Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16](F)[C:15]([F:19])=[CH:14][C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:28]=[C:29]([OH:37])[CH:30]=[N:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35]>CS(C)=O>[Cl:26][C:27]1[CH:28]=[C:29]([O:37][C:16]2[C:15]([F:19])=[CH:14][C:3]([C:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)=[O:5])=[C:2]([F:1])[CH:17]=2)[CH:30]=[N:31][C:32]=1[O:33][CH:34]([CH3:35])[CH3:36]
Reactant: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Reactant: CC(C)Oc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(Oc3cnc(OC(C)C)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.1 %

Procedure:
4-Methylphenyl 2,4,5-trifluorobenzoate (Preparation 12, 1.00 g, 3.54 mmol) and potassium carbonate (1.66 g, 12.04 mmol) were suspended in DMSO (24 mL). 5-chloro-6-isopropoxypyridin-3-ol (Preparation 15, 651 mg, 3.47 mmol) was added portionwise over 5 minutes. The mixture was stirred at room temperature for 60 minutes, then partitioned between water (100 mL) and EtOAc (2×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford a green oil (2.5 g) which crystallised on standing. The solid was triturated with heptane to afford the title compound as a colourless solid (1.01 g, 65%):
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:4].CCN=C=N[CH2:25][CH2:26][CH2:27][N:28](C)C.C(N(CC)CC)C.C1(N)CC1>ClCCl>[CH:27]1([NH:28][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:19])[CH:11]=2)[CH2:25][CH2:26]1
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
To a solution of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-benzoic acid (0.100 g, 0.38 mmol) in dry dichloromethane (1.5 mL) under a nitrogen atmosphere at room temperature, EDCI (0.0728 g, 0.38 mmol) was added followed by triethylamine (0.162 mL, 1.14 mmol), the resulting mixture was stirred at room temperature for further 5 minutes. Cyclopropylamine (0.027 g, 0.38 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organic layer was separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 95% to 5% methanol gradient) to afford N-cyclopropyl-3-(5-dimethylcarbamoyl-pent-1-ynyl)benzamide (25) (0.10 g, 0.34 mmol, 91% yield).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:15]=2)[CH2:10][CH:9]1[C:35](=[O:47])[NH:36][C:37]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:39][CH:38]1[CH:40]=[CH2:41])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([SiH](CC)CC)C>[CH2:45]([O:44][C:42]([C:37]1([NH:36][C:35]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[C:19]([CH3:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:47])[CH2:39][CH:38]1[CH:40]=[CH2:41])=[O:43])[CH3:46]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccc(OC)cc3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccc(OC)cc3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 3 h
Yield: 88.2 %

Procedure:
Compound 133 (915 mg, 1.417 mmol) was dissolved in dichloromethane (20 mL) and triethylsilane (0.56 mL). TFA (20 ml) was added dropwise at room temperature and the mixture was left for 3 h at room temperature. Removal of the solvent gave the title compound (737 mg, 88%) MS (M+H)+ 590.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]1[C:8]2[NH:9][C:10](=[S:14])[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1.[CH3:21]I>C1COCC1>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([S:14][CH3:21])[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1
Reactant: O=c1[nH]c(=S)[nH]c2c1cnn2CC(O)c1ccccc1
Reactant: CI
Solvent: C1CCOC1
Product: CSc1nc2c(cnn2CC(O)c2ccccc2)c(=O)[nH]1
Yield: 71.8 %

Procedure:
A solution of 7 (2.88 g, 10 mmol) and methyl iodide (7.10 g, 50 mmol) in anhydrous THF (20 mL) was refluxed for 12 h. The solvent and the excess of methyl iodide were removed by distillation under reduced pressure; the oil residue crystallized by adding CHCl3 (10 mL) and was purified by recrystallization with absolute ethanol to give 8a (2.17 g, 72%) as a white solid; mp 208-209° C. 1H NMR: δ 2.51 (s, 3H, CH3), 4.27-4.50 (m, 2H, CH2N), 5.04-5.18 (m, 1H, CHO), 5.68 (d, 1H, OH, disappears with D2O), 7.20-7.42 (m, 5H Ar), 7.97 (s, 1H, H-3). IR cm−1: 3544 (NH), 3450-3350 (OH), 1678 (CO). Anal. (C14H14N4O2S) C, H, N, S.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:6])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1F
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2F)cc1
Reaction time: 1 h
Yield: 253.2 %

Procedure:
To stirred 90° C. polyphosphoric acid (200 g) was added 14.29 g (10.2 mmol) of 2-fluorobenzoic acid and aniline (9.32 g 10.0 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 140° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 80 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 66 mL of 3N HCl added, the mixture poured into 1 L of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the solid which formed on stirring was collected. The Celite pad was washed well with methylene chloride, the methylene chloride removed and the residue was combined with the solid obtained from basification of the aqueous phase. The combined material was dissolved in refluxing ethanol (175 mL), and treated hot with 125 mL of water. The brown solid obtaing on cooling was additionally recrystallized twice from ethyl acetate-hexane. Final purification by flash column chromatography (methylene chloride) yielded the aniline as a white solid (5.45 g, 25%); mp 128°-130° C. 1H-NMR (250 MHz, d6-DMSO): 6.32 (s, 2H, NH2)6.60 (dd, 2H, J=8.6, 1.5 Hz, aromatic) 7.28-7.35 (m, 2H, aromatic) 7.40-7.60 (m, 4H, aromatic). MS (CI, CH4): 216 (M+1). Analysis for C13H10FNO: Calculated: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.46; H, 4.82; N, 6.21.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2cncc(Cl)c2N2CCC(C(N)=O)CC2)cn1
Yield: 28.4 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (20 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (8 mg, 29%), LC-MS (ESI, 3.5 min) Rt 1.20 min, m/z 320 (100%, [M+H]+); m/z (ESI) C15H19ClN5O requires 320.1273 found [M+H]+ 320.1272.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([NH:22][CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[N:28]([CH:34]2[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]2=[O:41])[CH2:27]3)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:42])=[O:11])=O)(C)(C)C.[ClH:43]>C(Cl)Cl.CCOCC>[ClH:43].[NH2:8][CH2:9][C:10]([O:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([NH:22][CH2:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[C:29](=[O:33])[N:28]([CH:34]2[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]2=[O:41])[CH2:27]3)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:42])=[O:11]
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC(=O)CN
Reaction time: 24 h

Procedure:
To a mixture of 5-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)-2-methylphenyl 2-(tert-butoxycarbonylamino)acetate (0.58 g, 1.0 mmol) in DCM (50 mL) is added 2M HCl in ether (1 mL), and the mixture is stirred for 24 hrs. The solid precipitate is filtered, rinsed with DCM (10 mL), and dried under vacuum to provide the product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH:16]=3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1.O[C:30]1[CH:34]=[CH:33][O:32][N:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:32]1[CH:33]=[CH:34][C:30]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH2:20][CH2:19][N:18]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:17][CH:16]=4)=[C:11]([F:28])[CH:10]=3)[CH2:4]2)=[N:31]1
Reactant: Oc1ccon1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Yield: 63.6 %

Procedure:
Prepared by the general method of Example 1 using as starting material 5(R)-hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one (WO97/30995; 4.0 g, 10.5 mmol), 3-hydroxyisoxazole (1.0 g, 11.8 mmol), triphenylphosphine (3.24 g, 12.4 mmol) and diisopropylazodicarboxylate (2.36 g, 11.7 mmol) in tetrahydrofuran (60 ml). Purified by flash chromatography (Merck 9385 silica; tert-butyl methyl ether/EtOAc/MeOH (70:30:0.5) eluant) to give the product (3.0 g, 64%) as a colourless crystalline solid. MS: ESP30 (M+H)+=450.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
740 g of bromo-p-xylene were initially introduced in acetic anhydride (ice-bath cooling) and nitrating acid (prepared from 400 ml of fuming nitric acid and 480 ml of concentrated sulfuric acid) was slowly added dropwise. During the addition, it was ensured that the internal temperature remained between 22° C.-25° C. When the addition was complete (duration about 5 hours), the ice bath was removed, and the mixture was stirred at RT for about a further 1 hour.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:7][N:6]=1)(=[O:4])=[O:3]>C(O)C.O1CCCC1.[C].[Pd]>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)cc2)cn1
Reaction time: 15 h
Yield: 100.3 %

Procedure:
To a solution of 2-(methylsulfonyl)-5-(4-nitrophenoxy)pyridine (9.88 g) in ethanol (150 mL) and tetrahydrofuran (150 mL) was added 10% palladium carbon (1 g), and the mixture was stirred under a hydrogen atmosphere for 15 hr. Palladium carbon was removed, and the residue was concentrated under reduced pressure to give the title compound (8.9 g, yield 100%) as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(O)C>O.[OH-].[Na+]>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[C:3]2[O:4][CH:5]=[CH:6][C:7](=[O:8])[C:2]=2[OH:1])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=c1ccocc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1ccoc(C(O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[4-Fluorophenyl)-hydroxy-methyl]-3-hydroxy-pyran-4-one: With stirring at room temperature, 5.6 g of pyromeconic acid (3-hydroxy-pyran-4-one) [CAS No.: 496-63-9] are dissolved in 10 ml of water and 24.5 ml of 2N NaOH. 6.33 g of 4-fluorobenzaldehyde and 25 ml of ethanol are added and the reaction mixture is stirred at room temperature for 18 hours. For working-up, the ethanol is removed using a rotary evaporator and the aqueous solution that remains is neutralised with 24.5 ml of 2N HCl. The product that has crystallised out is filtered off, washed with water and dried, yielding 2-[(4-fluorophenyl)-hydroxy-methyl]-3-hydroxy-pyran-4-one in the form of colourless crystals. M.p.: 154°-156° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=O.[NH2:16][C:17]1[C:18]([C:31]([NH:33][CH3:34])=[O:32])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=2)=[CH:21][N:22]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:16][C:17]1[C:18]([C:31]([NH:33][CH3:34])=[O:32])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:3][C:2]=3[F:1])[CH:24]=2)=[CH:21][N:22]=1
Reactant: CNC(=O)c1nc(-c2cccc(CN)c2)cnc1N
Reactant: O=Cc1ccc(-c2ccccc2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)c1nc(-c2cccc(CNCc3ccc(-c4ccccc4)cc3F)c2)cnc1N
Yield: 20.2 %

Procedure:
A solution of 3-fluorobiphenyl-4-carbaldehyde (0.030 g, 0.15 mmol), 3-amino-6-[3-(aminomethyl)phenyl]-N-methylpyrazine-2-carboxamide (0.038 g, 0.15 mmol), glacial AcOH (0.010 mmol, 0.15 mmol) and NaBH(OAc)3 (0.047 g, 0.22 mmol) in THF (0.6 mL) was stirred at r.t. for 12 h. Saturated NaHCO3 (aq) was added (25 mL) and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified via HPLC (reverse-phase, CH3CN/H2O with 0.1% TFA). Upon removal of CH3CN/H2O, the product was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, to provide 13.4 mg (20% yield) of 3-amino-6-[3-({[(3-fluorobiphenyl4-yl)methyl]amino}methyl)phenyl]-N-methylpyrazine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 8.84 (s, 1H), 8.79 (d, 1H), 8.09 (bs, 1H), 8.05 (m, 1H), 7.70 (m, 2H), 7.61 (t, 1H), 7.36-7.53 (m, 8H), 3.80 (d, 4H), 2.86 (d, 3H); MS (EI) for C26H24N5OF: 442 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH2:23][CH3:24])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[CH2:21][CH3:22].C(O)(=O)[CH2:27][C:28]([OH:30])=[O:29].Cl>N1CCCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH2:23][CH3:24])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:27][C:28]([OH:30])=[O:29])=[CH:15][C:14]=1[CH2:21][CH3:22]
Reactant: O=C(O)CC(=O)O
Reactant: CCc1cc(C=O)ccc1OCCCNc1cnn(CC)c(=O)c1Cl
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCc1cc(C=CC(=O)O)ccc1OCCCNc1cnn(CC)c(=O)c1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture comprising 1.34 g of 4-chloro-5-[3-(2-ethyl-4-formylphenoxy)propylamino]-2-ethyl-3(2H) pyridazinone (Compound No. 92), 0.73 g of malonic acid, one drop of piperidine and 12 ml of pyridine, were heated under stirring at 100° C. for 3 hours. After cooling, the reaction solution was acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed twice with water, and dried over sodium sulfate. Then, the solvent was distilled off, and the residue thereby obtained was crystallized from ethyl acetate-ethyl ether to obtain 1.2 g of the above identified compound as pale yellow crystals having a melting point of from 145° to 147° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2)=[O:1]
Reactant: N#Cc1ccc2[nH]c(CO)cc2c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc2[nH]c(C=O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
MnO2 (1.76 g) was added to a solution of 2-(hydroxymethyl)-1H-indole-5-carbonitrile (D24) (290 mg) in dichloromethane (100 mL) at RT. The reaction mixture was stirred at RT for 1 hour. The solid was filtered off and washed with dichloromethane. The filtrate was concentrated to afford 2-formyl-1H-indole-5-carbonitrile (D28) (230 mg) as a white solid. MS (ES): C10H6N2O requires 170; found 169.1 (M−H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1)=[O:21]
Reactant: NC1CCC(CNc2ccccc2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](CNc2ccccc2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 7 mL vial equipped with magnetic stirrer bar is added (4-Amino-cyclohexylmethyl)-phenyl-amine (41 mg, 0.2 mmol), 3-chlorobenzoyl chloride (20 mg, 0.16 mmol) and DCM (2 mL) followed by trethylamine (42 μL, 0.3 mmol). The mixture is stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was then evaporated to dryness and purified directly by preparative HPLC, [MH+343.19].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.CC(C)(C)[CH:17]=[O:18]>CCOCC>[F:8][C:5]1[N:6]=[CH:7][C:2]([CH2:17][OH:18])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Br)cnc1F
Reactant: CC(C)(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(CO)cnc1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
5-Bromo-2-fluoro-3-methylpyridine (2.0 g, 0.011 mol) was dissolved with stirring in anhydrous ether (30 mL) and cooled to −70° C. This was treated at <−60° C. with n-butyl lithium (4.8 mL, 2.5M in hexane, 0.012 mol) and the reaction mixture stirred at <−70° C. for one hour. Trimethylacetaldehyde (1.14 g, 0.013 mol) was added and the reaction mixture allowed to warm to −10° C. The reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to dryness. Purification of the residue by chromatography over silica (5-25% ethyl acetate:hexane) gave the desired product (1.6 g, 77%) as a clear oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>C1C=CC=CC=1>[C:7]1([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: C1CCNCC1
Reactant: O=C1CCCC1
Solvent: c1ccccc1
Product: C1=C(N2CCCCC2)CCC1
Temperature: 80 °C

Procedure:
Piperidine (4.0 g, 46.9 8 mmol) was added to a solution of cyclopentanone Compound 1a (4.0 g, 46.50 mmol) in benzene (100 mL) at ambient temperature under a N2 atmosphere. The mixture was refluxed at 80° C. for 5 hrs using a Dean Stark apparatus, then concentrated to dryness to provide 1-cyclopent-1-enyl-piperidine Compound 1b (7.0 g) as a crude oil which was used in the next step without further purification.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([CH2:9][F:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:18]>CCOCC>[NH2:1][C@H:2]([C:7]([CH2:9][F:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:18]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CF
Agent: Cl
Solvent: CCOCC
Product: CC(C)C[C@H](N)C(=O)CF
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of Boc-LeuCH2F (1.53 g, 6.19 mmol) in ether (30 mL) was added a saturated solution of HCl in ether (20 mL). The mixture was stirred vigorously; a precipitate formed within 15 minutes. After 1 hour, the mixture was filtered, the solids were washed with ether (2×30 mL) and were then pumped dry overniqht: a second crop was obtained from the filtrate, giving 0.60 g (54%) of LeuCH2F hydrochloride. Boc-Phe-Gly-LeuOH (synthesized in several steps via mixed anhydride coupling of the appropriate amino acid benzyl esters and subsequent hydrogenolyses, 0.762 g, 1.69 mmol) was dissolved in THF (10 mL), and was cooled to -20° C. NMM (0.186 mL, 1.69 mmol) was added, followed by IBCF (0.219 mL, 1.69 mmol). After 5 minutes, HCl.LeuCH2F (0.31 g, 1.69 mmol) was dissolved in DMF (2 mL), to which solution was added NMM (0.186 mL, 1.69 mmol). This mixture was swirled for approximately 15 seconds and was added to the mixed anhydride solution. After 45 minutes, the reaction was quenched with 1M HCl (20 mL), extracted with ethyl acetate (2×30 mL), the combined organics were washed with saturated aqueous NaHCO3 (30 mL), brine (20 mL), dried over MgSO4, filtered, and evaporated. The thick oil was then dissolved in 1:1 ether/CH2Cl2 (20 mL), and hexane (50 mL) was added. After one day, the evaporated to dryness, yielding 0.14 g of Boc-Phe-Gly-Leu-LeuCH2F.
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:18][C:19](=O)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][OH:34])[CH:23]=1)=O>>[C:1]1([C:13]2[C:14](=[O:15])[NH:16][C:19](=[O:18])[C:20]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][OH:34])[CH:23]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1cn(CCCO)c2ccccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCO)c2ccccc12

Procedure:
Beginning with 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide and 1-(3-hydroxypropyl)indole-3-glyoxylic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pt]
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from [2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example A) by hydrogenation with 5% Pt/C according to the general procedure J (method a). Obtained as a yellow solid (17.374 g).