Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]I.[C:3]([O:7][C:8](=[O:27])[NH:9][CH:10]([CH2:24][C:25]#[N:26])[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].O>CN(C)C=O>[C:3]([O:7][C:8](=[O:27])[N:9]([CH:10]([CH2:24][C:25]#[N:26])[CH:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:1])([CH3:5])([CH3:4])[CH3:6]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC(CC#N)C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C(CC#N)C(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
5.2 ml (82.9 mmol) of methyl iodide is added to a solution of 18.5 g (54.9 mmol) of (1-Cyanomethyl-2,2-diphenyl-ethyl)-carbamic acid tert-butyl ester in 100 ml of N,N-dimethyl-formamide, and the mixture is cooled to 0° C. 2.6 g (60.6 mmol) of 55% sodium hydride is added in several portions. After 1 h the mixture is warmed to RT and 75 ml of N,N-dimethylformamide is added for further dilution. After a total of 3.5 h the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over sodium sulfate and concentrated by evaporation. The title compound is obtained in the form of an orange-brown mass. TLC: ethyl acetate/hexane (1:4) Rf =0.35; Rt (HPLC)=20.0 min; 1H-NMR (300 MHz, CDCl3, RT) d 7.39-7.17 (m, 10H), 5.60-5.15 (m, 1H), 4.36-3.96 (m, 1H), 2.73/2.68 (s, 3H), 2.05 (m, 2H), 1.55/1.41 (s, 9H).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:27])[C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:36][N:35]=[N:34][N:24]=4)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:27])[C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(OCc4nnn[nH]4)cc3)ccc21

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(3-benzyl-1-methyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.137 g, 0.320 mmol) was reacted with NaN3 (0.104 g, 1.598 mmol) and NH4Cl (0.085 g, 1.598 mmol) in DMF (5 ml) to give the product (0.102 g, 0.216 mmol, 68%) as a pale-yellow solid, dec. 194-197° C. 1H NMR (DMSO-d6) δ 3.59 (s, 3H), 4.01 (s, 2H), 5.46 (s, 2H), 7.03-7.09 (m, 5H), 7.13-7.17 (m, 2H), 7.39-7.53 (m, 9H), 7.55 (d, J=1.2 Hz, 1H), 16.75 (broad s, 1H); IR (solid) 3020, 2920, 1605, 1520, 1480, 1450, 1370 and 1240 cm−1; [ESI(−)], m/z 470 (M−H)−; Anal. Calcd. for C30H25N5O: C, 76.41; H, 5.34; N, 14.85; Found: C, 76.35; H, 5.28; N, 14.90.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:22]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][CH2:22][C:24]5[S:25][CH:26]=[CH:27][N:28]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: O=Cc1nccs1
Product: c1cc(NC2=Nc3ccc(NCc4nccs4)cc3CO2)cc(C2CC2)c1
Yield: 46.1 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (158 mg, 0.57 mmol) and 2-formylthiazole (70 mg, 0.62 mmol) according to the procedure described for example 88. Obtained the title compound as a yellow foam (99 mg, 46%), MS (ISP) m/e=377.2 [(M−H)+].
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][CH2:13][N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[C:24]([O:23][C:21]([N:14]([C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[CH2:13][CH2:12][O:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([Cl:10])[CH:7]=1)[C:3]([OH:28])=[O:2])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.1 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid methyl ester (0.58 g) in a mixture of 1,4-dioxane (5 ml) and water (5 ml) was added 2M sodium hydroxide solution (0.72 ml). The reaction mixture was stirred at room temperature for 20 h, acidified by the addition of 2M hydrochloric acid (0.75 ml) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the aqueous layer removed and the organic phase washed with further water and dried with brine and over sodium sulphate. Concentration of the organic phase under reduced pressure gave the title compound as a yellow solid (0.32 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:38]>C(O)C>[ClH:38].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
In 1 L of absolute ethanol was added (S)—N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (41 g, 76.7 mmol) and the reaction was heated to 80° C. 41 mL of aqueous HCl (11.6 mL of concentrated HCl diluted in water) was added. After 2 hours, the resultant solid material was hot filtered, washed with ethanol (200 mL) and dried in vacuo to yield crude product as a solid which contained about 2% starting material. The solids were suspended in EtOH (1 L) and heated to 80° C. followed by 41 mL of aqueous HCl (11.6 mL of concentrated HCl diluted in water). After 3.5 hours the resultant solid material was hot filtered, washed with ethanol (200 mL) and dried in vacuo and to afford (S)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (35 g, 85%). Mass Spectrum (apci) m/z=455.2 (M+H−HCl).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(O)(=O)C>C1COCC1>[CH2:8]([O:7][C:6]([CH:21]1[CH2:20][CH:19]([C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:29])=[O:10])[CH3:9]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Temperature: 0 °C
Yield: 80 %

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 1.69 g, 42 mmol) in THF (80 ml) under N2 was added dropwise diethylcarbonate (4.85 ml, 40 mmol) at room temperature, followed by 4-(3′,4′-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalone 1 (5.82 g, 20 mmol) in THF (20 ml). The mixture was refluxed for 48 hours, then cooled to 0° C. Acetic acid (10 ml) was added dropwise, and the mixture was extracted with Et2O. The Et2O extracts were washed with saturated NaHCO3 solution, brine, dried over MgSO4, and evaporated. The residue was purified by chromatography, CombiFlash silica gel column (hexane:CH2Cl2=50:50) to give Compound 9 as a clear oil (5.81 g, 80%). 1H NMR (CDCl3) δ 1.30 (t, J=7.2 Hz, 3H), 2.77 (dd, J=16 Hz, 9.6 Hz, 1H), 2.91 (dd, J=15.6 Hz, 6.4 Hz, 1H), 4.10 (dd, J=12 Hz, 6.4 Hz, 1H), 4.19-4.30 (m, 2H), 6.87 (d, J=6.8 Hz, 1H), 7.00 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.27-7.36 (m, 5H), 7.89 (dd, J=8.4 Hz, 2.0 Hz, 1H), 12.50 (s, 1H). 13C NMR (CDCl3) δ 14.5, 29.1, 43.4, 61.0, 95.6, 125.0, 127.6, 127.9, 128.1, 130.2, 130.6, 130.7, 131.0, 131.3, 132.8, 140.4, 143.9, 164.8, 172.6.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[CH:47]=[C:48]([NH:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.[CH3:59][CH:60]([CH3:64])[C:61](=[S:63])[NH2:62]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:63][C:61]([CH:60]([CH3:64])[CH3:59])=[N:62][C:44]=2[C:46]2[CH:47]=[C:48]([NH:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])[CH:49]=[CH:50][CH:51]=2)[CH:40]=[CH:39][N:38]=1
Reactant: CC(C)C(N)=S
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 45.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6, using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (10.0 g, 30.14 mmol), and 2-methylpropanethioamide (3.73 g, 36.17 mmol), prepared by a procedure analogous to Intermediate 1, 5.74 g of the title compound was obtained. MS (ESI): 415 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH:15]1([O:14][CH2:13][CH2:12][NH:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([C:32]4[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:30][CH:31]=4)=[CH:3][N:4]=3)[N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Brc1cnc2ccc(NCCOC3CCCC3)nn12
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3ccc(NCCOC4CCCC4)nn23)cc1
Yield: 70 %

Procedure:
The 3-bromo-N-(2-(cyclopentyloxy)ethyl)imidazo[1,2-b]pyridazin-6-amine was coupled with (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid under the Suzuki coupling conditions as described in example 5.6.76, Part B to obtain 70% product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:11])=[N+]=[N-].CCOC(C)=O.O>C1COCC1>[NH2:7][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:11]
Reactant: Cc1ccc(C(C)N=[N+]=[N-])s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)N)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Add lithium aluminum hydride (29 mg, 0.72 mmol) to a solution of (±)-2-(1-azidoethyl)-5-methylthiophene (100 mg, 0.59 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight. Work-up the mixture with EtOAc and water. Filter the mixture over Celite®. Separate and wash the organic phase with brine. Dry over Na2SO4, filter and concentrate in vacuo. Purify by SCX chromatography. Rinse with DCM/methanol (1:1), load the crude mixture in methanol and elute sequentially with methanol and 1N ammonia in methanol to obtain the title compound as an oil (80 mg, 95%). GC-MS m/z 141 (M+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=O)[CH:25]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CN(C(ON1N=NC2[CH:46]=[CH:47][CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1>O>[N:49]1([C:27](=[O:29])[CH2:26][N:24]2[CH:25]=[C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)[CH:22]=[N:23]2)[CH2:48][CH2:47][CH2:46][CH2:44]1
Reactant: O=C(O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1)N1CCCC1
Reaction time: 0.08 h
Yield: 15.8 %

Procedure:
To a solution of example 155 (0.056 g, 0.145 mmol) in DMF (0.5 ml) N-ethyldiisopropylamine (0.018 g, 0.145 mmol) and HATU (0.055 g, 0.1.45 mmol) were added and stirred for 5 min. Pyrrolidine (0.020 g, 0.290 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.010 g, 16%). M.P.: 136-138° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.87 (dd, J=2.7 Hz, 1H), 8.52 (d, J=8.7 Hz, 1H), 8.45 (s, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.99 (s, 1H), 7.83 (m, 2H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H), 5.11 (s, 2H), 3.52 (t, J=6.7 Hz, 2H), 3.33 (m, 2H), 1.93-1.77 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[Cl:23][S:24](O)(=[O:26])=[O:25]>O>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:24]([Cl:23])(=[O:26])=[O:25])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCC(Cc2ccccc2)CC1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To the mixture of 1-(trifluoroacetyl)-4-benzylpiperidine (29.2 g, 108 mmol) and methylene chloride (10 ml) was dropwise added chlorosulfonic acid (36 ml, 539 mmol) at −10° C. for an hour. The mixture was stirred at 0° C. for an hour and then stirred at room temperature for an hour. The reaction mixture was poured into ice-cooled water (500 ml) and extracted with methylene chloride (200 ml×2). The extract was washed with an aqueous solution of 5% sodium bicarbonate (500 ml) and saturated brine (500 ml) successively. The organic phase was dried over magnesium sulfate (anhydrous), then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel 100 g, ethyl acetate/hexane=1/20→1/5) to give the title compound as a colorless powdery crystal (16.5 g, 41%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.[CH3:13][N:14](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:15].[B-](F)(F)(F)F.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:13][N:14]([CH3:15])[C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1nn(C)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (500 mg, 2.92 mmol) in DMF (5 ml) under inert gas atmosphere was treated with TBTU (1030 mg, 3.2 mmol), dimethylamine hydrochloride (262 mg, 3.2 mmol) and N,N-diisopropylethylamine (2.0 ml, 11.7 mmol) and stirring was continued for 4 h. All volatiles were removed and the crude product was extracted with water and ethyl acetate. The organic phase was washed with sodium bicarbonate and the aqueous phases were back-extracted with ethyl acetate and dichloromethane. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a dichloromethane/methanol gradient as white solid (230 mg, 40%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]2=[C:9]([C:13]3[CH:14]=[N:15][N:16]([CH3:28])[C:17]=3[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:10]=[C:11]([CH3:12])[N:7]2[N:6]=[CH:5][N:4]=1.C1N=C(N)C2N=CN([C@@H]3[O:42][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH3:1][NH:2][C:3]1[C:8]2=[C:9]([C:13]3[CH:14]=[N:15][N:16]([CH3:28])[C:17]=3[C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[N:10]=[C:11]([CH2:12][OH:42])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: CNc1ncnn2c(C)nc(-c3cnn(C)c3-c3ccc(C(F)(F)F)cc3)c12
Product: CNc1ncnn2c(CO)nc(-c3cnn(C)c3-c3ccc(C(F)(F)F)cc3)c12

Procedure:
N,7-Dimethyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine, at a substrate concentration of 50 μM, was incubated for 1 hour with rat liver microsomes and NADPH (1 mM) (21.1 mg/mL protein concentration; 25 mL incubation volume). Incubations were extracted with 4 volumes of acetonitrile. Following centrifugation at 3400 rpm, the supernatant was evaporated at 25° C. in a Turbovap. The residue was reconstituted with 5% aqueous acetonitrile and subjected to preparative reverse-phase HPLC purification (Column: Zorbax Rx-C8 [Agilent], 250×9.6 mm, 5 μm; Mobile phase A: aqueous 5 mM ammonium formate, pH 3; Mobile phase B: acetonitrile; Gradient: 10% to 90% B; UV detection at 254 mm). The fractions containing the M+16 metabolite were dried down to provide the product as a solid. MS m/z 404 (M+H). 1H NMR (600 MHz, DMSO-d6) δ 2.71 (d, J=4.8 Hz, 3H), 3.86 (s, 3H), 4.69 (s, 2H), 6.68 (br q, J=4.7 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.70 (s, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.85 (s, 1H).
Reaction SMILES: CN(C)C=O.[CH3:6][C@@:7]1([CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[N:13]=[C:12]2[S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[CH2:9][O:8]1.[N:29]1([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(OCC)(=O)C>[N+:16]([C:14]1[N:13]=[C:12]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[N:11]([CH2:10][C@:7]([OH:8])([CH3:6])[CH2:9][N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[O:36])[CH2:34][CH2:33]2)[CH:15]=1)([O-:18])=[O:17]
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Sc2ccccc2[N+](=O)[O-])CO1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccccc1[N+](=O)[O-]
Yield: 88.9 %

Procedure:
N,N-Dimethylformamide (0.25 ml) solution of (R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(2-nitrophenylthio)imidazole (50 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (51 mg) was stirred at 60° C. for 1 day. Water and ethyl acetate were added to the reaction mixture, the organic layer was taken by separation. The ethyl acetate layer was washed with water, an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/methanol=30/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(2-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (86 mg, yield: 87%) as yellow amorphous product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:35]([OH:39])[CH2:36][C:37]#[CH:38].[NH4+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[OH:39][CH2:35][CH2:36][C:37]#[C:38][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17]2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(I)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CCCO)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a degassed solution of 4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144) (0.20 g, 0.45 mmol) in DMF (5 mL) were added Pd(PPh3)2Cl2 (32 mg, 0.05 mmol), CuI (9 mg, 0.05 mmol), N,N-diisopropylethylamine (0.36 mL, 2.02 mmol) and 3-butyn-1-ol (70 μL, 0.90 mmol). The reaction mixture was stirred at room temperature overnight, poured into saturated aqueous NH4Cl (15 mL) and water (5 mL), extracted with ethyl acetate (2×50 mL). The combined organic phase washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 40% EtOAc in hexanes to give a light brown solid. The solid was triturated with hot hexanes containing 2% MeOH and 2% CH2Cl2 to afford 133 mg (76%) of the title compound (242) as light beige solid. mp 183-184° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.94 (s, 2H), 1.98 (s, 2H), 2.58 (t, J=6.8 Hz, 2H), 3.70 (t, J=6.8 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H). LCMS (APCI): m/z 389 (M+H)+, 387 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20]Cl>CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH3:20])=[O:13])[C:8]=2[C:15]([F:17])([F:18])[F:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: ClCCl
Solvent: CO
Product: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (Intermediate I-5D, 0.500 g, 1.94 mmol) in dichloromethane (5 mL) and methanol (1 mL) at room temperature was added trimethyldiazomethane (2.0 M in ether) (1.17 mL, 2.33 mmol) slowly over 10 min. During the addition, the solution remained colorless and the evolution of gas nitrogen was noted. Toward the end of the addition, the bubbling ceased and the solution became pale yellow. The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (40 mL) and washed with brine (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (0.509 g, 1.88 mmol, 97% yield) as a yellow oil. The product had an HPLC with a ret. time=2.52 min. (condition A); 1H NMR (400 MHz, CDCl3) δ ppm 4.05 (s, 3H), 7.50-7.64 (m, 3H), and 7.70 (d, J=7.48 Hz, 2H).