Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38]CC[CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].Cl[C:41]1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC1COC(C)(C)O1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:41])([CH3:38])[O:32]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Agent: CC1(C)OCC(CN=[N+]=[N-])O1
Product: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (1.37 mmol) and compound 410 (1.62 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 35:65 as the eluent to afford the title compound as yellow foam. 13C NMR (DMSO-d6) δ 194.9, 158.7 (dd), 155.7 (dd), 149.4, 145.2, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.5, 126.5 (dd), 125.0, 124.2 (dd), 122.3, 114.8, 111.9 (dd), 111.8, 109.0, 105.0 (dd), 73.7, 65.8, 52.0, 26.4, 25.1, 19.4
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH:16]1([CH2:19][N:20]2[C:28]3[N:27]=[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([NH:36][CH3:37])=[CH:32][CH:31]=4)[NH:25][C:24]=3[C:23](=[O:38])[N:22]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])[C:21]2=[O:47])[CH2:18][CH2:17]1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[NH:4]([C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:6]=1[C:7]([N:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:26]2[NH:25][C:24]3[C:23](=[O:38])[N:22]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[F:46])[C:21](=[O:47])[N:20]([CH2:19][CH:16]4[CH2:18][CH2:17]4)[C:28]=3[N:27]=2)=[CH:31][CH:32]=1)[CH3:37])=[O:9])[C:1]([CH3:2])=[O:3]
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: CC(=O)Nc1nc(C)cc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)cc(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 2-acetylamino-4,6-dimethylnicotinic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 1 equivalent of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and excess triethyl amine and a catalytic amount of 4-dimethylaminopyridine were added as the final reagents to the reaction mixture. The product was purified by chromatography using silica gel eluted with 93:7 chloroform/methanol. MS, m/z(M+)=624.4 and m/z(M−)=622.5.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1>C(Cl)Cl>[C:8]([NH:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(N)no1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)no1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Triethylamine (10 ml., 71.9 mmol) is added dropwise to an ice cold solution of 20.0 g. (71.6 mmol) of trityl chloride in 200 ml. of methylene chloride and the resulting solution is stirred at ice bath temperature for 5 minutes. 3-Amino-5-methylisoxazole (7.0 g., 71.5 mmol) in 50 ml. of methylene chloride is then added dropwise over 10 minutes. After the addition, the ice bath is removed and the stirring continued for 1.5 hours. The solution is washed with ice cold 1 N HCl, dried (MgSO4) and the solvent concentrated under reduced pressure until a white solid is present. Diethyl ether is added and the solid collected and dried to give 21 g. (85%) of the title compound as a white crystalline material; m.p. 196°-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:34][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCC1CCNCC1
Product: O=C(NCC1CCNCC1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to piperidin-4-ylmethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(piperidin-4-ylmethyl)terephthalamide. MS (Q1) 483 (M)+.
Reaction SMILES: [C:1]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:18].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>[OH:18][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:16])=[O:17]
Reactant: [OH-]
Reactant: O=C1CCCCCCCCCCCCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCO
Yield: 22360.1 %

Procedure:
15-pentadecanolactone (10 g, 42 mmols), potassium hydroxide (10 g, 0.18 mmols) and tetra-n-butylammonium bromide (1.34 g, 4.2 mmols) were dissolved in a mixed solvent of THF (100 ml) and water (30 ml), and heated under reflux for 12 hours. The reaction mixture was concentrated under reduced pressure to evaporate THF, and the aqueous layer was made acidic (pH=1) and then extracted with ether. The organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from acetone to obtain 10.4 g (yield: 97%) of 15-hydroxypentadecanoic acid as colorless needle-like crystals.
Reaction SMILES: [C:1]1([C:7]2([CH:12]=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:15][NH3+:16].N1C=CC=CC=1>C(O)C>[C:1]1([C:7]2([CH:12]=[N:16][OH:15])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH3+]O
Reactant: O=CC1(c2ccccc2)CCCC1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: ON=CC1(c2ccccc2)CCCC1
Yield: 66 %

Procedure:
A mixture of the above aldehyde (3.4 g, 20 mmol) and hydroxylammonium chloride (2.9 g, 42 mmol) in a mixture of absolute ethanol (30 ml) and pyridine (3.3 g, 42 mmol) was heated at reflux for 2 h. The solvent was evaporated in vacuo, the residue was treated with absolute ethanol (50 ml) and the suspension filtered. The solvent was evaporated from the filtrate in vacuo and the residue crystallised from a 4/1 mixture of n-heptane and ethyl acetate to give 2.5 g of 1-phenyl-1-cyclopentanecarboxaldehyde oxime.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:45][C:46]1[N:50]([CH3:51])[C:49]([CH3:52])=[N:48][N:47]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]3[N:50]([CH3:51])[C:49]([CH3:52])=[N:48][N:47]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nnc(CCl)n1C
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cc1nnc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS (m/e): 384.3 (MH+).
Reaction SMILES: [Cu:1].[CH2:2]1[C@H](N[C@@H]2[C@H](O)[C@@H](O)[C@H](O)C(CO)=C2)[C@H](O)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1CO.[Cu].C1[C@H](N[C@@H]2[C@H](O)[C@@H](O)[C@H](O)C(CO)=C2)[C@H](O)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1CO.C1OC(=O)C2C(Cl)=C(Cl)C(Cl)=C(Cl)C1=2.[Cu+].[CH3:86][C:87]1([CH:102]=[CH2:103])O[C:91](=[O:92])[N:90]([C:94]2[CH:95]=[C:96]([Cl:101])[CH:97]=[C:98]([Cl:100])[CH:99]=2)[C:88]1=[O:89].[Cu].C1OC(=O)C2C(Cl)=C(Cl)C(Cl)=C(Cl)C1=2>>[Cu:1].[CH3:2][C:87]12[C:88](=[O:89])[N:90]([C:94]3[CH:95]=[C:96]([Cl:101])[CH:97]=[C:98]([Cl:100])[CH:99]=3)[C:91](=[O:92])[C:102]1([CH3:103])[CH2:86]2
Reactant: OCC1=C[C@H](N[C@H]2C[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C=CC1(C)OC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: [Cu+]
Agent: [Cu]
Agent: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Product: CC12CC1(C)C(=O)N(c1cc(Cl)cc(Cl)c1)C2=O

Procedure:
The fungicidal preparations containing the inorganic copper fungicide and chemicals (such as fungicides, etc.) other than ingredients (a) and (b) include a Bordeaux mixture containing basic copper calcium sulfate; copper-sulfur fungicides, such as Engei Bordeaux (trade name, produced by Sankei Chemical Co., Ltd.), etc.; copper-validamycin fungicides; copper-validamycin-fthalide fungicides; copper-pyrifencox fungicides; copper(I)-vinclozolin fungicides; copper-fThalide fungicides; copper-procymidone fungicides, such as Scletane Wettable Powder (trade name, produced by Hokko Chemical Industry Co., Ltd.); copper(I)-fosetyl vegtable powders; copper-metalaxyl fungicides, such as Ridomil Copper Wettable Powder (trade name, produced by Nihon Nohyaku Co., Ltd.); iprodione copper(I) fungicides, such as Daisedo Wettable Powder (trade name, produced by Yashima Chemical Industry Co., Ltd.); iminoctadine triacetate-copper fungicides; oxadixyl copper(I) fungicides; oxolinic acid-copper fungicides; kasugamycin-copper fungicides, such as Kasumin Bordeaux Dust 3DL (trade name, produced by Hokko Chemical Industry Co., Ltd.), Kasumin Bordeaux (trade name, produced by Dai-ichi Noyaku K.K. and Hokko Chemical Industry Co., Ltd.), etc.; dithianon copper(I) fungicides; streptomycin-copper fungicides, such as Do Stomy Wettable Powder (trade name, produced by Nihon Nohyaku Co., Ltd.), etc.; sodium hydrogencarbonate-copper fungicides, such as G-Fine Wettable Powder (trade name, produced by Yashima Chemical Industry Co., Ltd.); and copper-organocopper fungicides, such as Oxy Bordeaux (trade name, produced by Sankyo Co., Ltd.), Kinset Wettable Powder (trade name, produced by Agro-Kanesho Co., Ltd.), Kinset Wettable Powder 80 (trade name:, produced by Agro-Kanesho Co., Ltd.), etc.
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[CH2:34][C@@H:33]([O:35][CH3:36])[CH2:32][C@H:20]1[C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.Br[Si](C)(C)C>ClCCl>[OH:5][P:4]([CH2:16][C:17]([N:19]1[CH2:34][C@@H:33]([O:35][CH3:36])[CH2:32][C@H:20]1[C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])=[O:22])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1C[C@@H](OC)C[C@H]1C(=O)OCOC(=O)C(C)(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](C(=O)OCOC(=O)C(C)(C)C)N(C(=O)CP(=O)(O)CCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
A solution of 2.9 g of (cis)-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-4-methoxy-L-proline, (2,2-dimethyl-1-oxopropoxy)methyl ester in 50 ml of dry dichloromethane is treated with 1.0 g of bromotrimethylsilane at 0° C., then stirred at room temperature for 16 hours under argon. The solvent is evaporated in vacuo and the oil residue is dissolved in ether and treated with an excess of saturated sodium. The aqueous portion is treated with 6 N HCl to pH 1.5 and the product is extracted into ethyl acetate, dried and evaporated in vacuo to give 1.4 g of product.
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)#[CH:3]
Reactant: Cc1ccc(N)cc1
Reactant: O=C([O-])OCC=Cc1ccccc1
Product: C#CC(Nc1ccc(C)cc1)c1ccccc1
Reaction time: 6 h
Yield: 76.6 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-toluidine (0.160 g, 1.5 mmol). The reaction was conducted at room temperature for 6 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be >99/1. The mixture was purified by flash column chromatography on silica gel (2% ethyl acetate in hexanes) to give the title compound (0.166 g, 76%). HPLC analysis indicated the enantiomeric excess of the product was 94% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 ml; TR=24.2 (minor), 32.2 (major) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.44-7.32 (m, 4H), 7.28 (dt, J=7.2, 2.0 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.65 (t, J=7.2 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 6.08 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.27 (dt, J=17.2, 1.2 Hz, 1H), 5.23 (dt, J=10.4, 1.2 Hz, 1H), 4.99 (t, J=4.4 Hz, 1 H), 3.88 (br s, 1H), 2.20 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[C:7]=1[S:26]([CH3:28])=[O:27].I[CH:30]([CH3:32])[CH3:31]>C(O)C>[CH:30]([O:25][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)([CH3:32])[CH3:31]
Reactant: CC(C)I
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A suspension of sodium ethoxide (0.34 g) in ethanol was added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in ethanol. 2-Iodopropane (1 ml) was then added and the mixture stirred overnight at 20° C. and evaporated. The residue (in dichloromethane) was water-washed, dried (magnesium sulfate), concentrated and purified by chromatography on silica gel to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(isopropyl)oxime (0.35 g), m.p.128-130° C. Compound 24.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1([CH3:31])[N:17]2[C:18](=[O:29])[C:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)=[CH:20][CH:21]=[C:16]2[C:15](=[O:30])[NH:14]1>CO.O.NN>[NH2:3][CH2:12][C:13]1([CH3:31])[N:17]2[C:18](=[O:29])[C:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)=[CH:20][CH:21]=[C:16]2[C:15](=[O:30])[NH:14]1
Reactant: CC1(CN2C(=O)c3ccccc3C2=O)NC(=O)c2ccc(Nc3ccncn3)c(=O)n21
Agent: NN
Solvent: CO
Solvent: O
Product: CC1(CN)NC(=O)c2ccc(Nc3ccncn3)c(=O)n21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (5, 0.085 g, 0.29 mmol) in methanol (20 mL), hydrazine hydrate (2 mL) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water, separated, dried over sodium sulphate and concentrated under reduced pressure, which was purified by repeated washing with diethyl ether and hexane to obtain 3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 15) as an off-white solid. Yield: 0.008 g, 9%; MS (ESI) m/z 287.05[M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.76 (d, J=7.8 Hz, 2H), 8.36 (d, J=5.9 Hz, 1H), 7.36 (d, J=6.0 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 3.55 (d, J=13.6 Hz, 1H), 2.92 (d, J=13.7 Hz, 1H), 1.75 (s, 3H), 1.44 (s, 1H), 1.41-1.34 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.Br[CH2:16][C:17]#[C:18][CH3:19].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[N:6]([CH2:16][C:17]#[C:18][CH3:19])[C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1
Reactant: CC#CCBr
Reactant: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCn1c(Br)nc(C(=O)OC)c1C(=O)OC
Yield: 75 %

Procedure:
A solution of 15.0 g (57.0 mmol) of dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 5.15 ml (57.0 mmol) of 1-bromo-2-butyne and 50 ml of N,N-diisopropylethylamine in 280 ml of tetrahydrofuran was refluxed for one hour. The mixture was concentrated by evaporation, the residue combined with approx. 100 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with 50 ml of water, dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant:dichloromethane with 0–2% ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.Br[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.Br>C(#N)C>[Br-:10].[C:18]([CH2:17][O:16][C:15]1[CH:21]=[CH:22][C:12]([CH2:11][N:3]2[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:4]2)=[CH:13][CH:14]=1)([OH:20])=[O:19]
Reactant: O=C(O)COc1ccc(CBr)cc1
Reactant: BrCc1cccc2ccccc12
Reactant: Clc1nc[nH]c1Cl
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)COc1ccc(Cn2c[n+](Cc3cccc4ccccc34)c(Cl)c2Cl)cc1
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 2-(4-(bromomethyl)phenoxy)acetic acid (1.80 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH2:16])=O>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:13]=[CH:14][NH:16][C:9]2=[O:11])([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Yield: 82 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 1 which is concerned with the preparation of starting materials, 5-nitroanthranilic acid was reacted with formamide to give 6-nitroquinazolin-4-one in 82% yield, m.p. 268°-271° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:28][C:26]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:28][CH3:26])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a mixture of 4,5-difluoro-2-nitrobenzoic acid (1.872 g, 9.22 mmol), methylamine hydrogen chloride (0.75 g, 1.2 eq), EDC (2.12 g, 1.2 eq), HOBt (1.5 g, 1.2 eq) in DMF (20 mL) was added DIEA (5.0 mL, 3.0 eq). The mixture was stirred at room temperature for 15 min. It was concentrated and the crude was dissolved in EtOAc. It was washed with a saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (20%˜80% EtOAc/Hex) to obtain the desired product 4,5-difluoro-N-methyl-2-nitrobenzamide (1.33 g, isolated yield 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].FC(F)(F)C(O)=O.[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:43][CH2:44][N:45]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH:10]([CH3:12])[CH3:11])[CH2:46][CH2:47]2)[CH2:21][CH2:22][CH2:23]1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Reactant: CC(C)Oc1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 55.7 %

Procedure:
A reaction mixture of 6-Chloro-5-isopropoxy-pyrimidin-4-ylamine (40.00 mg; 0.21 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (133.13 mg; 0.21 mmol; 1.00 eq.), and Cs2CO3 (277.84 mg; 0.85 mmol; 4.00 eq.) in DMSO 5.0 ml was stirred at 120° C. for 2 days, purified the product by HPLC, collected title compound 64 mg, yield 45.5%. LC-MS: (M+1=548, obsd.=548).
Reaction SMILES: [F-:1].[Cs+].[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([N+]([O-])=O)[CH:19]=3)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7].C(C12CCC(CCC3C=CC(Br)=CC=3)(CC1)CC2)CCCC.[Cu](C#N)C#N>CN1CCCC1=O>[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:1])[CH:19]=3)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [F-]
Reactant: CCCCCC12CCC(CCc3ccc(C#N)c([N+](=O)[O-])c3)(CC1)CC2
Agent: N#C[Cu]C#N
Agent: CCCCCC12CCC(CCc3ccc(Br)cc3)(CC1)CC2
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCCCC12CCC(CCc3ccc(C#N)c(F)c3)(CC1)CC2

Procedure:
7.6 g of caesium fluoride are added to a mixture of 3.55 g of 1-[4-pentylbicyclo(2.2.2)octyl]-2-(4-cyano-3-nitrophenyl)ethane (obtainable by nitrating 1-[4-pentylbicyclo(2.2.2)octyl]-2-(4-bromophenyl)-ethane, reacting the product with copper cyanide in N-methylpyrrolidone and subsequently purifying the product by chromatography) and 25 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, and the mixture is heated at 120oC for 5 hours. Adding water and working up after extraction gives 1-[4-pentylbicyclo(2.2.2)octyl]-2-(4-cyano-3-fluorophenyl)-ethane.