Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[N:13]1[CH:18]=CC=C[CH:14]=1.CNC.C1COCC1>O1CCOCC1>[NH2:1][C:2]1[C:7]([S:8]([N:13]([CH3:18])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: c1ccncc1
Agent: CNC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a cold (0 □C) suspension of 2-amino-5-bromo-3-pyridinesulfonyl chloride (92.1 mmol) in dry 1,4-dioxane (92 mL) was added pyridine (101.3 mmol) followed by a 2M solution of dimethylamine in THF (101.3 mmol). The reaction was allowed to warm to rt for 2 h, heated to 50 □C for 1 h, then cooled to rt. After standing for 2 h, the precipitate was collected by filtration and rinsed with a minimal amount of cold water. Drying the precipitate to constant weight under high vacuum provided 14.1 g (55%) of the title compound as a white solid. MS(ES)+ m/e 279.8, 282.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH:23]1(C=O)[CH2:25][CH2:24]1.C([O-])=O.[NH4+]>[Ru](Cl)(Cl)Cl.C(O)(C)C>[CH2:23]1[CH:25]([CH2:1][N:2]2[C@@H:12]3[CH2:13][C:14]4[CH:19]=[CH:18][C:17]([OH:20])=[C:16]5[O:21][CH:6]6[C:7]([CH2:9][CH2:10][C@:11]3([OH:22])[C@:5]6([C:15]=45)[CH2:4][CH2:3]2)=[O:8])[CH2:24]1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: O=CC1CC1
Agent: Cl[Ru](Cl)Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Into a round bottom flask was added noroxymorphone (2.19 g, 0.008 mole), cyclopropanecarboxaldehyde (1.07 g, 0.015 mole, 1.00 mL), ammonium formate (2.40 g, 0.038 mole), and isopropanol (20 mL, HPLC grade). After stirring for about 5 minutes, ruthenium (III) chloride (10 mg) was added. The mixture was stirred under nitrogen at room temperature for about 48 hours. HPLC indicated the reaction was complete. To the dark solution, distilled water (1 mL) was added and this mixture stirred for about 18 hours at room temperature. The entire mixture was evaporated under reduced pressure to a thick paste. Distilled water (10 mL) was added and the pH was adjusted to 9.4 from 7.0 using 29% NH3/H2O where a precipitate formed. The precipitate was filtered, washed with distilled water (10 mL), and dried overnight at 90° C. The dried precipitate yielded naltrexone base (2.35 g, 91% yield) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.C[Si]([Br:26])(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:26])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CO)cc2)c(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CBr)cc2)c(Cl)c1

Procedure:
To a solution of {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}methanol from II.1, step 3 (1 eq.) in CH2Cl2 (0.1M) at room temperature was added a solution of trimethyl silyl bromide (1.05 eq.) in CH2Cl2 (1.0M). The final mixture was stirred 1 h at room temperature and then concentrated in vacuo. To the resulting suspension was added silica gel and the mixture was evaporated in vacuo. Purification by column chromatography on silica gel, eluting with Hex/Et2O 5%, afforded the desired compound as a crystalline white solid.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]3[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=3)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[OH:56][C:57]1[C:66]2[C:61](=[C:62]([OH:67])[CH:63]=[CH:64][CH:65]=2)[N:60]=[C:59](C(O)=O)[CH:58]=1>>[OH:56][C:57]1[C:66]2[C:61](=[C:62]([OH:67])[CH:63]=[CH:64][CH:65]=2)[N:60]=[C:59]([C:16]([NH:18][C@H:19]([C:43]([NH:45][CH2:46][CH2:47][C:48]2[CH:55]=[CH:54][C:52]([OH:53])=[C:50]([OH:51])[CH:49]=2)=[O:44])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:17])[CH:58]=1
Reactant: O=C(O)c1cc(O)c2cccc(O)c2n1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(C[C@H](NC(=O)c1cc(O)c2cccc(O)c2n1)C(=O)NCCc1ccc(O)c(O)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagyl]dopamine (1.34 g, 1.8 mmol, example 7, step A) as described for example 7 (step B) using 4,8-dihydroxyquinoline-2-carboxylic acid (564 mg, 2.75 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using a solvent gradient from 30% to 60% EtOAc/CH2Cl2 containing 1% AcOH. The title compound was obtained as yellow crystals (663 mg, 52%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC
Reactant: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-chloro-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone (1 g, 3.9 mmol) was dissolved in 10 ml of dry THF and 7.8 ml of a 1M solution of dimethylamine in THF (7.8 mmol) were added. This reaction mixture was stirred at ambient temperature for 24 h. The solvent was removed under reduced pressure and the residue was crystallized from diethyl ether to give the expected compound 2-(dimethylamino)-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone in the form of a brown solid (Mp 130-132° C.).
Reaction SMILES: CS([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:36])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:17][CH:16]=2)[C:10]2[CH:37]=[CH:38][CH:39]=[CH:40][C:9]=2[S:8]1)(=O)=O.[C-:41]#[N:42].[Na+]>CN(C)C=O>[C:41]([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:36])[C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:20]=2)[C:10]2[CH:37]=[CH:38][CH:39]=[CH:40][C:9]=2[S:8]1)#[N:42]
Reactant: CS(=O)(=O)CCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Temperature: 70 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of Compound 16 as prepared in Example 11 (0.115 g, 0.197 mM) and sodium cyanide (20 mg) in dimethylformamide was stirred in a 70° C. oil bath for 4 hours. The reaction mixture was then cooled to RT and the DMF was removed under reduced pressure. The residual semi-solid was diluted with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined ethyl acetate extracts were dried (MgSO4) , filtered and evaporated in vacuo. The crude mixture was purified by chromatography to give pure product as a white solid (71 mg, 70%). m/z (MH+)518
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1.Br.O.[OH-].[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:11]([C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=3)[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)ccn1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2CCO)cc[nH]1
Yield: 31 %

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 mL of acetic acid was added 3 mL of 48% hydrobromic acid. The reaction mixture was heated at reflux for 3 hour. The cooled mixture was then treated with water, basified with ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (MeOH/CH2Cl2/NH4OH, 5:94:1) to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone, as a yellow solid (32% yield), mp: 250-251° C.; 1H NMR (DMSO-d6): δ 11.74 (s, 1H), 8.45 (d, J=5.0 Hz, 2H), 7.35 (m, 3H), 7.16 (m, 2H), 7.03 (d, J=5.0 Hz, 2H), 6.37 (s, 1H), 6.05 (d, J=5.2 Hz, 1H), 5.0 (m, 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for C21H17FN4O2.0.2H2O: C, 66.06; H, 4.65; N, 14.67. Found: C, 66.31; H, 4.49; N, 14.27.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][C:8]([CH3:10])=O>C(Cl)Cl>[CH3:7][C:8]1([CH3:10])[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4]1
Reactant: CC(C)=O
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC1(C)COC(C)(C)N1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Into a 500 mL, three-necked flask with a reverse Dean-Stark trap is added 45 g (500 mmol) of 2-amino-2,2-dimethylethanol, 40 g (700 mmol) of acetone and 200 mL of methylene chloride. The reaction mixture is heated to reflux for 16 hours until no starting 2-amino-2,2-dimethylethanol is detected. The reaction mixture is allowed to cool to ambient temperature and is than concentrated under vacuum (200 mm Hg/30° C.) to give 50 g (77.5% yield) of a colorless liquid. The product is identified by mass spectroscopy (m/z=129) and 1Hnmr analysis.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1>[CH3:22][O:23][CH2:24][C:25]([NH:9][C@@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:14])=[O:26]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 114 %

Procedure:
A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g, 0.90 mmol) in THF (9 mL) at 0° C. was treated with triethylamine (0.38 mL, 2.73 mmol) and methoxyacetyl chloride (0.09 mL, 0.98 mmol), stirred at 0° C. for 15 minutes and then at 25° C. for 2 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-33% ethyl acetate/chloroform to give the title compound (0.266 g).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(OCC)C>[Br:19][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]2[C:1]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CCCCCBr
Temperature: 25 °C
Reaction time: 9 h
Yield: 45 %

Procedure:
Then, 16.2 g of 5-phthalimido-1-pentanol was dissolved in 350 ml of diethyl ether, and 4.3 ml of phosphorus tribromide was added dropwise at 0° C. The reaction solution was stirred at room temperature for 9 hours and neutralized with saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give 9.2 g of 1-bromo-5-phthalimidopentane in a yield of 45%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC(=O)[NH:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41](Br)=[CH:42][CH:43]=1)(=[O:38])=[O:37])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:42][CH:43]=1)(=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and [2-(5-bromo-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.51) (193 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (158 mg, 56%). MS (ISN) 558.0 [(M−H)−]; mp 161° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([O:32][CH3:33])[CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:6]=3[N:21]=2)=[C:27]([O:32][CH3:33])[CH:26]=1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Yield: 96.5 %

Procedure:
A solution of 0.10 g (0.00032 mole) of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19), 0.060 g (0.00032 mole) of 4-amino-3-methoxy-benzoic acid methyl ester, 0.10 g (0.00049 mole) of p-toluene-sulfonic acid monohydrate and 4 mL of 2-propanol at 150 degrees for 1 hour in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-85:15%), to give 0.14 g of (rac)-4-(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid methyl ester as white powder.
Reaction SMILES: C(CC1(CC)CCC(C=C)CC1=O)(OC)=O.[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25]N)[CH3:18].C(Cl)(C)=O>CO>[NH:25]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: CCc1ccccc1NN
Agent: C=CC1CCC(CC)(CC(=O)OC)C(=O)C1
Solvent: CC(=O)Cl
Solvent: CO
Product: c1ccc2[nH]ccc2c1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
The more polar ketone isomer of 2-carbomethoxymethyl-5-ethenyl-2-ethylcyclohexanone (5.084 g, 22.66 mmol) and the 2-ethylphenylhydrazine (3.086 g, 22.66 mmol) were heated at reflux in 97 ml of methanol under nitrogen for 48 hours. The reaction was then cooled to 0° C., treated with 45.32 mmol (3.56 g, 3.22 ml) of AcCl and refluxed an additional 45 minutes. Cooling, concentration and flash chromatography afforded 2.772 g (8.52 mmol, 38%) of indole as an orange oil. Rf =0.47 in 15% ethyl acetate/petroleum ether on TLC.
Reaction SMILES: C(O[NH:5][C:6](=[NH:20])[CH2:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)(=O)C.C(OCC)(=O)C>C(O)C.[Pd]>[C:14]1([C:13]2[C:8]([CH2:7][C:6]([NH2:20])=[NH:5])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)ONC(=N)Cc1ncccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C(N)Cc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred degassed solution of (161) (2.7 g, 10.04 mmol) in ethanol (135 mL) was added 10% Pd—C (270 mg), the mixture was stirred 16 h under H2 (hydrogen bubbler) at room temperature. Silica thin layer chromatography was performed (ethyl acetate, Rf=0.1). The reaction mixture was filtered through celite, washed with 10% methanol in dichloromethane (5×100 mL), dried and concentrated. The yellow solid was washed with 10% ethyl acetate in hexane (3×30 mL) to get pure 2-(3-phenyl-pyridin-2-yl)-acetamidine with acetic acid (162) (1.7 g, 62.5%) as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[CH:25]=[C:26]([C:33](O)=[O:34])[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[N:24][CH:25]=2)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cnc2ccccn12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3ccccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Imidazo[1,2-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=492.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:18]1[CH:17]=[N:16][C:15]([CH3:14])=[CH:20][CH:19]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Cc1ccc(O)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cn1

Procedure:
A 3.74 g (20 mmol) sample of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 3.27 g (30 mmol) of 2-methyl-5hydroxypyridine were reacted with triphenylphosphine and DEAD (30 mmol each) in 100 mL of THF according to the procedure of Example 14a, to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][CH:42]([CH3:51])[C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>ClCCl>[C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:6]([C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=2)[CH:1]=[O:2])=[O:8])[CH2:47][CH2:46]1)(=[O:44])[CH:42]([CH3:51])[CH3:41]
Reactant: CC(C)C(=O)N1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol), 1-hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5.5 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C., and 2-methyl-1-(piperazin-1-yl)propan-1-one (1.06 g, 5.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (50 mL×2), 10% citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (1.44 g, yield: 95%) as a gum. LC-MS (ESI) m/z: 289 (M+1)+.
Reaction SMILES: [NH:1]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:46][CH2:45][CH2:44][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.CO.N(C(OC(C)(C)C)=O)[C@H](C(N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(OCC1C=CC=CC=1)=O)CCCCNC(OCC1C=CC=CC=1Cl)=O)=O)C)=O)=O)CCCNC(=N)NS(C1C=CC(C)=CC=1)(=O)=O)=O)CC(=O)N>CO>[NH:1]([C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:46][CH2:45][CH2:44][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([OH:36])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
At 0° C. to the solution of 550 mg (0.726 mmol) of Boc-Ala-Arg(Tos)-Pro-Ala-OBzl (SEQ ID NO: 7) in 20 ml of methanol 8 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Asn-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 17). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 330 mg (67%) of the title compound as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.CN1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)CCC1=O.BrC1C=NC=C(Br)C=1.[C:49]([O:53][C:54]([N:56]1[CH:61]=[C:60](B2OC(C)(C)C(C)(C)O2)[CH2:59][CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>>[C:49]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH2:59][C:58]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]4)[CH:3]=2)=[CH:57]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Reactant: CN1C(=O)CCc2cc(-c3cncc(Br)c3)ccc21
Agent: Brc1cncc(Br)c1
Agent: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(C4=CN(C(=O)OC(C)(C)C)CCC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 6-(5-bromo-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (prepared from 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) and 3,5-dibromo pyridine also with a procedure as used for the preparation of example 45) has been coupled to 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester to give the title compound as an amorphous colorless solid. MS: 420.5 (M+H+).