Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:23][C:24]([F:41])([F:40])[C:25]1[N:30]=[CH:29][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:36]3[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:28]4[CH:29]=[N:30][C:25]([C:24]([F:23])([F:40])[F:41])=[CH:26][CH:27]=4)=[CH:34][C:35]3=[O:39])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.75 g, 2.0 mmol), 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (0.59 g, 2.2 mmol), and Cs2CO3 (0.84 g, 2.6 mmol) were suspended in DMSO (6.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (86 mg, 0.59 mmol) and copper iodide (0.49 g, 2.6 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×50 mL). Activated charcoal was added to the organic solution, and the resulting suspension was filtered through a Celite® plug and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 12 column volumes and held for 2 column volumes; increased to 0:100 over 10 column volumes and held for 40 column volumes) gave the title compound (0.44 g, 39%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.26-7.95 (m, 2H), 7.84 (s, J=7.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.20 (dd, J=7.5, 2.4 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.36 (s, 2H), 4.57 (s, 2H), 3.75 (t, J=5.7 Hz, 2H), 3.67 (s, 3H), 2.99-2.81 (m, 2H), 1.42 (s, 9H); ESI MS m/z 556 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH:11]=[C:12]3[NH:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[C:6]2[N:5]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(OC([N:67]1[CH2:72][CH2:71][CH:70]([C:73](O)=[O:74])[CH2:69][CH2:68]1)=O)(C)(C)C>O.CN(C=O)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:4]2[CH:3]=[C:2]([NH:1][C:73]([CH:70]3[CH2:71][CH2:72][NH:67][CH2:68][CH2:69]3)=[O:74])[N:7]3[N:8]=[CH:9][C:10]([CH:11]=[C:12]4[C:13](=[O:18])[NH:14][C:15](=[O:17])[NH:16]4)=[C:6]3[N:5]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(Nc2cccc(Cl)c2)nc2c(C=C3NC(=O)NC3=O)cnn12
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)C(=Cc2cnn3c(NC(=O)C4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
To the reaction vial, 5-((7-amino-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (15 mg, 0.04 mmol) was added to DMF (0.2 mL) along with HBTU (30 mg, 0.08 mmol), DIEA (28 μL, 0.16 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (18 mg, 0.08 mmol). The reaction was stirred at room temperature for 8 hours then heated at 95° C. for 4 hours. The reaction was then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 1N HCl solution, and more water. The material was then dissolved in 5% DCM/MeOH and purified by prep HPLC. The isolated fractions were combined and evaporated to dryness. The material was dissolved in 1 mL of TFA/DCM (1:1) and stirred at room temperature for 1 hour. The solvent was removed by evaporation under a stream of nitrogen and the crude material was washed with 1N NaOH followed by water. The solid was collected by filtration and dried under vacuum overnight. The product, N-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxamide, was recovered as a solid in 2% yield. LCMS (M+1=481).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:16])[C:6]=1[NH:7][CH2:8][C:9]1[N:13]([CH3:14])[C:12]([SH:15])=[N:11][N:10]=1.[OH-].[Na+].[CH3:19]OS(OC)(=O)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:16])[C:6]=1[NH:7][CH2:8][C:9]1[N:13]([CH3:14])[C:12]([S:15][CH3:19])=[N:11][N:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1csc(C)c1NCc1nnc(S)n1C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1nnc(CNc2c(C)csc2C)n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 9.5 g (0.037 mol) N-(2,4-dimethyl-thien-3-yl)-N-(4-methyl-5-mercapto-1,2,4-triazol-3-yl-methyl)-amine, 1.1 g triethyl-benzyl ammonium chloride in 100 ml toluene and 30 ml aqueous 50% sodium hydroxide solution are added 4.7 g (0.037 mol) dimethylsulfate. The reaction mixture is stirred at room temperature for 5 hours, the organic layer is separated, washed with three 100 ml portions of water, dried over Na2SO4 and evaporated to dryness. The residue is recrystallized twice from ether giving the pure title compound, m.p. 92°-96° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)=[CH:21][CH:20]=2)[CH:7]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Product: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 84 °C
Yield: 46 %

Procedure:
100 mg of 4,6-dichloropyrimidine and 92 mg of p-morpholino aniline were dissolved in 5 mL of i-PrOH. The mixture obtained was refluxed at 84° C. for 6 hours under a nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(4-morpholinophenyl)pyrimidin-4-amine was obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:17][C:18]3[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)=[CH:8][C:9](OC(F)(F)F)=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][C:34]([O:37][C:38]([NH:40][C@H:41]([CH2:45][CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])[CH3:35].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:25][C:2]1([CH3:1])[C:6]2[C:7]([O:17][C:18]3[N:23]=[CH:22][C:21]([NH:24][C:42]([C@H:41]([NH:40][C:38](=[O:39])[O:37][C:34]([CH3:36])([CH3:35])[CH3:33])[CH2:45][CH3:46])=[O:43])=[CH:20][CH:19]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(OC(F)(F)F)cc(Oc2ccc(N)cn2)c2c1OCC2(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
6-{[3,3,7-Trimethyl-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-4-yl]oxy}pyridin-3-amine (Intermediate 29, 405 mg, 1.27 mmol) was suspended in ethyl acetate (4 mL). Triethylamine (0.44 ml, 3.175 mmol) was added followed by the addition of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (258 mg, 1.27 mmol). The resulting suspension was cooled to 0° C. and T3P 50% w/w solution in ethyl acetate (1.4 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature and stirred for a further hour. An aqueous saturated solution of Na2CO3 was added and the mixture stirred for 10 min. Two phases were separated and the organic layer was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 80:20 to cyclohexane/ethyl acetate 70:30 as eluents affording the title compound (0.50 g) as white foam.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:23]=[CH:22][C:15]([O:16][C:17]([CH3:21])([CH3:20])[CH2:18]Br)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[C:24]([O-:27])(=[O:26])[CH3:25].[K+]>CN(C=O)C>[C:24]([O:27][CH2:18][C:17]([O:16][C:15]1[CH:22]=[CH:23][C:12]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:14]=1)([CH3:21])[CH3:20])(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(OC(C)(C)CBr)cc2)c2ccccc21
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(C)(C)Oc1ccc(C2CCN(C)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3 g. of 2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-2-methyl-propyl bromide are dissolved in 20 ml. of DMF, 3 g. of anhydrous potassium acetate are added and the mixture is stirred for 3 hours at 60° C. Working up in the usual manner gives 2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-2-methyl-propyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C@H:3]1[OH:14].[ClH:16]>CO.[Pd]>[ClH:16].[CH3:1][C:2]1([CH3:15])[CH2:6][NH:5][CH2:4][C@H:3]1[OH:14]
Reactant: CC1(C)CN(Cc2ccccc2)C[C@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(C)CNC[C@H]1O
Reaction time: 18 h
Yield: 92.2 %

Procedure:
To a solution of (3S)-4,4-dimethyl-1-(phenylmethyl)-3-pyrrolidinol (J. Med. Chem. 1992, 35, 4205-4213) (0.7738 g, 3.769 mmol) in MeOH (38 mL) was added 1 N aq. HCl (3.8 mL, 3.8 mmol) and 10% Pd/C (50% water, 230 mg). The mixture was hydrogenated under balloon pressure for 18 h, and was then filtered through a 0.2 μm filter tip syringe. The resulting solution was concentrated in vacuo and azeotroped with MeOH (2×50 mL) to afford (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride (0.5267 g, 93% yield) as a light orange solid. LCMS: (M+H)+: 116.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[I:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[CH3:11][O:10][C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([I:12])[N:4]=1)=[O:9]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1nccnc1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(I)cnc1N
Temperature: 70 °C
Reaction time: 15 h
Yield: 61.5 %

Procedure:
Methyl 3-amino-2-pyrazinecarboxylate (10 g, 65.3 mmol) and N-iodosuccinimide (24 g, 106.7 mmol) were dissolved in anhydrous DMF (150 mL) and the mixture was stirred at 70° C. for 15 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature and a saturated aqueous solution of sodium thiosulfate (400 mL) was added. The suspension was sonicated for 15 minutes, concentrated under vacuum and dispersed in water. The crude product was filtered off and washed with cold ethanol. The residue was crystallized from ethanol, using decolorizing charcoal to afford 3-amino-6-iodo-pyrazine-2-carboxylic acid methyl ester (11.2 g, 61% yield) as orange needles. 1H-NMR (d6-DMSO) δ: 8.57 [1H] s, 7.59 [2H] s,br, 3.93 [3H] s. MS: m/z 280 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(COS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon 2.10 g (7.85 mmol) of methyl 2-(3-chloropyridin-2-yl)-5-hydroxymethyl-2H-pyrazole-3-carboxylate are introduced in 13 ml of dichloromethane and this initial charge is cooled to 0° C. and admixed dropwise in succession with 1.64 ml (11.8 mmol) of triethylamine and 0.67 ml (8.63 mmol) of methanesulphonyl chloride. It is stirred at this temperature for 30 minutes, diluted with 50 ml of dichloromethane and washed successively with 50 ml each of saturated aqueous sodium hydrogen sulphate solution, 10 percent strength aqueous hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and then the solvent is removed on a rotary evaporator.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[H][H]>O=[Pt]=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:6][NH:7][C:8]1[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(CNc2ccccc2[N+](=O)[O-])ccc1CN1CCCC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1cc(CNc2ccccc2N)ccc1CN1CCCC1

Procedure:
The title compound was prepared by the addition of Adam's catalyst (160 mg, 10% wt.) to a degassed solution of N-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-2-nitroaniline (1.6 g, 4.69 mmol) in absolute ethanol (25 mL). The atmosphere was replaced with hydrogen then the reaction was stirred vigourously at ambient temperature until all of the nitro compound had been consumed as determined by tlc (9:1 CHCl3:MeOH, 1% TEA). The reaction mixture was filtered through a bed of diatomaceous earth, then the solvent was removed under reduced pressure to give the diamine as a brown yellow oil (1.46 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[N:25]1([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]([CH3:19])[CH2:10]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: c1ccc2c(c1)CCN2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCc4ccccc43)CC2C)cc1OC
Yield: 51.1 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and indoline (436 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (267 mg, yield: 51%) as a white crystal. (cis:trans=1:1.8)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[C:9]([O:8][C:7](=[O:13])[NH:6][C@H:4]([CH3:5])[C@@H:2]([OH:1])[CH2:3][NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: NCCCc1ccc(F)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)CNCCCc1ccc(F)cc1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
The product from step c (823 mg, 4.39 mMol) and 3-(4-fluorophenyl)propylamine (674 mg, 4.39 mMol) were dissolved in anhydrous acetonitrile (10 ml). To this solution, lithium trifluoromethanesulfonate (1.44 g, 9.23 mMol) was added, and the solution was stirred overnight. The mixture was concentrated in-vacuo, then the residue was dissolved in EtOAc (60 ml), washed with saturated sodium bicarbonate (2×20 ml), followed by water (20 ml). The organic phase was dried over sodium sulfate and concentrated to a yellow oil. Purified via flash chromatography, eluting with EtOAc, 2.5% 7N NH4 in MeOH/EtOAc, 5% 7N NH4 in MeOH/EtOAc to yield 1.2 g of a colorless oil as product. ESI+MS detects 341 (M+H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C1COCC1>[CH2:34]([O:41][NH:42][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:17]=1[NH:16][C:15]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:14]=1[F:13])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Carbonyldiimidazole (3.1 g, 19.1 mmol) was added to a suspension of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid (Example H-4, 4.54 g, 15.9 mmol) in 120 mL of THF, and the mixture was stirred for 24 hours at 25° C. O-Benzylhydroxylamine hydrochloride (2.54 g, 15.9 mmol) and triethylamine (2.66 mL, 19.1 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 5.66 g of the title compound as an oil.
Reaction SMILES: P(=O)(O)(O)[OH:2].Cl[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][N:17]2[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([N:29](C)[C:30](=O)OC(C)(C)C)[CH3:28])[CH2:21][O:20][C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[N:9]([CH2:43][CH3:44])[CH:8]=1>C([O-])(O)=O.[Na+]>[CH2:43]([N:9]1[C:10]2[C:15](=[C:14]([CH2:16][N:17]3[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([NH:29][CH3:30])[CH3:28])[CH2:21][O:20][C:19]4[CH:39]=[CH:40][CH:41]=[CH:42][C:18]3=4)[CH:13]=[CH:12][CH:11]=2)[CH2:7][C:8]1=[O:2])[CH3:44]
Reactant: O=P(O)(O)O
Reactant: CCn1cc(Cl)c2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc4ccccc43)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN1C(=O)Cc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)NC)COc4ccccc43)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
Phosphoric acid (13.2 mg, 2 mL, 108 μmol, Eq: 1.00) was added to tert-butyl (S)-1-((S)-5-((3-chloro-1-ethyl-1H-indol-4-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (60 mg, 108 μmol, Eq: 1.00) and the mixture stirred at RT for 2 h. The mixture was diluted with sat. NaHCO3 and extracted with DCM. The combined extracts were concentrated and the residue was purified by preparative TLC to give the title compound (7 mg, 14%) as a solid. MS m/z 437 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][NH:34][CH2:35][CH2:36][OH:37]>>[C:23]([O:22][C:20]([C:6]1[C:7]([N:34]([CH2:35][CH2:36][OH:37])[CH3:33])=[N:8][C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CNCCO
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CN(CCO)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 92 step A from tert-butyl 6-chloro-4-phenyl-2-(trifluoromethylsulfonyloxy)quinoline-3-carboxylate (prepared in analogy to example 91 step A to C, 100 mg, 0.21 mmol) and 2-(methylamino)ethanol (0.164 ml, 2.05 mmol). Pale yellow solid (65 mg, 77%). MS (ESI): 413 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:21]([O:25][C:26]([N:28]([CH2:30][C:31](O)=[O:32])[CH3:29])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:31](=[O:32])[CH2:30][N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:29])[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CN(CC(=O)Nc1ncn(Cc2ccc(C(C)(C)C)cc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 2.50 g (9.18 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 3.27 g of 1-(4-t-butylbenzyl)-4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-5-imidazolecarboxamide (yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH:23]([NH2:32])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:17]1=[O:38])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:40]([O:44][C:45]([NH:47][C:48]([CH3:53])([CH3:52])[C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH:23]([NH:32][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])([CH3:53])[CH3:52])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:18]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:17]1=[O:38])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methylester, 25, (37 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (202 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][C:5]=1[NH2:6])([O-])=O.[C:20]([NH:24][C:25]#N)([O:22][CH3:23])=[O:21]>>[CH:14]1([CH2:13][CH2:12][S:11][C:8]2[CH:9]=[CH:10][C:4]3[N:1]=[C:25]([NH:24][C:20]([O:22][CH3:23])=[O:21])[NH:6][C:5]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)NC#N
Reactant: Nc1cc(SCCC2CCCCC2)ccc1[N+](=O)[O-]
Product: COC(=O)Nc1nc2ccc(SCCC3CCCCC3)cc2[nH]1

Procedure:
Repeating the reaction of Example 1 but using 10.0 g. of cyclohexylethylthiol gives 2-nitro-5-cyclohexylethylthioaniline. The nitro compound is reduced. The reduction mixture is reacted with carbomethoxycyanamide as described to give 5-cyclohexylethylthio-2-carbomethoxyaminobenzimidazole.