Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([C:13]([O:15][CH:16]3[CH2:21][NH:20][C:19](=[N:22][N+]([O-])=O)[NH:18][CH2:17]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O.[Pd]>[CH:13]([OH:15])=[O:14].[CH:1]1([C:7]2([C:13]([O:15][CH:16]3[CH2:21][NH:20][C:19]([NH2:22])=[N:18][CH2:17]3)=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OC1CNC(=N[N+](=O)[O-])NC1)C1(C2CCCCC2)CCCCC1
Agent: [Pd]
Solvent: O=CO
Product: NC1=NCC(OC(=O)C2(C3CCCCC3)CCCCC2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 155.1 %

Procedure:
A solution of 2-nitroiminohexahydropyrimidin-5-yl 1-cyclohexylcyclohexane-1-carboxylate (0.45 g) in formic acid (20 ml) was quickly dropped into a flask containing 10% palladium on carbon (0.4 g). The reaction mixture was stirred at room temperature overnight. The catalyst was filtered off, the solvent was removed and the residue was triturated with diethyl ether, affording 0.35 g of 2-amino-1,4,5,6-tetrahydropyrimidin-5-yl 1-cyclohexylcyclohexane-1-carboxylate formate. M.p. 160°-165° C. (dec.).
Reaction SMILES: [Cl:1][C:2]([Cl:6])=[CH:3][CH2:4][NH2:5].[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10]>>[Cl:1][C:2]([Cl:6])=[CH:3][CH2:4][NH:5][C:9](=[O:10])[CH:8]([Cl:12])[Cl:7]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NCC=C(Cl)Cl
Product: O=C(NCC=C(Cl)Cl)C(Cl)Cl

Procedure:
By reaction of the N-(3,3-dichloroallyl)amine with the dichloroacetyl chloride, as in Example 1, there was obtained N-(3,3-dichloroallyl)dichloroacetamide.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](O)[CH2:13][OH:14].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][O:5]1
Reactant: OCCO
Reactant: COc1ccc(Br)c(C=O)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(C2OCCO2)c1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
To a solution of Compound 19 (50.0 g, 0.23 mol) in toluene (650 mL) were added ethylene glycol (14.2 mL, 0.26 mol) and camphorsulfonic acid (10.7 g, 46 mmol). The reaction solution was heated under reflux with a Dean-Stark trap for 6 h and then cooled to room temperature and diluted with ethyl acetate (300 mL). The resulting solution was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo to give Compound 20 (61.5 g, quantitative) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.44 (d, J=8.5 Hz, 1H), 7.15 (d, J=3.5 Hz, 1H), 6.79 (dd, J=8.5, 3.0 Hz, 1H), 6.04 (s, 1H), 4.18-4.06 (m, 4H), 3.81 (s, 3H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=[NH:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:29]=2)[CH2:34][CH2:33]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: N=C(NO)C1CC1
Product: O=C(N1CCSCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 164 mg (1.640 mmol) of N-hydroxycyclopropanecarboximidamide were reacted Yield: 352 mg (47% of theory)
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[CH3:2].C([Li])CCC.CCCCCC.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]([OH:45])([C:36]([C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1)=[CH2:37])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1.[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]([OH:45])([C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:9]2[N:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]=[CH:7][N:8]=2)=[CH:40][CH:39]=1)=[CH2:37])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: CCOCn1cncn1
Reactant: C=C(c1ccc(I)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(c1ccc(-c2ncnn2COCC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A solution of 1-ethoxymethyl-1,2,4-triazole (0.79 g, 6.2 mmol-see Preparation 27) in tetrahydrofuran (THF) (8 ml) was stirred under a nitrogen atmosphere at -70° C. before treatment with a solution of n-butyllithium in hexane (2.5M, 2.5 ml, 6.2 mmol) The mixture was stirred for 0.25 hours and treated with a solution of anhydrous zinc chloride (1.2 g, 9.3 mmol) in THF (8 ml), then was allowed to warm to room temperature. To this mixture was added tetrakis(triphenylphosphine)palladium (0) (0.06 g, 0.06 mmol) and 2-(2,4-difluorophenyl)-3-(4-iodophenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (0.7 g, 1.5 mmol-see Preparation 20) and the mixture was heated under reflux for 4 hours. After being cooled, a suspension of ethylenediaminetetraacetic acid disodium salt (10 g, 27 mmol) was added, the mixture was adjusted to pH8 with saturated sodium carbonate solution and extracted with dichloromethane (2×100 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was chromatographed on silica by gradient elution with dichloromethanelmethanol (98:2, 97:3, 95:5). Fractions containing the desired product were combined, evaporated under reduced pressure and the residue was triturated with ether to afford the title compound (0.55 g, 78%) as a colourless solid, m.p. 160-162° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[NH:17][C:16]5[N:24]=[CH:25][CH:26]=[CH:27][C:15]=5[N:14]4[C:28]=3[C:29]3[CH:34]=[CH:33][C:32]([C:35]4([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.O1CCOCC1>CO>[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:9]3[CH:8]=[CH:7][C:6]4[C:2](=[O:1])[O:3][CH2:4][C:5]=4[CH:10]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc5c(c4)COC5=O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccc5c(c4)COC5=O)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 23 h
Yield: 94.7 %

Procedure:
tert-Butyl (1-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (39 mg, 0.064 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 23 hours. The mixture was concentrated, then sat.NaHCO3 aq. was added. The mixture was extracted with CH2Cl2+MeOH (×2), dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (CH2Cl2/MeOH=10:1) to afford the desired product (31 mg, 94%) as a pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.62 (s, 1H), 8.10 (dd, J=5.2 Hz and 1.7 Hz, 1H), 7.98 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.55 (dd, J=8.6 Hz and 1.1 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.37 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.13 (td, J=8.0 Hz and 1.1 Hz, 1H), 6.91 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.75 (dd, J=8.0 Hz and 4.6 Hz, 1H), 5.39 (s, 2H), 2.45-2.41 (m, 2H), 2.23-2.18 (m, 2H), 2.10-2.02 (m, 1H), 1.77-1.70 (m, 1H). LCMS: 512 [M+H].
Reaction SMILES: [NH:1]([C:8](=[O:43])[C:9]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33]C(=O)OC(C)(C)C)=[O:25])=[CH:22][CH:21]=1)([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[F:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24]([C:23]1[CH:22]=[CH:21][C:20]([C:9]([F:10])([C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:43])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:42][CH:41]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(F)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1ccc(C(F)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22.9 %

Procedure:
To a solution of tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate (11 mg, 0.019 mmol) in CH2Cl2 (3 mL) at room temperature was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature 45 min and concentrated. Purification by reverse phase HPLC (10% to 80% MeCN in water) gave 2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-2-fluoro-N,N′-diphenylmalonamide (2.1 mg, TFA salt, 19%) as a white solid: 1H NMR (600 MHz, CD3OD) δ 8.13 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.64-7.62 (m, 4H), 7.41-7.35 (m, 8H), 7.18 (t, J=7.6 Hz, 2H); ESIMS calcd 483.2 (M++H), found 483.1 (M++H). General Procedure for the Synthesis of Non-Symmetrical Malonamide Benzamides
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[Cu](C#N)[C:12]#[N:13]>CN1CCCC1=O>[I:10][C:4]1[N:3]=[C:2]([C:12]#[N:13])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1
Reactant: COc1ccc(I)nc1Br
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: COc1ccc(I)nc1C#N
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 30.4 %

Procedure:
To a solution of 2-bromo-6-iodo-3-methoxypyridine (627.4 mg, 1.999 mmol) in N-methylpyrrolidinone (10 mL) was added copper cyanide (202.6 mg, 2.262 mmol). The reaction mixture was stirred at 130° C. for 3.5 hours and then cooled to room temperature. The crude reaction was partitioned between ethyl acetate and water, the organic layer washed with brine, dried with magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (20 to 100% ethyl acetate in heptanes) to yield 157.8 mg (37%) of a mixture of the two regioisomeric products 6-bromo-5-methoxypicolinonitrile and 6-iodo-3-methoxypicolinonitrile. 1H NMR (400 MHz, DMSO) δ: 8.12 (d, J=8.3 Hz, 0.75H), 7.98 (d, J=9.0 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.69 (d, J=8.5 Hz, 0.75H), 3.98 (overlapping s and s, 6H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]1[O:7][CH2:6]1)Br.[CH2:8]([OH:17])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([O:17][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]1[O:7][CH2:6]1
Reactant: OCC=Cc1ccccc1
Reactant: BrCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: C(=Cc1ccccc1)COCC1CO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a four-neck 1000 ml round bottom flask, equipped with a mechanical stirrer, thermometer, and condenser, were added 50% w/w aqueous sodium hydroxide (“NaOH”) (250 ml), epibromohydrin (56 g, 400 mmol), and tetrabutylammoniumhydrogen sulfate (“TBAHS”) (5.2 g, 14.9 mmol). The mixture was stirred at room temperature for a period of time of about 20 minutes. To the mixture was added cinnamyl alcohol (50 g, 365 mmol), drop-wise over a period of time of about 60 minutes. The reaction was conducted at ice/water temperatures, and was allowed to continue overnight with stirring. Once the reaction was complete, the mixture was cooled and ice cold water (500 ml) was slowly added. The quenched reaction was allowed to stir for a period of time of about 30 minutes and then twice extracted with diethyl ether (250 ml). The organic portion was separated and twice washed with brine (250 ml), dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness in vacuo. Crude CGE was obtained as a clear amber liquid (67.0 g), which was distilled in vacuo (119-135° C. at 820 mTorr) to provide CGE (48.1 g, 247.8 mmol), as a clear colorless liquid. G.C. 98.0% (retention time 8.10 min.). 1H NMR (CDCl3) δ7.2-7.4 (br m, 5, C6H5), 6.65 (d, 1, —CH═), 6.25 (m, 1, ═CH—), 4.2 (br m, 2, CH2), 3.75 and 3.20 (d, 2, CH2), 3.45 (m, 1, OCH), 2.8 and 2.6 (d, 2, OCH2). FT-IR (neat) 3081, 3057, 3025, 2999, 2922, 2855, 1495, 1448, 1253, 1115, 969, 902, 855, 746, 694.
Reaction SMILES: [OH:1][CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6].[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)(Cl)Cl.C(N(CC)CC)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:31]1([CH:2]([O:1][C:37](=[O:39])[CH3:38])[CH2:3][NH:4][C:5]([C:7]2[N:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[O:6])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCC(O)c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OC(CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.5 %

Procedure:
To a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide (50 mg, 0.1 mmol) in chloroform (2 mL), acetic anhydride (0.25 mL), triethylamine (0.25 mL) and 4-dimethylaminopyridine (18 mg) were added. After stirred at ambient temperature for 6 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×10 mL) and dried over Na2SO4. The crude product obtained after removal of the solvent was purified by column chromatography eluted sequentially with hexane:ethyl acetate=1:1 and 1:2 to give a white powder (49.6 mg, 91.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 8.04, 7.75, 7.65, 7.57, 7.40-7.28, 7.00, 5.92, 4.07, 3.98, 3.90, 3.82-3.68, 3.36, 2.10. MS (ES+) m/z 508 (M+1).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)=[O:24])([CH3:13])[CH3:12]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
NaH (0.22 g, 5.0 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (15 mL), the suspension was cooled to 0° C. and 2-pyridylmethanol (0.55 g, 5.0 mmol) was added. The suspension was stirred at 0° C. for 1 h and added to a stirred solution of Intermediate 2 (0.66 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 2-pyridylmethanol in THF were added after 18 and 36 h, respectively. After 54 h the reaction mixture was quenched with water (10 mL), the solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 1%, 2% and 5% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 70% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyridin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (86.4 mg, 14.4%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31].C([BH3-])#N.[Na+]>O1CCCC1>[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]2[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:14]3[N:15]=2)=[CH:26][CH:25]=1
Reactant: COCCN
Reactant: COc1ccc(-c2cccc3nc(Nc4ccc(C=O)cc4)nn23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCNCc1ccc(Nc2nc3cccc(-c4ccc(OC)cc4)n3n2)cc1
Reaction time: 18 h
Yield: 32.9 %

Procedure:
A solution of 4-(5-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzaldehyde (47 mg, 0.14 mmol) and 2-methoxyethylamine (65 μL, 0.70 mmol) and 4 Å molecular sieves in tetrahydrofuran (5 mL) was stirred at 24° C. After 18 h, sodium cyanoborohydride (100 mg, 2 mmol) was added to the reaction mixture. After 1 h, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic was separated and washed with saturated aqueous sodium chloride solution (10 mL). The collected organic was dried over magnesium sulfate, filtered, and concentrated. Purification by preparative HPLC provided a tan solid (18.6 mg, 34%). LCMS (ESI) m/z: 404. 1H NMR (400 MHz, DMSO-d6), δ: 9.51 (s, 1H), 8.05 (d, J=8.8, 2 H), 7.62 (m, 3H), 7.52 (d, J=8.7, 1H), 7.20 (d, J=8.4, 2H), 7.16-7.10 (m, 3H), 3.87 (s, 3H), 3.62 (s, 2H), 3.39 (t, J=5.7, 2H), 3.23 (s, 3H), 3.17 (d, J=5.2, 2H), 2.63 (t, J=5.7, 2H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16]Br)[CH2:5]1)(=[O:3])[CH3:2].[C-:18]#[N:19].[Na+]>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:18]#[N:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)N1CC(CCBr)c2c(C)cc(C)cc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CC(CCC#N)c2c(C)cc(C)cc21
Yield: 101.9 %

Procedure:
1-Acetyl-3-(2-bromoethyl)-4,6-dimethylindoline (5.4 g), NaCN (3.7 g) and 18-crown-6 (480 mg) were suspended in CH3CN (50 ml), and the suspension was refluxed for 15 hr. CH3CN was evaporated under reduced pressure. CHCl3 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 4.5 g of 1-acetyl-3-(2-cyanoethyl)-4,6-dimethylindoline.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1>CN(C)C=O>[N+:1]([C:4]1[N:5]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=CN1CCC(CBr)CC1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCC(Cn2ccnc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
The mixture of 2-nitroimidazole (4.5 g, 40 mM) and 50% by weight NaH in mineral oil (1.92 g, 41 mM) in dimethylformamide (40 ml) was stirred at room temperature for 1/2 hr. A solution of 4-bromomethyl-1-piperidinecarboxaldehyde (8.3 g, 40 mM) in dimethylformamide (10 ml) was added to the above mixture and heated at 120° C. for 1/2 hr. After the reaction, solvent was removed in vacuo and water (50 ml) was added and the mixture was extracted with ethylacetate (2×75 ml). The extracts, dried over Na2SO4 was stripped to dryness which was then purified on silica gel column, eluted with 5% volume MeOH-95% volume CH2Cl2, to give 4[(2-nitro-1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde (2.4 g, 10 mL) in 25% yield.
Reaction SMILES: [O:1]=C1C2C(C=CN=2)=NC1=O.C1C=CC2SC3C=CC=CC=3NC=2C=1.[CH3:25][C:26]12[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:30](=[O:36])[O:29][C:27]2=[O:28].C(OCCO)(=O)C(C)=C>C1C(Cl)=CC=C(Cl)C=1>[CH3:25][C:26]1([CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:30]([OH:29])=[O:36])[C:27]([OH:1])=[O:28]
Reactant: CC12CCCCC1C(=O)OC2=O
Reactant: O=c1nc2ccnc-2c1=O
Agent: C=C(C)C(=O)OCCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccc(Cl)cc1
Product: CC1(C(=O)O)CCCCC1C(=O)O
Temperature: 112.5 °C

Procedure:
2.35 g (0.005 mol) of the diketopyrrolopyrrole of the formula XIX (Example 6) and 30 ml of dichlorobenzene are placed under nitrogen in a sulfonating flask, 5.0 mg (0.05 mmol) of thiodiphenylamine are added, and the mixture is heated with stirring at 110-115° C. 3.17 g (0.010 mol) of the methyl-hexahydrophthalic acid derivative (isomer mixture) of the formula ##STR43## (obtained by generally known methods from methylhexahydrophthalic anhydride and hydroxyethyl methacrylate) are added dropwise with vigorous stirring over the course of 15 minutes to the clear orange-red solution, stirring is continued for about 2 hours at 110-115° C., and then the mixture is cooled to room temperature. The clear dark red solution is washed in a separating funnel 3 times with 20 ml of 5% sodium hydroxide solution and 2 times with 30 ml of deionized water, and the organic phase is dried over MgSO4.H2O, filtered and concentrated to dryness under a high vacuum. The resulting product is recrystallized from 30 ml of ethanol, to give 3.05 g (81.3% of theory) of a crystalline product formula ##STR44## R= ##STR45## with a melting point of 69.6° C.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])[CH3:4])#[N:2].S(Cl)([Cl:16])=O>>[C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:16])=[O:9])[CH3:4])#[N:2]
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CC(C#N)c1cccc(C(=O)Cl)c1
Temperature: 80 °C

Procedure:
Thionyl chloride (10 mL) was added at 0° C. to 3-(l-cyanoethyl)benzoic acid (12, 500 mg, 2.85 mmol). The reaction mixture was heated at 80° C. for 2 h. The excess thionyl chloride was removed to give 3-(l-cyanoethyl)benzoyl chloride, which was used without further purification.
Reaction SMILES: [Br:1]Br.CO[C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9](OC)[C:10]=1OC.O>C(O)C>[Br:1][CH2:16][C:15]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=1)=[O:17]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: BrBr
Solvent: O
Solvent: CCO
Product: O=C(CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Bromine (160 mg, 1 mmol) was added dropwise to a stirred solution of an 1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL) and the solution was stirred at 0° C. for 1 h and then poured into water to form a precipitate. This was recrystallized from ethanol to give bromoacetophenone (70%) and used directly for next step. A mixture of bromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol) in ethanol was refluxed for 1 h. The reaction mixture was concentrated in vacuo and purified with flash column to give 2i (167 mg, 51.1%). 1H NMR (500 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s, 1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1 (M+Na)+.