Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[O:4]=[C:2]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)[C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[NH:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N[C@@H]2CCCC[C@H]2N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)N[C@@H]3CCCC[C@H]32)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 141.8 %

Procedure:
A solution of triphosgene (7.2 g, 24.2 mmol) in dichloromethane (300 mL) was added with a solution of tert-butyl 4-{[(1R,2R)-2-aminocyclohexyl]amino}piperidine-1-carboxylate (18 g, 60 mmol) and triethylamine in dichloromethane (600 mL) drop wise over a period of 1 h and stirred at room temperature for 22 h. An additional amount of triphosgene (8 g) and triethylamine (13 mL) were added and stirred at room temperature for another 22 h. An aqueous solution of sodium hydroxide (0.5N 200 mL) was added to the reaction mixture, layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was triturated with diethylether (80 mL) to give the title compound as white solid (11.1 g, 56%). 1H NMR (300 MHz, METHANOL-D4): δ ppm 4.25-4.05 (m, 2H), 3.80-3.65 (m, 1H), 3.10-2.90 (m, 2H), 2.85-2.65 (m, 2H), 2.20-1.90 (m, 2H), 1.90-1.55 (m, 4H), 1.55-1.30 (m, 11H)
Reaction SMILES: C(OC([N:8]([CH2:37][C:38]1[CH:47]=[CH:46][C:41]2[O:42][CH2:43][CH2:44][O:45][C:40]=2[CH:39]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[C:20](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][C:18]2=[O:36])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:42]1[C:41]2[CH:46]=[CH:47][C:38]([CH2:37][NH:8][CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[C:20](/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:19][C:18]4=[O:36])[CH2:13][CH2:14]3)=[CH:39][C:40]=2[O:45][CH2:44][CH2:43]1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To 1 mL of a chloroform solution containing 0.10 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 1 mL of trifluoroacetic acid was added and stirred for 2 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=5:1] to give 68 mg of ethyl (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate as a yellow oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH:9]([C:11]([O:13]C)=[O:12])[CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:18]([O:17][C:15]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1CC(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(C(=O)O)C1

Procedure:
To a solution of piperidine-1,3,5-tricarboxylic acid 1-tert-butyl ester 3,5-dimethyl ester (6.8 g, 22.5 mmol) in MeOH/water (4:1, 120 mL), K2CO3 (9.4 g, 68 mmol) is added. The reaction is stirred at reflux overnight. The MeOH is evaporated and the residue is extracted with dicholoromethane and 1N aq. HCl. The organic phase is dried over Na2SO4, filtered and evaporated to give a light yellow solid. MS (LC-MS): 274 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])=[N:3][CH:4]=1
Reactant: Cc1cccc(C)c1O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Oc1ncc(Cl)cc1N
Temperature: 50 °C

Procedure:
2-Bromo-3-nitro-5-chloropyridine (4.8 g, 20 mmol) and 2,6-dimethylphenol (5.0 g, 41 mmol) were magnetically stirred in dry DMF (65 mL) and potassium carbonate (11.0 g, 80 mmol) was added. The mixture was heated at 50° C. for 4 days, allowed to cool to room temperature and added to ice; the product was extracted with ethyl acetate (3×100 mL). The extracts were washed with saturated aqueous NaHCO3 and dried (MgSO4), filtered and concentrated to provide the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.Cl[C:27]([O:29][CH3:30])=[O:28].O>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC>[CH3:30][O:29][C:27]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:28]
Reactant: Cc1cccc([C@H](OCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cccc(C)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(m-tolyl)methyl)piperidine-1-carboxylate and DMAP in anhydrous CH2Cl2, Et3N was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate in anhydrous CH2Cl2 was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. Water was added to quench the reaction. The aqueous layer was extracted with CH2Cl2, the combined organic layers were washed with 10% citric acid and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative TLC to afford (R)-tert-butyl 3-((R)-(2-(methoxycarbonylamino)ethoxy)(m-tolyl)methyl)piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14]C)=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[Li+].Cl>CO>[OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COC(=O)c1ncc2cccnc2c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncc2cccnc2c1O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a slurry of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1, Step 2 (1.50 g, 7.35 mmol) in methanol (45 ml) was added lithium hydroxide (22.0 ml of a 1M aq. solution, 22.0 mmol) and the reaction was heated at 100° C. for 7 hrs. Upon cooling to room temperature, hydrochloric acid (22.0 ml of a 1M aq. solution, 22.0 mmol) was added and the reaction stirred for 16 hrs. The mixture was concentrated to a volume of 50 ml and neutralized with dilute NaHCO3 (pH=7) The resulting precipitate was collected by filtration and washed with water and dried in vacuo to afford the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[N:16]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochlorde salt, of Preparation 44, and 4-pyrimidin-2-yl-benzaldehyde, of Preparation 21, using the method described in Example 1, Step A except that the imine was formed in MeOH at reflux with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, 2H), 8.40 (d, 2H), 7.49 (d, 2H), 3.88 (s, 2H), 3.80 (s, 2H), 3.65 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][CH:6]=1)=[O:4].[Cl:11][C:12]([Cl:17])([Cl:16])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:13](=[O:14])[C:12]([Cl:17])([Cl:16])[Cl:11])[NH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]cc1C
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1C

Procedure:
WO 00/71129 describes the preparation of 1,4-dihydro-5-alkyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates, key intermediates in the synthesis of pyrrolotriazine carboxamide and benzamide compounds of formula I, by reacting a Michael acceptor such as methyl crotonate with an anion of tosylmethyl isocyanide (TosMIC) to give 4-methylpyrrole-3-carboxylic acid methyl ester. The resulting 4-methylpyrrole-3-carboxylic acid methyl ester is acylated with trichloroacetyl chloride in the presence of aluminum chloride to afford 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester. Treatment of 2-trichloroacetyl-3-methylpyrrole-4-carboxylic acid methyl ester with sodium methoxide produces 3-methylpyrrole-2,4-dicarboxylic acid methyl ester. N-amination of 3-methylpyrrole-2,4-dicarboxylic acid methyl ester using an aminating reagent such as diphenyl phosphoryl hydroxylamine affords 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester. Finally, reaction of 1-amino-3-methylpyrrole-2,4-dicarboxylic acid methyl ester with formamide at elevated temperature gives 1,4-dihydro-5-methyl-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (Hunt, J. T.; Bhide, R. S.; Borzilleri, R. M.; Qian, L. WO 00/71129, Nov. 30, 2000). Although a number of 1,4-dihydro-5-substitued-4-oxo-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylates can be prepared by this method, this process is limited due to its lengthy chemical transformations, the use of hazardous aminating reagents and expensive chromatographic separation of products. WO 02/40486 describes an improved synthesis of 3-methylpyrrole-2,4-dicarboxylates by condensing ethaldehyde and isocyanoacetates in the presence of DBU. The synthesis is shorter, however, generation of the side-product, cyanide, is a safety concern. Preparation of 6-ethyl-1,2,4-triazin-5-one by Raney nickel mediated desulfurization of 6-ethyl-1,2,4-triazin-5-one-3-thione has been reported (Taft, W. E.; Shepherd, R. G. J. Med. Chem. (1967), 10, at 883).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:23](O)=[O:24])[C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:15][NH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C:26]([O:28][CH3:29])=[O:27].[CH2:30]([NH2:45])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][NH2:44]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:11]3=[C:10]([C:23](=[O:24])[NH:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:45][C:23]([C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:26]([O:28][CH3:29])=[O:27])[CH:4]=4)[N:13]=[C:12]4[NH:14][N:15]=[C:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:11]=34)=[O:24])[CH:9]=2)=[CH:4][C:3]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc(-c2cc(C(=O)O)c3c(-c4ccccc4)n[nH]c3n2)ccc1F
Reactant: NCCOCCOCCOCCOCCN
Product: COC(=O)c1cc(-c2cc(C(=O)NCCOCCOCCOCCOCCNC(=O)c3cc(-c4ccc(F)c(C(=O)OC)c4)nc4[nH]nc(-c5ccccc5)c34)c3c(-c4ccccc4)n[nH]c3n2)ccc1F
Yield: 66 %

Procedure:
Obtained according to the process described in Step 1.10, using 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid [described in Step 1.9.] and 3,6,9,12-tetraoxatetradecane-1,14-diamine, in the form of a white powder (yield: 66%).
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2].[CH3:19][C:20]([CH3:35])([C:24]([NH:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:21](O)=[O:22]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:21](=[O:22])[C:20]([CH3:19])([CH3:35])[C:24]([NH:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[O:25])[C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCN1C(=O)[C@@H](N)CN(C(C)=O)c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)CN(C(C)=O)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid yielded the title compound as a white solid; MS: m/e=493 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=[N:16][N:15]=2)=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O>ClC(Cl)(Cl)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:28][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A mixture of compound D (8.0 g; 21 mM), N-bromosuccinimide (4.53 g; 25 mM) and azo(bisisobutyronitrile) (73 mg) in 1,1,1-trichloroethane (methyl chloroform) (50 mL) was heated under reflux for 4 hours. The mixture was cooled to ambient temperature, washed with water (3×50 mL), and the suspended solid collected by filtration to give 5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (E) (7.3 g), m.p. 192°-195° C.; NMR (CDCl3): 4.4(2H, s), 6.52(2H, d), 6.85(2H, d), 7.07(2H, d), 7.4(1H, d) 7.7 (2H,m), 7.9(1H, d).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](#[N:10])[C:7]([CH3:9])=[CH2:8]>>[N:1]1([CH2:8][CH:7]([CH3:9])[CH2:6][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=C(C)C#N
Reactant: c1c[nH]cn1
Product: CC(CN)Cn1ccnc1

Procedure:
A mixture of 15.0 g. of imidazole and 25 ml. of methacrylonitrile was heated at reflux temperature for 18 hours and then concentrated to remove the volatile material. The residue was mixed with 150 ml. of ethanol, 75 ml. of ammonium hydroxide and 6 g. of Raney Nickel catalyst and reduced in a Parr hydrogenator under hydrogen pressure until reduction was complete. The catalyst was removed by filtration and the mother liquor was concentrated to remove the solvents. The residual oil was used in reactions without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Fc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(Cl)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-fluoro-5-chloropyridine, and K2CO3 in DMAC was stirred at 120° C. for 16 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 458.95 (M+H).
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]>CCCCCC.C(OCC)C>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC1=CC=CC1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]C1(CCCC)C=CC=C1

Procedure:
Being cooled in an ice-water bath, a solution of 49.8 ml of butyl lithium(0.125 mol) in 2.5M hexane was slowly dripped to a solution of 15.2 g(0.125 mol) of butyl-cyclopentadiene in 200 ml diethylether with stirring. After the dripping was finished, the resultant mixture was continuously stirred for 1 hour, a white muddy solution of butyl-cyclopentadienyl lithium was then obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH3:12])[N:3]=1.CCO.[CH2:16]([NH2:18])[CH3:17]>C(Cl)Cl.O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([CH2:17][CH2:16][NH2:18])[N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: CCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: CCN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCn1nc(Br)c([N+](=O)[O-])c1CCN
Yield: 45.6 %

Procedure:
A mixture of 3,5-dibromo-1-ethyl-4-nitro-1H-pyrazole (28.4 g; 95 mmol), EtOH (470 ml) and ethylamine (45.0 g, 700 mmol) was refluxed for 3 hours. The reaction medium was concentrated to the maximum under reduced pressure (rotary evaporator, water bath at 40° C.). The brown oil obtained was suspended in DCM (250 ml) and water (250 ml). The aqueous phase was washed with DCM (50 ml). The combined aqueous phases were extracted with DCM (50 ml) and the combined organic phases were then dried over NaSO4. After evaporating off the solvent, a solid was obtained (24.6 g), which was purified by chromatography on silica gel (eluent: EtOAc/hexane) to give (5-bromo-2-ethyl-4-nitro-2H-pyrazol-3-yl)ethylamine (11.4 g, 45%) in the form of a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:46]([N:54]1[C:59](=[O:60])[CH:58]=[CH:57][NH:56][C:55]1=[O:61])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCCCCC.CCOC(C)=O>[C:46]([N:54]1[C:59](=[O:60])[CH:58]=[CH:57][N:56]([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:55]1=[O:61])(=[O:53])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: OCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(c1ccccc1)n1c(=O)ccn(CCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
Polymer supported triphenyl phosphine (2.5 eq, 3 mmol/g loading) was swelled in dry THF for 15 minutes then the alcohol 14 (1 eq, 300 mg) and the N3-benzoyluracil (1.5 eq) were added into the suspension, which was shaken at room temperature under atmosphere of nitrogen. A solution of DIAD (2 eq) in THF was added slowly into the suspension. The reaction was shaken overnight until the disappearance of the alcohol was observed by TLC. The resin was then filtered off and washed with THF (5 ml). The solvent was removed under reduced pressure to afford a residue which was taken in a mixture of Hexane/EtOAc (50:50). The formed white precipitate was removed and the solution was concentrated to an orange oil and purified by flash chromatography using a mixture of Hexane/EtOAc (40:60) as eluent which gave the title compound (250 mg, 53%).
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]([O:14][OH:15])([CH2:7][CH2:8][C:9]([CH3:13])([O:11]O)[CH3:10])[CH3:6].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:16]([O:15][O:14][C:5]([CH3:6])([CH3:4])[CH2:7][CH2:8][C:9]([OH:11])([CH3:13])[CH3:10])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(CCC(C)(C)OO)OO
Reactant: CC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)CCC(C)(C)OOC(=O)C(C)(C)C
Reaction time: 2 h

Procedure:
A jacketed reactor equipped with a mecahnical stirrer, a thermometer and a dropping funnel was charged with 18.7 g (0.150 mole) of 45% KOH, 15.0 g of water, 27.6 (0.120 mole) of 77.6% (wetted solid) 2,5-dimethyl-2,5-dihydroperoxyhexane and 100 ml of methylene chloride. To the resulting two liquid phase mixture at 28° to 30° C. was added 12.8 g (0.100 mole) of 94.3% pivaloyl chloride over a period of about 30 minutes. The resulting mixture was then stirred for 2.0 hours at 28° to 30° C. after which the mixture was cooled to 15° to 20° C. and was allowed to separate into phases. The upper aqueous layer was removed and was discarded. The resulting product solution was then washed with 50 ml of 20% KOH solution at 0° C. and then with 50 ml of 7.7% sodium hydrogen carbonate solution at 15° to 20° C. The methylene chloride solution was then cooled to 0° to 10° C. and was reacted with 187 g of buffered sodium sulfite solution (consisting of 7.6 g of acetic acid, 8.4 g of sodium acetate, 19 g of sodium sulfite and 152 g of water) in order to covert the 4-hydroperoxy-1,1,4,4-tetramethylbutyl peroxypivalate that was formed in the peroxidation reaction to 4-hydroxy-1,1,4,4-tetramethylbutyl peroxypivalate, the desired product. A thick emulsion resulted which required three days of storage in the refrigerator to separate into two liquid phases. The upper aqueous layer was removed and an equal volume of diethyl ether was added in order to facilitate further processing. The solution was dried over anhydrous MgSO4 and after separation of the spent desiccant by filtration the solvents were remove in vacuo at 0° to 10° C. Some solids were removed by filtration and the resulting liquid weighed 20.4 g. The assay of the product was 90.3% according to peroxyester active oxygen content. The corrected yield was 74.9%. An infrared spectrum of the product showed a broad OH band centered at 3300 to 3400 cm-1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.O=S(Cl)Cl.[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1)=[O:23]>ClC(Cl)C>[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[C:27]([C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:15])[CH:28]=1)=[O:23]
Reactant: COC(=O)c1ccc[nH]1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)c2c(-c3ccccc3)noc2C)c[nH]1
Temperature: 25 °C

Procedure:
A mixture of 406 mg (2 mmol) 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (commercially available) and 4 mL SOCl2 was heated to reflux for 3 h. After evaporation of all volatiles the residue was added to a mixture of 206 mg (2 mmol) 1H-pyrrole-2-carboxylic acid methyl ester (commercially available) and 440 mg (3 mmol) AMCl3 in 25 mL dichloroethane and heated to reflux for 3 h. After cooling to room temperature the precipitate was collected and washed with dichloromethane. The residue was purified on silica eluting with a gradient of ethyl acetate and heptane affording 210 mg (37%) of the title compound as white foam. (m/e): 311.0 (MH+; 100%).