Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH:42]([NH:45][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:31])[CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)C1

Procedure:
3-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared was prepared starting from intermediate M and 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester. MS calcd. for C26H30ClN4O4 [(M+H)+] 497.2, obsd. 497.2.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C([O:7][CH:8]=[C:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.C(OCC)(=O)C.Cl>C(O)C.O>[O:7]=[C:8]1[NH:4][CH:2]=[N:3][CH:15]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: N=CN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnc[nH]c1=O
Temperature: 120 °C

Procedure:
A mixture of formamidine hydrochloride (4.02 g, 49.9 mmol) and diethyl ethoxymethylenemalonate (5 ml, 24.95 mmol) in ethanol (4.99 ml) was heated to 120° C. (by microwave irradiation) for 15 h. After the reaction mixture was cooled to room temperature, ethyl acetate, hydrochloric acid (1M), and water were added. The aqueous layer was washed with ethyl acetate and then extracted with 3:1 chloroform:isopropanol. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to afford ethyl 6-oxo-1,6-dihydropyrimidine-5-carboxylate as an orange solid. LRMS (ESI) calc'd for (C7H9N2O3) [M+H]+, 169.1; found 169.1.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C(O)C>[N:16]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: Nc1ccccn1
Reactant: CC(C(N)=O)c1ccc(C(=O)CCl)cc1
Solvent: CCO
Product: CC(C(N)=O)c1ccc(-c2cn3ccccc3n2)cc1
Yield: 65.2 %

Procedure:
A mixture of 9 g of 2-[4-(chloroacetyl)phenyl]propionamide, 30 ml of ethanol and 7.6 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The crystalline precipitate is filtered off and recrystallized from aqueous dimethylformamide to give 6.9 g of 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionamide as colorless scales melting at 219°-220°C.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])=[CH:5][C:4]=1C)#N.[OH-:16].[Na+].[CH2:18]([OH:21])[CH2:19]O>O>[CH3:3][C:4]1[CH:5]=[C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:19]=1[C:18]([OH:21])=[O:16]
Reactant: OCCO
Reactant: Cc1cc(S(F)(F)(F)(F)F)ccc1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S(F)(F)(F)(F)F)ccc1C(=O)O
Temperature: 130 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A mixture of 4-cyano-3-methylphenylsulfur pentafluoride (41.2 g, 169.4 g), NaOH (20.4 g, 510 mmol) and water (60 ml) in ethylene glycol (160 ml) was heated to 130° C. and stirred at this temperature for 4 h. It was then cooled to room temperature and diluted with MTB (150 ml) and water (250 ml), and the mixture was filtered with suction. The phases of the filtrate were separated, and the aqueous phase was acidified with concentrated aqueous HCl solution, and the precipitated solid was filtered off with suction. 41.1 g (93%) of 2-methyl-4-pentafluorosulfuranylbenzoic acid were obtained as colorless crystals, m.p. 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: NCc1cccnc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Yield: 71.2 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.40 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 3-(aminomethyl)pyridine (0.16 g, 1.48 mmol) in dioxane (1 ml) and NaHCO3 (0.37 g, 4.49 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with dichloromethane-methanol (20:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.35 g, 71%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.76 (3H, s); 4.09 (2H, d, J=6.0 Hz); 6.72 (1H, d, J=16.2 Hz); 7.29 (1H, dd, J=8.0 and 5.0 Hz); 7.51-8.12 (6H, m); 8.27 (1H, br t, J=6.0 Hz); 8.31-8.50 (2H, m).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[C:6]=1[CH3:29].COC(=O)CC1C2C(=NC=CC=2)NC=1C.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.BrCC1C=CC(S(C)(=O)=O)=CC=1C(F)(F)F>CN(C=O)C>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]2[CH3:29])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To an ice-cooled solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (400 ml) under an inert atmosphere of Argon is added dropwise, BEMP (18.1 ml, 62.8 mmol) over two minutes. After stirring at 10° C. for 40 minutes, the resulting solution is treated dropwise with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (23.8 g, 75.4 mmol) and allowed to warm to room temperature while stirring overnight. The reaction is concentrated in vacuo with toluene azeotroping and the resulting oil is partitioned between water (400 ml) and DCM (500 ml) and extracted with DCM (500 ml). The organic portions are combined and washed with water (2×200 ml). The resulting suspension is filtered and concentrated in vacuo with toluene azeotroping. The crude is purified by chromatography on silica eluting with iso-hexane/acetone (16:4) to yield the titled product. (MH+441)
Reaction SMILES: [B:1]([OH:4])([O-:3])[O-:2].[B:5]([OH:8])([OH:7])[OH:6].[B:9]([OH:12])([OH:11])[OH:10].[B:13]([OH:16])([OH:15])[OH:14].[Na+].[Na+].[Ti:19].OO>O>[B:1]([O-:4])([O-:3])[O-:2].[Ti+4:19].[B:5]([O-:8])([O-:7])[O-:6].[B:9]([O-:12])([O-:11])[O-:10].[B:13]([O-:16])([O-:15])[O-:14].[Ti+4:19].[Ti+4:19]
Reactant: OB(O)O
Reactant: [Ti]
Reactant: [O-]B([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Product: [O-]B([O-])[O-]
Product: [Ti+4]

Procedure:
200 g of disodium tetraborate was dissolved in 800 ml of hot deionized water. The water is in the temperature range of about 85° C. to about 95° C. 150 g of 45% titanium III sulfate was added to the above solution to form a dark slurry. 35% H2O2 was added drop-wise to the slurry until a homogenous yellow suspension resulted. The product was filtered in a Büchner funnel, and the cake was washed with deionized water. Solids were determined to be 19.8% by oven drying.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[C:14]1([CH2:20][C:21]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>CCO>[N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]2[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:32][C:30](=[O:31])[NH:29]2)=[CH:8][CH:7]=1
Reactant: NC(N)=O
Reactant: O=Cc1ccc(-c2nn[nH]n2)cc1
Reactant: O=C(Cc1ccccc1)c1cccnc1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2cccnc2)=C(c2ccccc2)C(c2ccc(-c3nn[nH]n3)cc2)N1
Yield: 24.8 %

Procedure:
A mixture of 4-(2H-tetrazol-5-yl)benzaldehyde (106 mg), 2-phenyl-1-(pyridin-3-yl)ethanone (Intermediate 31) (100 mg, 0.51 mmol), urea (120 mg, 2.0 mmol) and conc. HCl (0.2 mL) in EtOH (5 mL) was refluxed under N2 overnight. The mixture was concentrated under reduced pressure and purified by prep-HPLC (0.1% TFA as additive) to give Compound 162 (50 mg, 2-step yield 25%). 1H NMR (DMSO-d6 400 MHz): δ 8.97 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.89 (s, 1H), 8.05-7.97 (m, 2H), 7.85 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.49-7.44 (m, 1H), 7.07-7.00 (m, 3H), 6.89-6.85 (m, 2H), 5.38 (s, 1H). MS (ESI): m/z 396.4 [M+1]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([N+:14]([O-])=O)[C:3]=1[NH2:17].[H][H].[I:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[C:22]=1[CH:29]=O>CO.[Pd]>[I:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[C:22]=1[C:29]1[NH:14][C:4]2[CH:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:7]=[C:2]([CH3:1])[C:3]=2[N:17]=1
Reactant: Cc1cc(N2CCOCC2)cc([N+](=O)[O-])c1N
Reactant: [H][H]
Reactant: COc1nccc(I)c1C=O
Agent: [Pd]
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(N3CCOCC3)cc2[nH]1
Temperature: 0 °C

Procedure:
2-Methyl-4-morpholin-4-yl-6-nitro-phenylamine (15.2 g, 64 mmol) was suspended in methanol (200 ml) in a PARR flask. Palladium on carbon (1.0 g, 10% Pd) was added and the suspension shaken under 60 psi of hydrogen overnight. The mixture was filtered through a pad of celite (under argon) into a 3-neck flask, the celite rinsed with methanol and the filtrate diluted with methanol to a total volume of 500 ml and cooled to 0° C. A solution of 4-Iodo-2-methoxy-pyridine-3-carbaldehyde (14.6 g, 55.5 mmol) in methanol (500 ml) was added slowly (during 3 hours). After addition of ˜¼ of the solution the system was opened to air and stirred over the weekend, thereby reaching room temperature. The reaction mixture was concentrated in vacuo, filtered through a pad of silica (eluent: methylenechloride-ethyl acetate-methanol 55-40-5) then crystallized from ethyl acetate. The title compound was isolated as brown solid (12.68 g, 51%). Flash column chromatography of the mother liquor (gave additional 2.90 g (12%). [pack column with methylene chloride, elute compound with methylene chloride-ethyl acetate 6-4, then methylenechloride-ethyl acetate-methanol 58-40-2]. LCMS (M+H)+ m/z 451 (t=1.03 min.). 1H NMR (500 MHz, CDCl3) δ 7.76 (1H, d, J=5.3 Hz),), 7.42 (1H, d, J=5.3 Hz), 6.85 (1H, broad s), 6.82 (1H, s), 3.86 (4H, t, J=4.5 Hz), 3.79 (3H, s), 3.12 (4H, t, J=4.5 Hz), 2.60 (3H, s), 2.21 (3H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH2:13]([C:15]1[S:19][C:18]([CH2:20][C:21]([CH3:23])=O)=[N:17][CH:16]=1)[CH3:14].[NH2:24]/[C:25](/[CH3:29])=[CH:26]\[C:27]#[N:28]>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:20]([C:18]3[S:19][C:15]([CH2:13][CH3:14])=[CH:16][N:17]=3)=[C:21]([CH3:23])[NH:24][C:25]([CH3:29])=[C:26]2[C:27]#[N:28])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: C/C(N)=C/C#N
Reactant: CCc1cnc(CC(C)=O)s1
Reactant: COc1cc(C#N)ccc1C=O
Solvent: CC(C)O
Product: CCc1cnc(C2=C(C)NC(C)=C(C#N)C2c2ccc(C#N)cc2OC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
47.6 mg (0.295 mmol) of the compound from example 3A, 50 mg (0.295 mmol) of the compound from example 24A and 24 mg (0.295 mmol) of 3-aminocrotononitrile are dissolved in 2 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 23 mg (19% of theory) of the title compound are obtained in 90% purity (by LC-MS) and can be further purified by crystallization from ethyl acetate. 3 mg (3% of theory) of the target compound are thus isolated in pure form.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>O.CC(C)=O>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:11][CH2:10][CH:9]([O:12][CH3:13])[O:8][CH3:7])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(CNC(=O)c1ccc(Br)cc1)OC
Temperature: 25 °C

Procedure:
Potassium carbonate (8.0 g) was added to a solution of 2,2-dimethoxyethylamine in water (90 ml) and acetone (40 ml) at rt. The reaction mixture was cooled in an ice-water bath and 4-bromobenzoyl chloride (16.4 g) dissolved in acetone (70 ml) was added drop-wise over 90 min. The stirred reaction mixture was allowed to warm to rt. After a further 2 h the reaction mixture was extracted into EtOAc (3×75 ml), the combined organics were washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated to give the amide as an off white solid (18.5 g). LCMS electrospray (+ve) 289 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([NH:34][CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([NH:34][CH3:35])=[O:33])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+]([O:53][N:54]2N=NC3C=CC=C[C:55]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:70]N(C=O)C>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[C:25]([C:27](=[O:28])[N:54]([O:53][CH3:70])[CH3:55])[CH:24]=[CH:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C(=O)O)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Product: CON(C)C(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid [prepared in a manner analogous to that described in Int-20-0] (750 mg, 1.55 mmol), N-methyl-O-methyl-hydroxlyamine HCl salt (227 mg, 2.33 mmol, 1.5 equiv) N,N-diisopropylethylamine (1.6 mL, 9.30 mmol, 6.0 equiv) and PyBOP (1.01 g, 1.94 mmol, 1.25 equiv) in DMF (23 mL) was stirred at room temperature for 24 h. The resulting mixture was added to ice water (25 mL). The resulting mixture was extracted with EtOAc (4×25 mL). The combined organic phases were washed with water (2×50 mL), dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 25 g SNAP cartridge: 100% hexane for 1 min., gradient to 75% hexane/25% EtOAc over 1 min., 75% hexane/25% EtOAc for 3 min., gradient to 50% hexane/50% EtOAc over 1 min., 50% hexane/50% EtOAc for 4.5 min, gradient to 25% hexane/75% EtOAc over 2.5 min., gradient to 100% EtOAc over 2 min., 100% EtOAc for 10.6 min.) to give (1-{4-[7-(methoxy-methyl-carbamoyl)-3-phenyl-imidazo[1,2-a]pyridin-2-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (679 mg, 76%):
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([CH3:10])[N:4]=1)[CH3:2].[F:11][C:12]1[C:17]([O:18][C:19](=O)[O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=[C:16]([F:33])[C:15]([F:34])=[C:14]([F:35])[C:13]=1[F:36]>C1COCC1>[F:11][C:12]1[C:17]([O:18][C:19](=[O:20])[NH:9][C:7]2[CH:6]=[C:5]([CH3:10])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=2)=[C:16]([F:33])[C:15]([F:34])=[C:14]([F:35])[C:13]=1[F:36]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCc1cc(N)cc(C)n1
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc(C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-ethyl-6-methyl-pyridin-4-ylamine (1.33 g, 9.8 mmol) in THF (25 mL) is slowly added to a solution of bis(pentafluorophenyl)carbonate (3.99 g, 10.1 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.
Reaction SMILES: [N+](C1C=CC(C([N:10]2[C:16]3OC=C[C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=O)=CC=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[CH:11]1[C:12]2[N:13]([CH:20]=[CH:21][CH:22]=2)[CH2:14][CH:15]=[CH:16][N:10]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C1=CN=Cc2cccn2C1
Reaction time: 5 h

Procedure:
A mixture of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH3:37])[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:32]=[CH:31][C:30]([CH:33]([CH3:37])[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C(=O)O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)cc1

Procedure:
(4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-phenyl)-propionic acid was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 4-bromo phenyl propionic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H34N4O3 (m/e) 486, obsd 487 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.C([Li])CCC.[I:24]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([I:24])=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(I)cc2c(Cl)ccnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (235 mg, 0.831 mmol) was dissolved in tetrahydrofuran (3 mL) under nitrogen atmosphere. After cooling to −78° C., n-butyllithium (0.675 mL, 1.080 mmol, 1.6 M hexane solution) was slowly added dropwise. The resulting mixture was stirred for 1 hour. After adding a solution of iodine (253 mg, 0.997 mmol) in tetrahydrofuran (2 mL), the mixture was slowly heated to room temperature. One hour later, the mixture was extracted with dichloromethane and water and the organic layer was washed with sodium chloride aqueous solution. The organic layer was dried with magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1) to give the target compound as a yellow oil (339 mg, 0.83 mmol, 97% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[O:39]1[C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=[N:40]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:44]([C:43]1[O:39][N:40]=[CH:41][CH:42]=1)=[O:45])[CH:29]=3
Reactant: O=C(Cl)c1ccno1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)c1ccno1
Yield: 45 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 45% yield. LCMS for C22H18ClN6O2(M+H)+: m/z=433.1. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.52 (s, 1H), 9.49 (s, 1H), 8.75 (d, 1H), 8.12 (s, 1H), 7.84 (m, 1H), 7.56 (m, 1H), 7.48 (m, 1H), 7.27 (m, 1H), 7.20 (d, 1H), 7.06 (dd, 1H), 6.85 (m, 1H), 6.82 (m, 1H), 2.84 (m, 4H).