Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Br:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>CO>[NH2:17][C:2]1[C:3]2[C:10]([Br:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCCOCn1cc(Br)c2c(Cl)ncnc21
Solvent: CO
Product: Nc1ncnc2c1c(Br)cn2COCCO
Temperature: 125 °C

Procedure:
5-Bromo-4-chloro-7-(2-hydroxyethoxymethyl)pyrrolo-[2,3-d]pyrimidine (8b, 0.7 g) was dissolved in dry methanol (10 mL) and methanol saturated with ammonia (40 mL) was then added to this solution. The reaction mixture was heated at 125° C. in a sealed reaction vessel for 10 hours. The solvent was removed at 40° C. under reduced pressure and the resulting solid was then subjected to column chromatography. Elution of the silica gel column (20×3 cm) with 5% MeOH in CHCl3 yielded a solid after evaporation of the appropriate UV absorbing fractions.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[F:20][C:21]([F:29])([F:28])[C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:27][C:24]1[S:25][CH:26]=[C:22]([C:21]([F:29])([F:28])[F:20])[N:23]=1)=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Nc1nc(C(F)(F)F)cs1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A mixture of 3,4-dinitrobenzoic acid (1.78 g, 8.4 mmol) and thionyl chloride was stirred for 2 h at reflux. The mixture was concentrated i.vac., toluene and 4-trifluoromethyl-thiazol-2-ylamine (1.49 g, 8.4 mmol) were added and the mixture was stirred at 120° C. for 3 days. Then the mixture was filtered and dried i.vac.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].I(Cl)(=O)=O.[I:10](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1.[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[C:35]([CH2:41][C:42]([CH3:44])=[CH2:43])[C:34]=1[OH:45]>CO>[I:10][CH2:43][C:42]1([CH3:44])[CH2:41][C:35]2[C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]([CH3:32])[C:34]=2[O:45]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(C)c2c(c1C)OC(C)(CI)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 183.4 %

Procedure:
Calcium carbonate (1.37 g, 13.7 mmol) and benzyltrimethylammonium dichloroiodate (4.04 g, 11.6 mmol) were sequentially added to a solution of toluene (20 mL)/methanol (10 mL) containing 2,3,5-trimethyl-6-(2-methylprop-2-en-1-yl)phenol (1.00 g, 5.26 mmol) synthesized in Reference Example 2 under ice-cooling condition, and the mixture was stirred at 0° C. for 30 minutes. After that, the reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to separate an organic layer. The organic layer was washed with 10% sodium sulfite aqueous solution and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-95:5) to give 3.05 g of the title compound (yield: 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:39]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)=[O:40])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (60 mg, 0.147 mmol) in CH2Cl2 (2 mL), the solution made in Step 1 of 4-methylpiperazine-1-carbonyl chloride (62 mg, 0.163 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction was then partitioned between EtOAc (50 mL) and 10% aqueous potassium carbonate. (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried with sodium sulfate and concentrated under vacuum. The residue was triturated with ether to yield 16 mg (20%) of product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.91 (s, 1 H), 7.78 (d 1 H), 7.58 (s, 1 H), 7.33 (m, 5 H), 7.13 (d, 1 H), 6.66 (s, 1 H), 5.64 (s, 2 H), 3.90 (m, 1 H), 3.60-3.30 (m, 8 H), 2.50-2.00 (m, 9 H); ES-MS m/z 536.3 [M+H]+, HPLC RT (min) 2.13.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11]([N+:28]([O-:30])=[O:29])=[C:10]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:9]=1.[F:37][CH:38]([F:50])[C:39]1[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:41]=2[N:40]=1>CN(C=O)C.O>[F:50][CH:38]([F:37])[C:39]1[N:43]([C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[C:11]([N+:28]([O-:30])=[O:29])=[C:10]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[N:9]=2)[C:42]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:41]=2[N:40]=1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(N3CCOCC3)c2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Reaction time: 60 h
Yield: 89 %

Procedure:
Powdered K2CO3 (1.305 g, 9.44 mmol) was added to a stirred suspension of tert-butyl 4-{[2-chloro-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate (U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which is incorporated herein by reference in its entirety) (1.047 g, 2.36 mmol) and 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) (608 mg, 3.07 mmol) in DMF (70 mL) at room temperature, and the mixture was stirred for 2.5 days. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration and dried. Recrystallization from CH2Cl2/MeOH gave tert-butyl 4-{[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate (1.27 g, 89%): mp 229-231° C.; 1H NMR (CDCl3) δ 8.64 (d, J=7.7 Hz, 1H), 7.81 (dd, J=8.4, 0.6 Hz, 1H), 7.36 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.36 (m, 1H), 4.11 (m, 2H), 4.06 (s, 3H), 3.85 (t, J=4.9 Hz, 4H), 3.65 (t, J=4.6 Hz, 4H), 3.01 (t, J=11.5 Hz, 2H), 2.08 (m, 2H), 1.64-1.51 (m, 2H), 1.48 (s, 9H); Anal. Calcd. for C27H34F2N8O6: C, 53.6; H, 5.7; N, 18.5. Found: C, 53.35; H, 5.7; N, 18.8%.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[O:10]1[CH:16]2[CH:11]1[CH:12]=[CH:13][CH2:14][CH2:15]2.CO>[Pd].O1CCCC1>[OH:10][CH:11]1[CH2:16][CH2:15][C:14]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])=[CH:13][CH2:12]1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C1=CC2OC2CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(C2=CCC(O)CC2)c(=O)[nH]c1=O
Reaction time: 4 h
Yield: 16.2 %

Procedure:
6.3 g (50 mmol) of thymine are treated with 2 mol % of the palladium(0) catalyst prepared in situ as described above and with one equivalent of 3,4-epoxycyclohexene in tetrahydrofuran first at 0° C. and then for 4 hours at the reflux temperature. Methanol is added to the reaction mixture, the suspension is filtered, the filtrate is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 20/1. 1.8 g (16.2% of theory) of 1-[(4RS)-4-hydroxy-cyclohex-1-en-1-yl]thymine of melting point 223° C. are obtained. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 11.23 (s, 1H), 7.69 (s, 1H), 4.59 (m, 1H), 2.84 (t, 1H), 2.42-1.81 (m, 6H), 1.79 (s, 3H), 1.61 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].II>C(OCC)C.C1C=CC=CC=1.[Zn]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[OH:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)cc21
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Yield: 95.8 %

Procedure:
A mixture of 6-fluoro-1-indanone (5.0 g, 33.3 mmol), ethyl bromoacetate (8.3 g, 50.0 mmol, Aldrich), activated zinc powder (3.2 g, 50.0 mmol, Mallinckrodt; Org. Synth., Coll. Vol. 6, 290, 1988) and a few crystals of iodine in diethyl ether-benzene (1:1, 100 mL) was heated at reflux under nitrogen for 24 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue in diethyl ether was vigorously stirred with excess dilute ammonium hydroxide, dried and concentrated to give ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate as an amber oil (7.6 g, 97%);
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[NH:14][C:15]1[C:16]2[CH:23]=[C:22]([CH:24]=O)[NH:21][C:17]=2[N:18]=[CH:19][N:20]=1>O.CO>[CH3:2][O:3][N:4]=[CH:24][C:22]1[NH:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([NH:14][C:13]3[CH:26]=[CH:27][CH:28]=[C:11]([Cl:10])[CH:12]=3)[C:16]=2[CH:23]=1
Reactant: CON
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CON=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4 h

Procedure:
69.3 mg (0.83 mmol) of O-methylhydroxylamine hydrochloride and 69.3 mg (0.845 mmol) of sodium acetate in 1 ml of water are added to 163.3 mg (0.5 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage1.6) in 1 ml of methanol. The suspension is heated to boiling for 4 h, cooled and filtered, and the residue is washed with water/isopropanol and finally diethyl ether. 4-(3-Chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde O-methyl oxime is obtained; HPLC: tRet(Grad20)=11.3; TLC-Rf=0.31 (CH2Cl2/methanol 10:1) FAB-MS: (M+H)+=302.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[Br:10]N1C(=O)CCC1=O.O>C1COCC1>[Br:10][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: COC(=O)C1CCOC1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(Br)CCOC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5.0 g (38.419 mmol) of methyl tetrahydrofuran-3-carboxylate (Journal of Organic Chemistry; 1996; 2690) were dissolved in 200 ml of THF and cooled to −78° C., and 76.83 ml (76.83 mmol) of bis(trimethylsilyl)lithium amide (1 M in THF) were then added. After 30 min at −78° C., 10.26 g (57.63 mmol) of N-bromosuccinimide, suspended in 50 ml of THF, were added slowly. The mixture was then allowed to warm to RT overnight. Water was added, and the mixture was extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted two more times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried with sodium sulphate, filtered and concentrated. The crude product was purified by chromatography on silica gel (mobile phase:dichloromethane). This gave 491 mg (6% of theory) of the title compound.
Reaction SMILES: [Cl-].[CH:2]1([CH2:9][NH2+:10][CH2:11][CH2:12]Cl)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:10]([CH2:9][CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:12][S:26]1
Reactant: ClCC[NH2+]CC1CCCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1>C(O)C.C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Reaction time: 18 h
Yield: 109.3 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-nitroindole (0.550 g, 1.39 mmol) in a mixture of ethanol (120 mL) and THF (40 mL) was added 10% palladium-on-charcoal (0.30 g) and the mixture was hydrogenated on a Parr shaker at 40 psi for 18 h. The mixture was then filtered through Celite and the catalyst was washed with additional ethanol-THF. Evaporation of the filtrate gave the essentially pure title compound (0.557 g, 100%) as a brown foam. A sample of this material (0.143 g) was treated with excess methanolic HCl and the resulting solution was diluted with acetone to give a precipitate. The precipitate was filtered and then crystallized from ethanol to give 0.100 g of a purplish solid, mp 192° C. (dec): IR (KBr) 3410, 3200, 1630, 1540 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.22(br s, 1H), 10.20 (br s, 2H), 8.60 (m, 1H), 8.20 (s, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.6, 1.9 Hz, 1H), 4.89-4.82 (m, 2H), 3.91 (s, 3H), 3.8-3.0 (br m, 8H), 2.76 (m, 2H). Anal Calcd. for C20H26N6O. 4 HCl. H2O: C, 45.29; H, 6.08; N, 15.85. Found: C. 45.32; H, 5.97; N, 15.59.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]cnc2cc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Br)ncn2C1CCCCO1
Yield: 74.1 %

Procedure:
A mixture of 5-bromo-6-methyl-1H-benzo[d]imidazole (2.0 g, 9.6 mmol), p-TsOH (17 mg, 0.1 mmol), and dihydropyran (8.1 g, 96 mmol) in THF (30 mL) was heated to reflux overnight. The solvent was concentrated in vacuo and EtOAc (50 mL) and water (50 mL) were added to the residue. The pH was adjusted to about 8 with K2CO3. The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (2:1) to afford 5-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a yellow solid (2.1 g, 71%). MS (ESI): m/z=295.2 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:31][C:2]([F:1])([F:30])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N(CCC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
To a solution of tert-butyl 4-(2-(2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)ethyl)piperidine-1-carboxylate (650 mg, 1.476 mmol) in dichloromethane (DCM) (4 mL) was added TFA (1 mL, 12.98 mmol), and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated and the residue was dissolved in DCM (20 mL). The resulting solution was washed with 10% NaHCO3 aqueous solution. The organic phase was collected and dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 470 mg of product as oil. MS: (M+H)+=341.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.33-1.79 (m, 7H), 1.93-2.10 (m, 2H), 2.27-2.59 (m, 1H), 2.84-3.06 (m, 2H), 3.15-3.25 (m, 1H), 3.66 (t, J=7.20 Hz, 2H), 7.09-7.41 (m, 5H).
Reaction SMILES: Cl.[CH:2]([NH:5][C:6]1([C:10]([NH2:12])=[O:11])[CH2:9][NH:8][CH2:7]1)([CH3:4])[CH3:3].Cl[C:14]1[N:19]2[N:20]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:18]2[N:17]=[C:16]([CH3:37])[N:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:21]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:18]2[N:17]=[C:16]([CH3:37])[N:15]=[C:14]([N:8]3[CH2:9][C:6]([NH:5][CH:2]([CH3:4])[CH3:3])([C:10]([NH2:12])=[O:11])[CH2:7]3)[N:19]2[N:20]=1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: CC(C)NC1(C(N)=O)CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC(NC(C)C)(C(N)=O)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 1.5 h

Procedure:
To a mixture of 3-isopropylaminoazetidine-3-carboxylic acid amide hydrochloride salt (I-3A-1c; 72 mg, 0.361 mmol) and 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 102 mg, 0.261 mmol) in methylene chloride (1.3 ml) was added diisopropylethylamine (0.16 ml, 0.91 mmol), dropwise. After stirring for 90 minutes, the reaction was extracted from saturated aqueous NaHCO3 with methylene chloride. The combined extracts were dried (MgSO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12M column using 0-5% methanol in methylene chloride as eluant. The resultant solid was triturated from methanol and then dried, in vacuo, to afford 3A-1 (104 mg, 78%) as a colorless solid: +ESI MS (M+1) 510.1; 1H NMR (400 MHz, CD2Cl2) δ 7.47-7.34 (m, 6H), 7.21 (d, J=8.7 Hz, 2H), 6.96 (br s, 1H), 5.42 (br s, 1H), 5.22 (br m, 1H), 4.73 (br m, 2H), 4.18 (br m, 1H), 3.11 (septuplet, J=6.2 Hz, 1H), 2.48 (s, 3H), 1.06 (d, J=6.2 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:43][C:44](=[O:46])[NH2:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](CC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Asn-OtBu (38 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ12.11-12.80 (br.s, 1 H), 8.94 (s, 1 H), 7.99 (s, 1 H), 7.28 (m, 7 H), 7.18 (m, 3 H), 7.03 (m, 1 H), 6.96 (m, 2 H), 6.87 (m, 5 H), 4.50 (m, 1 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 2.91 (s, 3 H), 2.55 (m, 2 H), 2.44 (m, 2 H), 2.39 (s, 3 H), 2.11 (t, 2 H), 1.76 (m, 2 H); MS (APCI+) m/z 673 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[P:5](Cl)(=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:5]([N:3]=[C:2]=[S:1])([O:9][CH2:10][CH3:11])=[O:12])[CH3:8]
Reactant: N#C[S-]
Reactant: CCOP(=O)(Cl)OCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(N=C=S)OCC
Temperature: 25 °C

Procedure:
To a mixture of 8.02 g of dry sodium thiocyanate in 100 ml of dry toluene at 0° C., under a nitrogen atmosphere is added 13.1 ml (16.6 g) of diethyl phosphorchloridate dropwise with stirring. The mixture is warmed to ambient temperature and stirred 20 hours. The mixture is filtered through a pad of Celite and the pad is washed with two 50 ml portions of toluene. The filtrate is washed with 50 ml of ice cold 10% sodium bicarbonate solution, 50 ml of ice water and dried over anhydrous magnesium sulfate. The mixture is filtered and the filtrate used without further purification is subsequent reaction.
Reaction SMILES: [OH:1][C:2]([P:14](=[O:17])([OH:16])[OH:15])([P:10](=[O:13])([OH:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.I[CH3:19]>[OH-].[Na+].O.C(O)C>[OH-:1].[OH:1][C:2]([P:14]([OH:15])([OH:16])=[O:17])([P:10]([OH:11])([OH:12])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[CH3:19]
Reactant: CI
Reactant: O=P(O)(O)C(O)(Cc1ccccn1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[n+]1ccccc1CC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 80 °C
Yield: 165.4 %

Procedure:
[1-Hydroxy-2-(2-pyridinyl)ethylidene]bis[phosphonic acid] (3.53 mmol, 1.0 g) is dissolved in 8.8 ml of 1N sodium hydroxide solution and 8.8 ml of distilled water. To this is added iodomethane (17.67 mmol, 1.1 ml) in 18 ml of ethanol. This reaction mixture is heated at 80° C. until complete. The solvent is concentrated in vacuo and the residue is recrystallized from ethanol and water to yield 0.92 g of 2-(2 -hydroxy-2,2-diphosphonoethyl)-1-methyl pyridinium hydroxide, inner salt, monosodium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([CH2:13][NH2:14])[CH2:6]2.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18]>CC1OCCC1>[CH2:17]([O:16][C:15](=[O:19])[NH:14][CH2:13][C@H:7]1[CH2:6][C:5]2[C:8]1=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:18]
Reactant: CCOC(=O)OCC
Reactant: COc1cc2c(cc1OC)C(CN)C2
Solvent: CC1CCCO1
Product: CCOC(=O)NC[C@H]1Cc2cc(OC)c(OC)cc21

Procedure:
5 mg of 1-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine and 12.6 mg (10 eq) of diethyl carbonate are dissolved in 2-MeTHF.