Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C>[OH:23]/[N:22]=[C:14](\[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)/[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1ccc(Oc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=N/O)c1ccc(Oc2ccccc2)cc1
Yield: 27.5 %

Procedure:
A mixture of ethyl 4-phenoxyphenylglyoxylate (37.9 g), hydroxylamine hydrochloride (11.7 g), sodium acetate (17.3 g) and ethanol (200 ml) was heated under reflux for 15 hours. The reaction mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residual crystals were recrystallized from toluene-hexane to obtain ethyl E-2-hydroxyimino-2-(4-phenoxyphenyl)acetate (11.0 g, yield 28%) as a colorless oil. m.p. 131-132° C.
Reaction SMILES: [C:1](O)(C(F)(F)F)=[O:2].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][NH:24][S:23](=[O:27])(=[O:26])[NH:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:28][C:29]([C:31]2[N:32](COCC[Si](C)(C)C)[CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1>C(Cl)Cl.CCO>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][NH:24][S:23](=[O:26])(=[O:27])[NH:22][CH2:21]3)[C:17]([CH2:1][OH:2])=[CH:16][C:15]=2[NH:28][C:29]([C:31]2[NH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2cc(CO)c(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
TFA (0.3 mL) was added to a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide (as prepared in Example 5, step (d), 21 mg, 0.030 mmol) in DCM (1 mL) and EtOH (30 μL). The resulting mixture was stirred at RT for 2 h and concentrated in vacuo. The residue obtained was purified on silica (20-50% EtOAc-hexane) to obtain the title compound (8.0 mg, 46%): 1H-NMR (CD3OD; 400 MHz): δ 8.10 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 5.78 (br s, 1H), 4.7 (ABq, 1H, J=16 Hz), 4.48 (ABq, 1H, J=16 Hz), 4.3 (m, 1H), 3.87 (m, 1H), 3.52 (m, 1H), 3.6 (m, 1H), 3.18 (m, 1H), 2.62 (br s, 1H), 2.22-2.34 (m, 4H), 1.72-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H24N6O4S, 439.1 (M−H2O+H), found 439.2.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:6]=1)=[N+]=[N-].[H][H]>[Pd]>[NH2:1][CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:6]=1
Reactant: [N-]=[N+]=NCc1nn(C2CCCCO2)c2nc(F)ccc12
Reactant: [H][H]
Agent: [Pd]
Product: NCc1nn(C2CCCCO2)c2nc(F)ccc12
Reaction time: 0.75 h

Procedure:
Compound 2-4 (135 mg; 0.49 mmol) was hydrogenated in the presence of 10% Pd on carbon catalyst (25 mg) under 1 atmosphere hydrogen pressure (balloon) at room temperature. After 45 minutes LC-MS indicated that the reduction was complete. The reaction mixture was filtered through Celite, and the filtrate concentrated in vacuo to give the title product as a clear oil/solid. MS M+1=251. 1H NMR (CDCl3): 1.61 (m, 1H), 1.78 (m, 2H), 1.92 (dd, 1H), 2.03 (br m, 1H), 2.13 (br m, 1H), 2.60 (br m, 1H), 3.80 (br t, 1H), 4.12 (dd, 1H), 4.22 (br s, 2H), 5.93 (dd, 1H), 6.78 (dd, 1H), 8.21 (t, 1H).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[NH2:35])([CH3:25])[CH3:24]>>[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[NH:35][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1)([CH3:34])[CH3:33]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: Cc1nc(NCc2ccccn2)nc(Nc2c(C(C)C)cccc2C(C)C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,6-diisopropylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.13 (d, J=32.78 Hz, 12H), 2.12 (s, 3H), 2.31 (s, 3H), 3.00-3.12 (m, 2H), 4.40 (d, J=5.10 Hz, 2H). 5.40 (s, 1H), 5.65 (s, 1H), 6.85 (s, 1H), 7.04 (bs, 1H), 7.19 (d, J=7.52 Hz, 2H), 7.20-7.30 (m, 1H), 7.42 (t, J=7.52 Hz, 1H), 8.43 (d, J=4.03 Hz, 1H); MS (ESI) m/z 390.5 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: NS(=O)(=O)c1cccnc1Cl
Product: CNc1ncccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
10 g of 2-chloropyridine-3-sulfonamide (obtained in Stage A of Preparation 6) are dissolved in 100 cm3 of 40% aqueous methylamine solution and the solution is introduced into a sealed tube. The tube is placed at 150° C. for 18 hours. After cooling, the reaction mixture is concentrated under vacuum (rotary evaporator) to a volume of 30 cm3. The crystalline precipitate corresponding to the title compound is collected on a filter, washed with water and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:13]([O:12][C:10]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of piperidin-4-yl-methanol (0.57 g, 5 mmoles), benzyl chloroformate (0.75 ml, 5.5 mmoles), and sodium bicarbonate (0.46 g, 5.5 mmoles) in CH2Cl2 was stirred at room temperature for 2 hours, diluted with H2O and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound (0.95 g, 3.8 mmoles).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:36])=[O:35]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Yield: 138.7 %

Procedure:
Under a nitrogen atmosphere, 29.16 g (97.67 mmol) of phytanol and 9.27 g (117.2 mmol) of pyridine were dissolved in 220 ml of dry methylene chloride, and 20.48 g (107.4 mmol) of p-toluenesulfonyl chloride was added little by little under ice cooling, in order to prevent the liquid temperature from exceeding 10° C. After the completion of addition, agitation was continued for 12 hours until phytanol disappeared, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 61.31 g of phytanyl tosylate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH2:16]([NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:17]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][CH3:17]
Reactant: COc1ccc(N)c(CO)c1
Reactant: CCNC1CCCCC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(Cc1cc(OC)ccc1N)C1CCCCC1

Procedure:
2-Amino-N-cyclohexyl-N-ethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and N-ethyl-cyclohexylamine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1Cl)C2
Yield: 199.7 %

Procedure:
A mixture of 7-(2,5-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g), aminoguanidine hydrochloride (0.43 g), concentrated hydrochloric acid (0.82 ml), water (0.82 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue recrystallized from water to give 7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 120) (1.3 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:30]=3[N:31]=2)[CH2:23]1>>[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([NH:36][C:9](=[O:11])[CH:8]=[CH:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=4)=[CH:32][C:30]=3[N:31]=2)[CH2:23]1
Reactant: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(C=CC(=O)Nc2ccc3oc(N4CCC(N(C)C)C4)nc3c2)cc1
Yield: 72.2 %

Procedure:
Prepare according to Method C (Example 9), using 4-methoxycinnamic acid (110 mg, 0.617 mmol), oxalyl chloride (300 μL, 3.43 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzooxazol-5-ylamine (99 mg, 0.402 mmol) to afford the title compound (118 mg, 72%). mass spectrum (m/e): 407.4 [M+H], 405.3 [M−H].
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[C:9]1([S:8][C:4]2[N:3]([O:2][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccnc1Sc1ccccc1
Agent: Cl
Product: CN(C(=O)On1ccnc1Sc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-phenylsulfanylimidazole hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (61%, oil).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (271 mg, 66%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a mixture of ethyl 3-[{[4-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (667 mg) obtained in Example A75(4) in tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (2.6 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (4 mL), and 1N hydrochloric acid (2.6 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 min, and the resulting precipitate was collected by filtration to give the title compound (509 mg, 81%) as a colorless amorphous form.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]([O:70][N+:71]([O-:73])=[O:72])[CH2:65][O:66][N+:67]([O-:69])=[O:68])=[O:58])([CH3:55])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]>ClCCl.CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]([O:70][N+:71]([O-:73])=[O:72])[CH2:65][O:66][N+:67]([O-:69])=[O:68])=[O:58])([CH3:55])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A dichloromethane/methanol (3.5 mL, 1:7) solution of 1-[({[5,6-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]-1-methylethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (0.190 g, 0.192 mmol) was heated in a microwave apparatus (90° C., 20 minutes). Then the solution was concentrated and the residue was purified by flash chromatography (Biotage SP1, 25+M column, dichloromethane/methanol 98/2), affording the title compound. 1H NMR (300 MHz, CDCl3) δ 8.04-8.01 (m, 1H), 7.63-7.61 (m, 2H), 7.52 (dd, 1H), 7.32-7.28 (m, 1H), 6.91 (t, 1H), 6.81 (d, 3H), 6.68 (d, 2H), 5.62 (s, 2H), 5.25-5.23 (m, 1H), 4.72 (dd, 1H), 4.28-4.26 (m, 2H), 4.05 (t, 2H), 1.78-1.52 (m, 10H), 1.49-1.42 (m, 6H).
Reaction SMILES: [OH:1][CH:2]1[C:17](=[O:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:4]2[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1[CH:31]=[N:30][C:29]([CH:32]2[CH2:34][CH2:33]2)=[CH:28][N:27]=1>C(#N)C>[CH:32]1([C:29]2[N:30]=[CH:31][C:26]([O:1][CH:2]3[C:17](=[O:18])[N:5]4[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:9][CH:4]4[CH2:3]3)=[N:27][CH:28]=2)[CH2:34][CH2:33]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(O)CC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of the product from Example 205B (89 mg, 0.347 mmol) in anhydrous acetonitrile (3.5 mL) was added cesium carbonate (226 mg, 0.695 mmol) and 2-bromo-5-cyclopropylpyrazine (104 mg, 0.521 mmol). The resulting mixture was stirred under N2 at 50° C. for 48 hours. The mixture was allowed to cool to room temperature, and then it was partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane to give the title compound (82 mg, 63%).
Reaction SMILES: [CH2:1]([OH:3])C.Cl[P:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N>>[C:12]1([P:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:3][CH3:1])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: N
Product: COP(c1ccccc1)c1ccccc1
Yield: 72.9 %

Procedure:
210 g (6.56 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 200 g (0.907 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature with vigorous stirring. 18 g (1.06 mol) of ammonia gas are then introduced. The mixture is then stirred without cooling for 10 hours and filtered by suction. The filtrate is freed from methanol and excess ammonia in vacuo. The residue is filtered by suction through a glass frit. 143 g of crude methyl diphenylphosphinite are obtained. This corresponds to a yield of 73% of theory.
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([NH:10][C:11]1[CH:23]=[CH:22][C:14]2[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][O:21][C:13]=2[CH:12]=1)(=[O:9])=[O:8].[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:6][S:7]([NH:10][C:11]1[CH:23]=[CH:22][C:14]2[O:15][CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:30][CH:31]=3)[CH2:19][CH2:20][O:21][C:13]=2[CH:12]=1)(=[O:8])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCOc3ccc(NS(C)(=O)=O)cc3OCC2)cc1

Procedure:
To tetrahydrofuran add 9-[(methylsulfonyl)amino]-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine, pyridine, and 4-[(methylsulfonyl)amino]benzoyl chloride. Monitor the progress of the reaction by thin-layer chromatography. Upon completion, remove the solvent in vacuo. Partition the residue between aqueous NaHCO3 and EtOAc. Separate the layers and wash the organic layer with 1M aqueous HCl. Separate and dry (Na2SO4) the organic layer. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:23]([Mg]Br)#[CH:24].O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([OH:22])[C:23]#[CH:24])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Reactant: C#C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a cold (−78° C.) suspension of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was added ethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol). The reaction mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was poured into water and adjusted to neutral pH with 1N aqueous hydrochloric acid. The aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration provided 1-[2-(4-fluorophenyl) -6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (11.9 g, 96%) as a tan solid. Rf 0.18 (4:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35 (d, 1H), 7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MS m/z 335 (M+1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13](#[N:17])[CH2:14][CH:15]=[CH2:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>C1COCC1>[C:13]([CH:14]([CH:15]=[CH2:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:17]
Reactant: CCOC(=O)CBr
Reactant: C=CCC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CC(C#N)CC(=O)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M in THF, 33 mL, 82 mmol) was added dropwise to a solution of diisopropylamine (9.0 g, 90 mmol) in THF at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. To the mixture was added a solution of 3-butenenitrile (5.0 g, 74.6 mmol) in THF (30 mL) dropwise at −78° C. The resultant mixture was stirred at the temperature for 1 hour, then a solution of ethyl bromoacetate (13.7 g, 82.06 mmol) in THF (30 mL) was added dropwise at −78° C. to the reaction mixture. The reaction mixture was stirred at −78° C. for an additional 1 hour. The reaction mixture was poured into a solution of saturated aqueous ammonium chloride and extracted with tert-butyl methyl ether (3×300 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to afford ethyl 3-cyanopent-4-enoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.83-5.71 (m, 1H), 5.53-5.49 (m, 1H), 5.36-5.33 (m, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.79-3.71 (m, 1H), 2.81-2.73 (m, 1H), 2.69-2.61 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).