Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[N:24]OCC)[CH:21]=4)[NH:16][N:15]=3)[CH:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:28][NH:29][C:30](=O)[CH2:31][N:32]([CH3:34])[CH3:33].C[O-].[Na+]>CO>[CH3:33][N:32]([CH2:31][C:30]1[N:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:13]=[CH:12][CH:11]=2)[NH:28][N:29]=1)[CH3:34]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CCC4)c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CCC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclobutyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (460 mg, 1.06 mmol), N-amino-2-(dimethylamino) acetamide (372 mg, 3.17 mmol) and sodium methoxide (608 μL of a 25% w/w in methanol) in anhydrous methanol (7.0 mL) with a reaction time of 44 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a pale yellow solid. The residue was dissolved in a minimum amount of anhydrous methanol and excess 1.0 N HCl in anhydrous ethyl ether was added dropwise to precipitate the desired product as the bis-hydrochloride salt. The product was collected and dried under vacuum to afford the title compound (27 mg, 5% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 10.6 (br s, 1H), 8.89 (d, 1H), 8.84 (s, 1H), 8.4 (s, 1H), 8.17 (d, 1H), 8.12 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.63 (t, 1H), 4.5–4.4 (m, 1H), 4.44 (s, 2H), 2.83 (s, 6H), 2.23–2.0 (m, 4H), 1.72–1.62 (m, 2H); ES-MS (m/z) 416 [M+H]+ (HCl salt not detected).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:25]2([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]2)=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][CH2:44][N:45]1[CH2:51][CH:50]([OH:52])[C:47]2([CH2:49][CH2:48]2)[CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:52][CH:50]1[C:47]2([CH2:49][CH2:48]2)[CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:22]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:23]([C:25]5([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]5)=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:51]1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1O
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.2 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (260 mg, 0.534 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (266 mg, 1.068 mmol) and Cs2CO3 (520 mg, 1.602 mmol). The reaction was then stirred at rt for 2 days. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (264 mg, 77%).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:34][C:33]1[CH:32]=[C:31]([CH3:35])[NH:30][C:29](=[O:36])[C:28]=1[CH2:27][NH:26][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N:3]([CH2:1][CH3:2])[CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[C:5]=1[CH3:17]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, 580 mg, 1.68 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one HCl salt (477 mg, 2.53 mmol) in DMSO (6 mL) was added PyBOP (1.57 g, 3.02 mmol) and hunig base (650 mg, 5.04 mmol). The reaction mixture was stirred at 23° C. for 20 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=25/1) to give the titled compound as a white amorphous (386 mg, 48% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.27 (s, 1H), 7.18 (t, J=5.7 Hz, 1H), 5.95 (s, 1H), 4.55 (d, J=5.9 Hz, 2H), 3.17 (dq, J=6.4, 3.3 Hz, 2H), 3.08 (q, J=7.0 Hz, 2H), 2.81 (m, 2H), 2.70 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.78-1.93 (m, 2H), 1.70 (m, 2H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 479.2, [M+Na] 501.3; HPLC 96.8% purity.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:20][CH2:21][CH2:22][CH:4]2[NH:3]1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].Br[CH2:33][CH2:34][O:35][CH2:36][CH2:37]Br>CC#N>[N:19]1([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]3[N:5]4[CH2:20][CH2:21][CH2:22][CH:4]4[NH:3][S:2](=[O:1])(=[O:23])[C:7]=3[CH:8]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: Nc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(N4CCOCC4)c3)cc21

Procedure:
A mixture of 300 mg (0.90 mmol) of {3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl}amine, 192 mg of Na2CO3 (1.81 mmol), 5 mg of NaI, 126 μl of 2-bromoethyl ether (0.905 mmol) in 6 ml of CH3CN is refluxed overnight. The suspension is filtered; the filtrate is evaporated, taken up in CH2Cl2 and washed with saturated NaCl solution. After evaporation in vacuo, the expected product is purified by chromatography on silica (CH2Cl2/acetone 96/4).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[CH:15]=[CH:16][N+]([O-])=O.[N+:25]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])#[C-:26]>C1COCC1>[Cl:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[C:15]1[CH:16]=[CH:26][NH:25][C:27]=1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Cl
Reactant: [C-]#[N+]CC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccccc1)c1[nH]ccc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 15 %

Procedure:
DBU (1 eq) was added to a stirred solution of 2,4-Dichloronitrostyrene (1) (1 eq) and benzyl 2-isocyanoacetate (0.9 eq) in THF at −78° C. under N2. The reaction was allowed to warm to room temperature over 2 h. The reaction could be followed by TLC eluting with CHCl3 (Rf=0.3). After stirring for an additional 12 h, the reaction was diluted with CH2Cl2 and EtOAc. The organic mixture was washed with 0.1 N HCl, water, sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to an oil. The crude product was purified using silica column chromatography eluting with CHCl3 to obtain pure phenylmethyl 3-(2,4-dichlorophenyl)pyrrole-2-carboxylate (2) (15% yield).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccccc1Cl
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-(trifluoromethyl)-benzenesulfonamide (1.5 g, 3.03 mmol) in anhydrous THF (15 mL) was added 2 M isopropylmagnesium chloride in THF (3.3 mL, 6.6 mmol) at −20° C. The temperature was allowed to slowly rise to 10° and then 2-chloro-N-methoxy-N-methylbenzamide (1.2 g, 6.0 mmol) was added and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred for 16 h. It was then quenched with saturated aqueous NH4Cl (50 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using ethyl acetate-hexane mixtures (2:98, 5:95) to provide 4-chloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide mass spectrum m/z 574.8 (M+Na); 521.0 (M−31).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([N:18](CC)CC)C.CN.CO>CO>[CH3:16][NH:18][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: CN
Solvent: CO
Product: CCOC(=O)c1ccc(NC)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate (10.0 g, 46.9 mmol) prepared in the Step 1-1-1 was dissolved in methanol (40 ml), and triethylamine (10 ml, 70.4=01) was added thereto. Under an ice cooling, a 40% methylamine-methanol solution (5.50 g, 70.4 mmol) was added to the mixture. After the resulting mixture was stirred for one hour under an ice cooling, ice water was added thereto. The precipitate was separated by filtration and washed with water. The washed product was subjected to through circulation drying overnight to give the title compound (10.4 g, 99%) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[CH:22]=[C:10]2[NH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]3)=[N:13][CH:14]=[C:9]2[N:8]=1.CC[O:26]C(C)=O.[ClH:30]>CO>[OH2:26].[ClH:30].[CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[CH:22]=[C:10]2[NH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]3)=[N:13][CH:14]=[C:9]2[N:8]=1
Reactant: CCOC(C)=O
Agent: Cc1cc(-c2cc3[nH]c(C4CCNC(C)C4)ncc-3n2)c(C)s1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing 2,5-dimethyl-3-(1-pyrrolidinylvinyl) thiophene (freshly prepared before use) (1.40 g, 6.76 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (1.40 g, 6.76 mmol), N,N-diisopropyl ethyl amine (Aldrich Chemical Company) (1.2 mL, 6.76 mmol), piperidine (Aldrich Chemical Company) (1.1 mL, 10.8 mmol), NEt3 (Aldrich Chemical Company) (1.0 mL) and SnCl2 (20 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 335 mg (15%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.40 (s, 3), 2.42 (s, 3), 2.50 (s, 3), 3.70 (br s, 4), 6.36 (s, 1), 7.04 (s, 1), 10.82 (s, 1). MS m/z: 327 (M+1). To a hot solution of 2,5-dimethyl-3-(2-methyl-4-piperidyl pyrrolo[4,5-d]pyrimidin-6-yl)thiophene (0.35 g, 1.02 mmol) in 5:1 EtOAc:MeOH (40 mL) was added 1M etheral HCl (Aldrich Chemical Company) (1.00 mL, 1.00 mmol). Crystallization occurred as the mixture cooled and the precipitate was collected by filtration, washed with Et2O (2×5 mL) and dried under vacuum to give 222 mg (60%) of the title compound as a beige colored solid. Mp: 240-241.5° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.70 (br s, 6), 2.44 (s, 3), 2.50 (s, 3), 2.55 (s, 3), 4.02 (br s, 4), 6.54 (s, 1), 7.06 (s, 1), 11.89 (s, 1), 14.15 (s, 1). MS m/z: 327 (M+1). Anal. Calcd for C18 H22N4S.HCl.1.5H2O: C, 55.53; H, 6.68; N, 14.40; Cl, 9.00; S, 8.23. Found C, 55.62; H, 6.66; N, 14.31; Cl, 9.31; S, 8.28.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][C:21](=[O:24])[CH:22]=[CH2:23]>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7](=[O:8])[CH2:23][CH2:22][C:21](=[O:24])[CH3:20])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C=CC(C)=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 59.2 %

Procedure:
In a small vial charged with 4-(trifluoromethyl)benzaldehyde (3.00 mL, 21.98 mmol) in Ethanol (Volume: 9.5 mL) was added triethylamine (6.13 mL, 44.0 mmol), but-3-en-2-one (2 mL, 21.98 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (1.109 g, 4.40 mmol). The reaction mixture was heated at 80° C. for 16 h and then concentrated. The residue was treated with 1N HCl and extracted with DCM (3×). The organic layer was dried with MgSO4. The crude product was added to an 80 g ISCO silica gel column and was purified with a gradient of 0% to 40% EtOAc/hexanes. The product was obtained as a colorless crystalline solid (3.18 g, 13.02 mmol, 59.2% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 8.07 (d, 2H), 7.71 (d, 2H), 3.26 (t, 2H), 2.91 (t, 2H), 2.25 (s, 3H); MS m/z: 245.18 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4](N)[CH:3]=1.[I:22]CI.C(ON=O)(C)(C)C>CCOC(C)=O>[I:22][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=1
Reactant: ICI
Reactant: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Product: Cc1cc(I)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
A suspension of Example A2 (0.62 g, 2.2 mmol), KI (3.7 g, 22.3 mmol), and diiodomethane (5 mL, 62 mmol) was treated with t-butylnitrite (1.4 mL, 11.7 mmol) and stirred at RT for 12 h. The mixture was treated with EtOAc, washed successively with satd. NaHCO3 (3×), 10% Na2S2O3 (2×), and brine (2×) and the combined aqueous washes were back-extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to afford 2-iodo-4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.51 g, 59%). MS (ESI) m/z: 393.0 (M+H+).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)=[O:5].[CH3:19][Mg+].[Br-].O>C1COCC1>[N:13]1([C:8]2[N:7]=[C:6]([C:4](=[O:5])[CH3:19])[CH:11]=[C:10]([CH3:12])[N:9]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc(C)nc(-n2ccnc2)n1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
To a solution of 2-imidazol-1-yl-6-methyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (162 mg, 0.800 mmol) in THF (10 mL) at 0° C. was added MeMgBr (0.8 mL, 3M in Et2O, 2.40 mmol). The solution was warmed to rt and stirred for 20 min. Water was added and the mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave 143 mg (88%) of 1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethanone as a yellow solid. [M+H]+ 203.17.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])#[N:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C1C=CC=CC=1>C(N(CC)CC)C>[CH3:18][S:19]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:21])=[O:20]
Reactant: CCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-cyano-2 -(2,4-dichlorophenyl)hexan-1ol (5.6g., 0.02 mole) and methane sulfonyl chloride (2.9g., 0.025 mole) in 200 ml. of benzene is added dropwise at 10° C., 2.8g. (0.027) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 6.3g. of product.
Reaction SMILES: [CH2:1]([N:8]1[C:15]2[CH:14]3[CH2:16][CH:13]3[CH2:12][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.[Zn+2].[Br-].[Br-]>[CH2:1]([N:8]1[C:15]2[CH:14]3[CH2:16][CH:13]3[CH2:12][C:11]=2[C:10]([C:17]2[N:19]=[N:20][NH:21][N:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1nn(Cc2ccccc2)c2c1CC1CC21
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: c1ccc(Cn2nc(-c3nn[nH]n3)c3c2C2CC2C3)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonitrile (11.1 g, 47.2 mmol) in DMF (125 mL) was added ZnBr2 (18.4 g, 70.6 mmol) followed by NaN3 (12.2 g, 188 mmol). The mixture was heated to 120° C. and stirred for 18 h under N2 atmosphere. The reaction was cooled to rt and the DMF was removed in vacuo. The crude residue was diluted with EtOAc (200 mL) and HCl (3N aq., ˜100 mL) and stirred for 10 min. The layers were separated and the aqueous phase was back-extracted with EtOAc (150 mL). The combined organics were washed with NaOH (1M aq., 2×250 mL) and the organic layers were discarded. The basic aqueous phase was acidified with 6 N HCl to pH ˜2 and was extracted with EtOAc (2×250 mL). The extracts were washed with brine (150 mL), dried over MgSO4, filtered, and concentrated to give 2-benzyl4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene as a light brown solid. 1H NMR (400 MHz, MeOD): δ 7.33 (5H, m), 5.42 (1H, d, J=14.8 Hz), 5.35 (1H, d, J=15.2 Hz), 3.01 (1H, dd, J=16.4, 6.4 Hz), 2.88 (1H, d, J=17.6 Hz), 2.28 (1H, m), 2.11 (1H, M), 1.14 (1H, m), 0.33 (1H, m). HPLC/MS: Alltech® Prevail C18 column (5μ, 50×4.6 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 3.5 ml/min, tr=2.14 min, ESI+=279.3 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[CH2:50]([C:52]1[N:57]=[C:56]([NH2:58])[CH:55]=[CH:54][CH:53]=1)[CH3:51]>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:58][C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([CH2:50][CH3:51])[N:57]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: CCc1cccc(N)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol). The reaction mixture was stirred for 2 hours. After this time, 6-ethyl-2-pyridinamine (159 mg, 1.3 mmol) was added to the mixture, which was then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the resulting residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organic phases were dried over sodium sulfate and concentrated. The crude product residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to provide 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (359 mg, 0.79 mmol, 79% yield) as a clear oil. MS: 457 ([M+H]+).
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CS(C)(=O)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
Methyl vinyl sulfone (1.8 mL, 20.1 mmol) was added to a solution of 1-(tert-butyloxycarbonyl)piperazine (1.50 g, 8 mmol) in methanol (84 mL). The reaction mixture was stirred at room temperature for 4 h and concentrated to a white solid. Purification of the solid by flash column chromatography (silica gel, eluting with 1-5% methanol in methylene chloride) gave 1-tert-butyloxycarbonyl-4-(2-methanesulfonylethyl)piperazine as a white solid (2.29 g, 95%).