Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])=[N+](C)C)C>C1COCC1>[C:18]([O:20][N:49]1[C:54](=[O:55])[CH2:53][CH2:52][C:50]1=[O:51])(=[O:19])[CH2:17][CH2:16][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][C:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 18 h
Yield: 29 %

Procedure:
To a solution of mono-tert-butyl octadecanedioate (1,00 g, 2.7 mmol) in dry THF (8 ml), was added DIPEA (0,555 ml, 3.2 mmol) followed by TSTU (1,00 g, 3.2 mmol). The reaction mixture was stirred under nitrogen for 18 h. The solvent had evaporated. AcOEt was added to the residue and the resulting suspension was filtered. The filtrate was washed with cold 0.1 M HCl (2×) and water, dried and concentrated to give succinimidyl tert-butyl octadecandioate as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=O)=[CH:9][C:8]=1[CH:25]=[C:26]([Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>ClCCl>[Cl:3][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([CH:25]=[C:26]([Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:9]=2)[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(Cl)=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)=Cc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)ccc1Cl
Reaction time: 2 h

Procedure:
13.8 ml of phosphoryl chloride were added dropwise to 12.6 g of 3-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl]-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, and stirring was carried out for 2 hours at room temperature. Thereafter, 2.1 ml of dimethylformamide were added and stirring was continued for 15 hours at 110-115° C. The reaction mixture was evaporated down under reduced pressure, the residue was added to 150 ml of ice water and the mixture was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed with water, 10% strength sodium bicarbonate and again with water, dried over sodium sulfate and evaporated down. The oil obtained was subjected to flash chromatography (dichloromethane), and the crystalline solid obtained therefrom was stirred with petroleum ether, removed, washed with a little petroleum ether and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19](=[O:24])C(F)(F)F)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:29]>CN(C)C=O.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]([C:19]([OH:24])=[O:29])=[C:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)C(F)(F)F)c3ccccc32)C1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(c(C(=O)O)c3ccccc32)C1
Yield: 86.2 %

Procedure:
To a solution of 0.29 g (0.77 mmol) 10-(2,2,2-trifluoro-acetyl)-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 7 ml N,N-dimethylformamide were subsequently added 0.22 g (4.6 mmol) sodium hydride (50% in oil) and a solution of 0.070 ml (3.9 mmol) water in 1 ml N,N-dimethylformamide at room temperature. The reaction mixture was diluted with tert-butyl methyl ether after 2 h and extracted with 1 M sodium hydroxide solution (2×30 ml). The combined aqueous layers were acidified (pH 1-2) with 2 M hydrochloric acid at 0° C. and extracted with tert-butyl methyl ether (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (0.21 g, 86%) as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].[OH-].[Ba+2].[OH-].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:16][O:17][C:18]([C:20]1[CH:25]=[C:24]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc(-c2cccc(OCc3ccccc3)c2)c1
Yield: 55.3 %

Procedure:
A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.176 g, 0.67 mmol), 3-methoxycarbonylphenylboronic acid (0.18 g, 1 mmol), barium hydroxide (0.25 g, 1.47 mmol), Pd(PPh3)4 (0.077 g, 0.067 mmol), DME (5 mL) and H2O (3 mL) was microwaved with vigorous stirring using a CEM-discover system (ram time: 2 min, hold time: 5 min, temperature: 120° C., pressure: 200 psi, power: 250 W). The crude reaction mixture filtered through a plug of celite and concentrated in vacuo. The residue obtained was purified by flash column chromatography (25% diethyl ether-hexane) to give the title compound (29) (0.118 g, 60% yield) as a viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=O.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[N:14]([CH3:13])[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:7][N:6]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(-c2ccccc2F)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.23 g yield starting from 2-fluorobenzoic hydrazide (0.44 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.50 g). MS (m/z): 245 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([CH3:29])=[N:25][O:26][C:27]=2[CH3:28])[O:20][N:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([CH3:29])=[N:25][O:26][C:27]=2[CH3:28])[O:20][N:19]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C)noc2C)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][N:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[CH:53]=[N:52]1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:54]4[CH:53]=[N:52][N:51]([CH3:50])[CH:55]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cn1cc(CN)cn1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (1-methyl-1H-pyrazol-4-yl)methanamine, the title compound was obtained as a colorless solid in 44% yield: mp 173-175° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.29 (t, J=6.0 Hz, 1H), 7.57 (s, 1H), 7.38-7.32 (m, 3H), 7.23-7.17 (m, 2H), 4.42 (s, 2H), 4.18 (d, J=6.0 Hz, 2 H), 3.99 (t, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.45 (t, J=9.0 Hz, 2H), 2.45 (s, 3H); MS (ES+) m/z 429.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.[NH:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:15]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:14]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:15]1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COC(=O)c1cc[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(-c2ccc(OC)cc2OC)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dimethoxyphenylboronic acid 1 (2.88 g, 15.8 mmol, 1.00 equiv) in DMF (100 mL) was added methyl 1H-pyrazole-3-carboxylate (3.00 g, 23.7 mmol, 1.50 equiv), Cu(OAc)2 (5.70 g, 31.6 mmol, 2.00 equiv), and pyridine (3.76 g, 47.4 mmol, 3 equiv). The resulting solution was stirred for 2 h at 90° C. The solids were filtrated off by filtration and the filtrate was extracted by EtOAc (200 mL×3). The combined organic layers were dried by anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with PE/EA (3/1). This resulted in 1.5 g (36%) of methyl 1-(2,4-dimethoxyphenyl)-1H-pyrazole-3-carboxylate 2 as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, J=2.4 Hz, 1H), 7.61 (d, J=9 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.59 (s, 1H), 7.73, 6.58 (d, J=8.7 Hz, 1H). LC-MS: m/z=263 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][C:21]([N:25]([CH2:29][CH:30]=[CH2:31])[CH2:26][CH:27]=[CH2:28])([CH3:24])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:23][CH2:22][C:21]([N:25]([CH2:26][CH:27]=[CH2:28])[CH2:29][CH:30]=[CH2:31])([CH3:24])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Yield: 20.6 %

Procedure:
Following general procedure F, {6-Bromo-4-[4-(diallylamino)-4-methylcyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (96 mg, 0.198 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (86 mg, 0.297 mmol) to afford the desired product (23 mg, 27%) as a yellow solid: ESI MS m/z 564 [C32H35Cl2N3O2+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:6]#[N:7])[CH2:15][CH2:16]1
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(CN2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) and morpholine (0.65 g, 7.46 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.66 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-(morpholinomethyl)-5-nitrobenzonitrile (0.87 g, 85%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (br s, 1 H), 8.41 (br s, 1H), 8.01 (br s, 1H), 3.74 (br t, 4H, J=4.4 Hz), 3.64 (s, 2H), 2.48 (br t, 4H, J=4.4 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].OC1C=NC=CC=1.C1([O:21][C:22](=O)[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])C=CC=CC=1>C(OCC)(=O)C>[CH2:28]([O:27][C:25]([NH:24][CH2:23][C:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:21])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1CCNCC1
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1ccccc1
Agent: Oc1cccnc1
Agent: [Na]
Solvent: CCOC(C)=O
Product: O=C(NCC(=O)N1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
8.5 g. of piperidine and 1.2 g. of the sodium salt of 3-hydroxypyridine are added to 100 ml. of ethyl acetate, and 28.5 g. of benzyloxycarbonylglycine phenyl ester is added thereto with stirring at room temperature, whereupon reaction immediately starts and is complete in 2 hours. The product is worked up as previously described to give an oil which is crystallized from acetone-water. 18.7 g. of N-(benzyloxycarbonylglycyl)-piperidine are obtained (yield: 68%). m.p. 111° - 112°C. A single spot is obtained therefrom by thin layer chromatography. An additional 5.9 g. of crystals are obtained from the mother liquor, (yield: 21%). m.p. 109.5° - 112°C.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]>O>[Cl:10][C:11]1[CH:16]=[C:15]([N+:6]([O-:9])=[O:7])[C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]
Reactant: Clc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl

Procedure:
A mixture of 300 ml concentrated H2SO4 (98%) and 150 ml concentrated HNO3 (90%) was prepared in a 2 liter flask equipped with an agitator, thermometer, and dropping funnel. A total of 90.8 gm of 1,2,4-trichlorobenzene (0.5 mol) was added to the acid mixture at 70°-90° C. over a 1 hour period of time. The reaction was maintained at this temperature for 2 to 3 hours or until analysis of the reaction mixture showed the reaction to be complete. Work-up of the product involved addition of 1 liter of cold water to the reaction mass while maintaining a temperature from 55°-65° C. Separation of the organic and aqueous layers gave the desired product, 1,2,4-trichloro-5-nitrobenzene. Crude yield is 95-98% of theory with an isomer purity of 91-95%. Subsequent reactions outlined in Example 1 show this material to be suitable for preparation of TCDD free 2,4,5-TCP and 2,4,5-T.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:22]([NH:24][CH3:25])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:22]([NH:24][CH3:25])=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 25.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (132 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (53.1 mg, 0.117 mmol, 25.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.02 (m, 3 H) 2.10-2.24 (m, 1 H) 2.51 (br. s., 4 H) 2.75 (d, J=4.55 Hz, 3 H) 3.03 (br. s., 4 H) 3.36-3.45 (m, 3 H) 3.52-3.65 (m, 1 H) 3.93-4.03 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.17 (d, J=8.34 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) 7.75 (dd, J=8.34, 2.02 Hz, 1 H) 7.86 (d, J=2.02 Hz, 1 H) 8.41 (q, J=4.13 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C23H27ClN6O2, 455; found, 455.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([CH:31]1[CH2:33][CH2:32]1)[NH2:30]>>[CH:31]1([C:29]2[N:30]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:5][CH:2]([OH:1])[CH2:3]4)=[O:7])[CH2:9]3)[O:25][N:28]=2)[CH2:33][CH2:32]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 29.6 mg (0.295 mmol) of N′-hydroxycyclopropanecarboximidamide (Example 78A) were reacted according to the General Method 1. Yield: 54 mg (44% of theory).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1)[CH3:2].C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH3:40])[CH2:13][CH2:14]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1)[CH3:2]
Reactant: CCc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
2-(2-(2-(2-((2-Ethyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (8) (84 mg, 0.16 mmol) was dissolved in methanol (8 mL), 37% formaldehyde solution (53 μL, 0.66 mmol) was added and the mixture stirred for ten minutes at room temperature. Sodium tris(acetoxy)borohydride (174 mg, 0.821 mmol) was added, and after two hours the mixture was concentrated. The residue was diluted with 10% sodium hydroxide (15 mL) and brine (15 mL), and the mixture extracted with ethyl acetate (4×25 mL). The combined ethyl acetate phases were washed with brine, dried over sodium sulfate, evaporated and the residue evaporated from DCM to give the title compound (9) (72 mg, 84% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.46 (s, 1H), 8.49 (s, 1H), 7.36 (s, 1H), 7.21 (t, J=4.6 Hz, 2H), 7.18-7.10 (m, 4H), 7.06 (dd, J=8.2, 1.6 Hz, 1H), 6.88 (s, 1H), 3.44 (s, 2H), 3.07-2.90 (m, 4H), 2.86 (d, J=11.3 Hz, 2H), 2.57 (q, J=7.5 Hz, 2H), 2.48-2.37 (m, 1H), 2.19 (s, 3H), 2.02-1.89 (m, 2H), 1.79-1.59 (m, 4H), 1.09 (t, J=7.5 Hz, 3H). LCMS Method C: rt 5.04 min; m/z 526.2 [M+H]+; m/z 524.2 [M−H]−.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.ClCC(C1CCC(CCCCC)CC1)=O.C([C@H]1CC[C@H](C(O)=O)CC1)CCCC>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: CCCCCC1CCC(C(=O)CCl)CC1
Agent: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 25 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (160 mg, 0.50 mmol), and triethylamine (352 uL, 2.53 mmol, 5.0 eq), in THF (2 mL), was treated with 232 mg (1.0 mmol) of 1-chloro-2-(4-pentylcyclohexyl)-2-oxoethane (prepared from trans-4-pentylcyclohexanecarboxylic acid using the procedure described in example 1) to provide 154 mg, (25%) of L-isoleucine, N-[1-(2-(4-pentylycyclohexyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:19]>C(O)C.N1CCCCC1>[CH2:36]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2.4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)amide as a yellow solid (57.3 mg, 47%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:18]([C:32]#[N:33])[C:17]1=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:26]2[CH2:31][CH2:30][N:29]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:28][CH2:27]2)=[C:18]([C:32]#[N:33])[C:17]1=[O:34])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
2-Thiophene carbonyl chloride (0.16 mL, 1.5 mmol) was added to a stirred solution of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (9) (345 mg, 1 mmol) in pyridine at 0° C. The solution was allowed to come at room temperature and further stirred overnight at room temperature. The solution was poured into ice water and the solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with linear gradients of 0-3% MeOH in CH2Cl2 to yield 273 mg (45%) of 1-benzyl-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (10) as white solids. MP: 263° C.; 1H-NMR (DMSO-d6): δ 3.75 (m, 4H), 3.94 (m, 4H), 5.58 (s, 2H), 7.15 (dd, J=3.5, 4.8 Hz, 1H), 7.19-7.29 (m, 5H), 7.40 (dd, J=4.8, 8.0 Hz, 1H), 7.52 (dd, J=4.0, 5.2 Hz, 1H), 8.35 (dd, J=1.6, 8.0 Hz, 1H), 8.72 (dd, J=1.6, 8.0 Hz, 1H); EIMS: 456 (M+1). Anal. C25H21N5O2S (C,H,N).