7]([N:10]3C(C)(C)[NH:14][C@H:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]3=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:24]([OH:26])=[O:25].CC(C)=[O:30]>>[CH3:27][C:2]1([CH3:1])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:14])[C:18]3[CH:23]=[CH:22][C:21]([OH:30])=[CH:20][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:24]([OH:26])=[O:25]
Reactant: CC(C)=O
Reactant: CC1(C)S[C@@H]2[C@H](N3C(=O)[C@@H](c4ccccc4)NC3(C)C)C(=O)N2[C@H]1C(=O)O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O

Procedure:
The procedure of Example 1 was repeated with the substitution for the hetacillin therein of an equimolar weight of heta-amoxicillin (also called p-hydroxyhetacillin or the acetone adduct of amoxicillin) to produce the title compound. The product appeared by NMR to be 85-90% pure with respect to the acetone adduct group.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[C:11]=3[CH3:18])[S:9][C:5]=2[CH:4]=1.[B]>>[OH:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=3[CH3:18])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3cccc(OC)c3C)sc2c1
Agent: [B]
Product: Cc1c(O)cccc1-c1nc2ccc(O)cc2s1
Yield: 90.2 %

Procedure:
6-Methoxy-2-(2-methyl-3-methoxy-phenyl)-benzothiazole (64 mg, 0.224 mmol) was treated with boron tribroride under standard condition to give 6-hydroxy-2-(2-methyl-3-hydroxy-phenyl)-benzothiazole (52 mg, 90% yield) as a yellow solid. Mass spec: MH+=258.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[CH:10]([CH2:18][CH3:19])[CH2:9]1)(=[O:6])=[O:5])[CH3:2].[OH-].[Na+]>>[CH2:20]([N:3]([CH2:1][CH3:2])[S:4]([CH2:7][CH:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH:10]([CH2:18][CH3:19])[CH2:9]1)(=[O:6])=[O:5])[CH3:21]
Reactant: CCOC(=O)C1CC(CS(=O)(=O)N(CC)CC)CC1CC
Agent: [Na+]
Agent: [OH-]
Product: CCC1CC(CS(=O)(=O)N(CC)CC)CC1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
A mixture of ethyl 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate (0.570 g, 1.784 mmol) in NaOH (1 N aqueous, 10 mL, 10 mmol) was stirred at ambient temperature for about 72 h. The mixture was partitioned with DCM (10 mL). The aqueous phase was acidified to about pH=4 by addition of 6 N aqueous HCl. The solution was partitioned with DCM (10 mL). The aqueous phase was washed with DCM (2×10 mL). The organic layers were combined, dried over anhydrous MgSO4, and concd under reduced pressure to give 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylic acid (0.375 g, 72%) as yellow oil: LC/MS (Table 1, Method b) Rt=1.95 min; MS m/z: 292 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[C:17]([C:21]1[O:25][N:24]=[C:23]([N:26]=[C:27]=[O:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:27]([NH:26][C:23]2[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O:25][N:24]=2)=[O:28])=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2F)cc1
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCc3ccccc3F)cc2)no1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(2-Fluoro-benzyloxy)-phenylamine (0.12 g, 1 eq) was mixed with 5-tert-Butyl-3-isocyanato-isoxazole (0.9 g 1 eq) and dissolved in dry toluene. The reaction stirred at 80° C. overnight. The solvent was removed and purified by HPLC. Yield: 85 mg (31%), LC/MS [MH+] 384.
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].C([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O>CO>[CH3:7][O:6][CH:3]([O:4][CH3:5])[C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Reactant: COC(OC)OC
Solvent: CO
Product: COC(OC)c1ccc(/C=C/C(=O)O)cc1
Temperature: 0 °C

Procedure:
38.81 mL (0.354 mmol) of trimethylorthoformate is added to a suspension of 25 g (0.141 mol) of (E)-3-(4-formylphenyl)acrylic acid in 350 mL of methanol and the mixture is refluxed for 48 hours. After cooling, the reaction mixture is filtered and the filtrate is evaporated down. The residue is taken up in 500 mL of dichloromethane and filtered through CELITE® filter aid. The filtrate is evaporated down to 150 mL and cooled to 0° C. The precipitate formed is filtered off, washed with dichloromethane/petroleum ether (1:1), and dried at 60° C. in the circulating air dryer. Yield: 12.05 g (31.5% of theory); C12H14O4 (M=222.24); calc.: molecular ion peak (M+H)+: 245; found: molecular ion peak (M+H)+: 245; Rf value: 0.6 (silica gel, petroleum ether/ethyl acetate (1:1)).
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:34]=[CH:35][CH:36]=2)O1>>[NH2:22][C:3]1[C:2]([C:35]2[CH:34]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:32]=[CH:31][CH:36]=2)=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[N:6]=[CH:5][N:4]=1
Reactant: Nc1ncnc(Oc2ccc(Oc3ccccc3)cc2)c1Br
Reactant: CCC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCC(=O)Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 82 %

Procedure:
N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide was prepared from 5-bromo-6-(4-phenoxyphenoxy)pyrimidin-4-amine and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide using Method C (82% yield). HPLC: 99%, RT=4.286 min. MS: m/z=427 [M+H]+, RT=4.25 min. 1H-NMR (DMSO-d6) δ 9.93 (s, 1H), 8.10 (s, 1H), 7.64-7.63 (m, 2H), 7.38 (t, 3H), 7.12 (t, 1H), 7.08-7.05 (m, 3H), 6.99 (d, 4H), 6.60 (broad s, 2H), 2.32 (q, 2H), 1.07 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[K].CCO[C:14](S)=[S:15].C(OCC)C>C(O)C>[SH:15][C:14]1[NH:1][C:2]2[C:3](=[O:9])[NH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Nc1ccnc(O)c1N
Reactant: CCOC(=S)S
Agent: [K]
Solvent: CCOCC
Solvent: CCO
Product: O=c1[nH]ccc2nc(S)[nH]c12
Temperature: 25 °C

Procedure:
A suspension of 5.0 g (39.96 mmol) of 3,4-diamino-2-hydroxypyridine and 12.82 g (80.0 mmol) of potassium-ethyl xanthogenate in 100 ml of ethanol was refluxed for three hours. The mixture was then cooled to ambient temperature and combined with approx. 20 ml of diethyl ether. The precipitated product was filtered off, washed with approx. 10 ml of diethyl ether, dried, dissolved in approx. 30 ml of water and this solution was acidified with concentrated hydrochloric acid. The product precipitated was suction filtered, washed with 15 ml of water and dried at 50° C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=NC=C1.ClC1C=CC=CC=1C(=O)C1C=[C:24]([N+:26]([O-])=O)[CH:23]=CC=1N1C(CN2C(=O)C3=CC=CC=C3C2=O)=NN=C1CN(C)C.O.NN>C(O)C>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:23][CH:24]=[N:26]1
Reactant: C1=CNc2ccccc2C=N1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner [1,4]benzodiazepin. in Example 27, 2'-chloro-5-nitro2-[3-[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-nitro-1-[(dimethylamino)methyl] -6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]1,4]benzodiazepin.
Reaction SMILES: [NH2:1][C@H:2]([CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[N+:38]([O-:40])=[O:39]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH3:19][S:16]([NH:15][CH2:14][C@@H:2]([NH:1][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[N+:38]([O-:40])=[O:39])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)CNS(C)(=O)=O
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
tert-Butyl (4S)-4-amino-5-[(methylsulfonyl)amino]pentylcarbamate (6.88 g, 23.3 mmol) was dissolved in 100 mL of dry CH2Cl2 and the solution was cooled to 0° C. under N2. Triethylamine (6.49 mL, 46.6 mmol) and 4-chloro-3-nitroquinoline (4.85 g, 23.3 mmol) were then added and the reaction was allowed to warm to ambient temperature and stirred for 2 days. The reaction mixture was then concentrated under reduced pressure to give a yellow solid. The solid was triturated with 100 mL of hot H2O with stirring. The suspension was cooled and filtered to give 12.0 g of a pasty, yellow solid. The pasty solid was dissolved in methanol and CHCl3 and concentrated to give a yellow solid. The solid was then stirred in 100 mL of hot CHCl3, cooled and the solid was collected by filtration to give tert-butyl (4S)-5-[(methylsulfonyl)amino]-4-[(3-nitroquinolin-4-yl)amino]pentylcarbamate (8.00 g) as a yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[CH3:25][N:26]([CH3:31])[CH2:27][C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH3:25][N:26]([CH2:27][C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1)=[O:29])[CH3:31]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)CN(C)C)C1
Reaction time: 4.5 h

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benziniidazol-1-yl]pyrimidine (EXAMPLE 18) (21 mg, 0.065 mmol) in CH2Cl2 (0.6 mL) was added N,N-dimethylglycine (10 mg, 0.098 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.098 mmol) at room temperature. After stirring for 4.5 h, the reaction mixture was diluted with EtOAc (5 mL) and was washed with H2O (2×2 mL) and brine. The organic layer was dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography (1:9 2M NH3 in MeOH:CH2Cl2) to obtain the title compound. Presence of rotamers in Partial 1H NMR (500 MHz, CDCl3): δ 8.6 (s, 1H); 8.35 (br s, 1H); 8.12 (d, J=7.5 Hz, 1H); 7.82 (br s, 1H); 7.35 (br s, 2H); 6.75 (two d, J=5.3 Hz, 1H); 4.54 (m, 1H); 2.24 (s, 3H); 2.19 (s, 3H); 1.28 (br s, 3H). Mass spectrum 408.4 (ESI, M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH3:37][NH:38][CH3:39].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([N:38]([CH3:39])[CH3:37])=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CNC
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)N(C)C)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and dimethylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 536.03 (M+H).
Reaction SMILES: [K].C([C:5]([F:16])([F:15])[C:6]1[N:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)(O)=O.C(OC(C)C)(=O)C.S(=O)(=O)(O)O.[OH-].[Na+].Cl>O>[F:16][CH:5]([F:15])[C:6]1[N:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1
Reactant: O=C(O)c1cnc(C(F)(F)C(=O)O)cn1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1cnc(C(F)F)cn1
Temperature: 75 °C
Reaction time: 16.5 h
Yield: 64.2 %

Procedure:
To a mixture of potassium salt of 5-[carboxy(difluoro)methyl]pyrazine-2-carboxylic acid (IV, 1.00 g, 3.32 mmol) which was obtained from example (1-3)-B, isopropyl acetate (4 mL), and water (2 mL) were added concentrated sulfuric acid (0.60 mL, 10.8 mmol), and the organic layer was separated. The aqueous layer was re-extracted with isopropyl acetate (4 mL) followed by combining the obtained two organic layers. After stirring the mixture at 75° C. for 16.5 h, the mixture was stirred at 80° C. for 6 h and cooled to room temperature. After polish filtration of the mixture through a filter and rising the filter with isopropyl acetate (1 mL), water (4 mL) and aqueous sodium hydroxide solution (48%, 973 mg, 8.33 mmol) were added to the filtrate, and then the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid (0.83 mL, 10.0 mmol), and the resulting mixture was stirred while in ice-cooling for 17 h. The precipitated solids were collected by filtration, washed with water (0.5 mL), and dried at 50° C. under reduced pressure to afford the title compound (V, 371 mg, 64% yield) as pale brown solids.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:16]1([C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.C([BH3-])#N>ClCCl.CO>[C:16]1([C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH2:24][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=3)[CH2:3][CH2:4]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
A suspension of 4-piperazin-1-ylbenzonitrile hydrochloride (1.30 g, 5.00 mmol) and 3,3-diphenylacrylaldehyde (1.56 g, 7.50 mmol)) in dichloromethane (10 mL) and methanol (10 mL) was neutralized to pH 5 with diisopropylethylamine, treated with polymer-supported cyanoborohydride (2.47 mmol/g, 6 g, 14.82 mmol), shaken at room temperature for 24 hours, and filtered. The resin was washed with 1:1 dichloromethane/methanol (10 mL×3) and the combined filtrates were concentrated. The concentrate was purified by silica gel chromatography eluting with a gradient from 10%-50% ethyl acetate/hexanes to provide the desired product (1.60 g, 84%). MS (CI) m/e 380 (M+H)+.