Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]3)[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][C:4]=2[CH:3]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=1>CN(C=O)C.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>[Cl:14][C:12]1[CH:13]=[C:8]([C:6]2[C:5]3[N:15]([CH2:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]4)[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@H:19]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:17][C:4]=3[CH:3]=[C:2]([C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[N:41]=3)[N:7]=2)[CH:9]=[N:10][CH:11]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc3nc(N4CCOC[C@H]4c4ccccc4)n(C[C@H]4CC[C@H](C)CC4)c3c(-c3cncc(Cl)c3)n2)n1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (Example 2.1, Step 3; 130 mg, 0.242 mmol), 2-methoxy-6-(tri-n-butylstannyl)pyridine (122 mg, 0.308 mmol), and Pd(PPh3)4 (28.0 mg, 0.0242 mmol) in DMF (2.9 mL) was degassed and heated at 100° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous KF solution (10 mL), water (2×10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded 4-(5-chloropyridin-3-yl)-6-(6-methoxypyridin-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine. MS ES calc'd. for C35H37ClN6O2 [M+H]+ 609. found 609.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[C:9]([C:11]1[CH:12]=[C:13]([CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])([OH:10])=[O:8]
Reactant: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)O)c1
Reaction time: 5 h
Yield: 125.2 %

Procedure:
Methyl 3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2,2-dimethylpropanoate (310 mg, 0.870 mmol) was dissolved in 7 ml of mixed solvent of ethanol with tetrahydrofuran at a ratio of 1:1, 10% palladium on activated carbon (20 mg) was added thereto, and normal pressure hydrogenation was conducted for 5 hours. After completion of the reaction, catalyst was filtered and the filtrate was concentrated to obtain 290 mg (90%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[O:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].O>CO>[N:1]1([CH:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:19])[F:17])[OH:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1ccccc1C1OC1(Cn1cncn1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(C(=Cn1cncn1)c1ccc(Cl)cc1)c1ccccc1C(F)(F)F

Procedure:
4 g of 2-(1,2,4-triazol-1-ylmethyl)-2-(4-chlorophenyl)-3-(2-trifluoromethylphenyl)oxirane are dissolved in 80 ml of methanol and, after addition of 1.2 g of sodium methylate, refluxed for one hour. The solution is then cooled to room temperature (20° C.), 50 ml of water are added and the mixture is extracted by shaking several times with methyl tert-butyl ether. The isolated organic phase is washed twice with water, dried over sodium sulfate and concentrated, resulting in 3.8 g (95 %) of 1-(1,2,4-triazol-1-yl)-2-(4-chlorophenyl)-3-(2-trifluoromethylphenyl)-1-propen-3-ol, melting point 161° C.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][C:23]([CH:29]1[CH2:31][CH2:30]1)([CH3:28])[CH2:24][C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[CH2:24][C:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]2[CH2:5][C:2]([F:21])([F:1])[CH2:3]2)=[CH:11][N:10]=1)=[O:14])([CH:29]1[CH2:31][CH2:30]1)[CH3:28]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Reactant: CC(N)(CC(N)=O)C1CC1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 223b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (70 mg, 63%) as a racemate; MS (ESI, m/z): 437.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][C:14](OCC)=[N:13][CH2:12][CH2:11]1)=[O:9].O.[NH2:20][NH2:21]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:11][CH2:12][NH:13][CH:14]([NH:20][NH2:21])[CH2:15]1)=[O:9]
Reactant: NN
Reactant: CCOC1=NCCN(C(=O)c2ccccc2Cl)C1
Solvent: ClCCl
Solvent: O
Product: NNC1CN(C(=O)c2ccccc2Cl)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[(2-chlorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (I39) (0.755 g, 2.83 mmol) dissolved in Dichloromethane (DCM) (10 mL) was added to hydrazine hydrate (0.220 mL, 7.08 mmol, commercially available from e.g. Alfa Aesar, Acros or Fluka) dissolved in Dichloromethane (DCM) (5 mL) and stirred at 25° C. for 4 hr. The solvents were removed in vacuo and the residue azeotroped with toluene (3×25 mL), to afford product in 715 mg that was used in the subsequent step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:21][C:18]1[CH:17]=[N:16][C:15]([NH:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(Br)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cnc(N[C@@H]2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (˜0° C.) solution of (R)-3-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (775 mg) in dry DCM (10 mL) was added slowly TFA (0.831 mL). The reaction mixture was stirred at RT for 20 h, 5 eq more of TFA (0.831 mL) was added and the stirring was continued for 2 h. The reaction was concentrated in vacuo to yield the title compound as a bis-trifluoroacetate salt which was used for the next step without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[O:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:8]([Cl:7])(=[O:11])=[O:9]
Reactant: c1ccoc1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccco1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
Phosphorus pentachloride (15.29 g, 73.44 mmol) was added portionwise (caution, foaming) over 5 min at 0° C. to chlorosulfonic acid (21.39 g, 183.6 mmol) and the resulting solution was stirred at 0° C. for 10 min. Then, furan (5.0 g, 73.44 mmol) was added in one portion and the resulting dark suspension was stirred at 0° C. for 15 min during which time foaming occurred and subsided. The reaction mixture was then poured onto ice and the resulting suspension was extracted with CH2Cl2 (150 mL). The organic extract was filtered through a pad of celite, washed with brine and dried over MgSO4. The solvent was removed in vacuo to provide 2-furansulfonyl chloride as a black oil (1.01 g, 7.9%). 1H-NMR (DMSO-d6, 400 MHz) δ 7.4 (d, 1H); 6.38 (d, 1H); 6.35 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nccs1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2cn3ccsc3n2)c1
Reaction time: 18 h
Yield: 82.9 %

Procedure:
To a mixture of 2-aminothiazole (2.7 g, 26.7 mmol) and 2-bromo-3′-methoxyacetophenone (6.0 g, 0.0262 mol) was added absolute ethanol (100 ml). The reaction was allowed to reflux with vigorous stirring for 18 hours (checked by HPLC). The reaction mixture was reduced to half its original volume in vacuo. The remaining liquid was poured onto ice and the solution made basic by the addition of ammonium hydroxide solution (30%). The resulting fine solid was filtered and washed with water resulting in a dark yellow solid product. The solid product was dried in a vacuum oven at 50° C. to provide 6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole (5.0 g, 81%). 400 MHz 1H NMR (DMSO-d6) δ 8.18 (s, 1H), 7.88 (d, J=4.4 Hz, 1H), 7.36-7.42 (m, 2H), 7.28 (t, J=8.1 Hz, 1H), 7.22 (d, J=4.4 Hz, 1H), 6.82 (ddd, J=8.1, 2.6, 1.1 Hz, 1H), 3.80 (s, 3H). LCMS: 231 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:21]([C:18]2[CH:19]=[N:20][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)nc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of benzylpiperazine (0.45 mL, 2.59 mmol) in methylene chloride (15 mL), cooled on an ice-bath, was 6-chloropyridine-3-sulfonyl chloride (0.50 g, 2.36 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) added slowly. The reaction was stirred for 30 min and the formed white precipitation was filtered and washed with methylene chloride and water affording, after drying, 0.68 g (82% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.70 (d, J=3 Hz, 1 H), 8.14 (dd, J=8, 3 Hz, 1 H), 7.76 (d, J=8 Hz, 1 H), 7.50-7.43 (m, 2 H), 7.38-7.30 (m, 3 H), 4.23 (br s, 2 H), 3.79-3.63 (m, 2 H), 3.45-3.18 (m, 2 H), 3.11-2.96 (m, 2 H), 2.96-2.81 (m, 2 H); MS (ES) m/z 352 (M++1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Solvent: C1COCCO1
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 5 h
Yield: 17.3 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) (103 mg, 0.26 mmol) in dioxane (5 mL) at room temperature (20° C.) was added methyl chloroformate (32 uL, 0.23 mmol). The reaction mixture was stirred for 5 h. The solvent was removed in vacuo and the residue purified by prep HPLC (low pH) to afford an orange solid (18 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:35](=[O:37])[CH3:36])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCC4)c23)ccc1OCc1ccccn1
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCC1
Yield: 42 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclobutylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 42% yield; NMR spectrum (DMSO-d6) 1.50-1.65 (m, 2H), 2.01 s, 3H), 2.12-2.21 (m, 4H), 3.94 (t, 2H), 4.28-4.38 (m, 3H), 5.31 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 7.32-7.40 (m, 2H), 7.57-7.62 (m, 2H), 7.69-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.97 (s, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.90 (s, 1H); Mass spectrum MH+ 518.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:5]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:32]([OH:42])=[CH:31][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH2:28][CH2:29][CH3:30])=[C:14]([NH:18][C:19](=[O:27])[CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH3:4].O>C1COCC1>[CH2:3]([C:5]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:32]([OH:42])=[CH:31][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH2:28][CH2:29][CH3:30])=[C:14]([NH:18][C:19](=[O:27])[CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([O-:24])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH3:4].[Na+:2]
Reactant: CCCc1c(NC(=O)CC(C)(C)C(=O)O)cccc1OCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(NC(=O)CC(C)(C)C(=O)[O-])cccc1OCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Add 1 N sodium hydroxide (404 mL) dropwise to a solution of 4-[[3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxy-phenoxy]propoxy]-2-propyl-phenyl]amino]-2,2-dimethyl-4-oxo-butanoic acid (223 g, 404 mmol) in THF (1115 mL) and stir at ambient temperature for 15 min. Reduce the volume in vacuo and add water (1300 mL). Remove additional solvent using a membrane pump, to avoid heating the solution, to obtain a final volume of 1250 mL. Lyophilize the remaining solution in batches to yield the title compound (230 g, 99%) as an off-white solid. ES/MS m/z 552 (M+1, free base).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([OH:25])=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:23]([OH:25])=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Yield: 89.1 %

Procedure:
A solution of Z-Leu-Lys(Boc)-OH 41.5 g, 0.084 mol) in methanol (210 mL) was hydrogenated in a Vibromixer apparatus using 10% Pd/C (5.0 g) for 3.5 h. The precipitated product dissolved on addition of H2O (120 mL). The catalyst was removed by filtration (celite); washed twice with H2O and the combined filtrate evaporated to near dryness. The residue was reevaporated from MeOH (2×) and Et2O (2×). The solid product was collected, washed with Et2O and dried to afford 26.9 g of white solid. Recrystallization from warm iPrOH (420 mL) and MeOH (350 mL) afforded, after drying, 24.6 g of white crystalline product (81.5%); mp 142°-143°; Rf 0.63 (n-BuOH:AcOH:EtOAc:H2O; 1-1-1-1); [α]D25 +20.76° (c 1, MeOH). Anal: calcd. for C17H33N3O5 (359.47): C, 56.80; H, 9.25; N, 11.69. Found: C, 56.72; H, 9.55; N, 11.57.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[CH:19][C:18]=3[N+:29]([O-])=O)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>CO.[Pd]>[NH2:29][C:18]1[CH:19]=[CH:20][C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:22][C:17]=1[C:16]([NH:15][C:12]1[CH:11]=[N:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:32]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])cn2)cc1C
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)cn2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.3 %

Procedure:
Into a 500-mL round bottom flask, was placed a solution of N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-2-nitro-5-(piperidin-1-yl)benzamide (3.66 g, 8.47 mmol, 1.00 equiv) in methanol (150 mL). The mixture was treated with Pd/C (aqueous) (3.66 g) and stirred under a hydrogen atmosphere for 4 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.88 g (55%) of product as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Solvent: c1ccccc1
Product: Fc1ccc(C=C(c2ccccc2)N2CCOCC2)cc1

Procedure:
A mixture of 4-fluorobenzyl phenyl ketone (50g), morpholine (45g) and benzene (100ml) was refluxed overnight with molecular sieve, type 4A, to afford 2-(4-fluorophenyl)- 1-phenyl-1-morpholinoethylene. The latter compound (0.2 mole), cyanoacetamide (0.2 mole), diethylamine (2ml), sulphur (0.2 mole) and ethanol (100 ml) were stirred overnight at room temperature and then added to water. The crude product was recrystallised from ethanol and then from nitromethane to give pure 2-amino-5-(4-fluorophenyl)- 4-phenyl-3-thiophene carboxamide, m.p. 205°-7°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH2:6][CH2:5]2
Reactant: CCCS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CCN2
Product: CCCS(=O)(=O)N1CCc2cc(Br)ccc21
Yield: 52.6 %

Procedure:
This compound was prepared using the general procedure for sulfonylation of indolines and tetrahydroquinolines as described in Example 4 using 5-bromoindoline (0.396 g, 2.0 mmol) and propylsulfonyl chloride (0.34 mL, 3 mmol) to provide 5-bromo-1-(propylsulfonyl)indoline (0.32 g). MS (ES) m/z 303.6; HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>C(O)C>[OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncccc1CO
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: OCc1cccn2cc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A mixture of 1.24 g (10 mmole) of 3-hydroxymethyl-2-pyridinamine and 2.0 g (10 mmole) of α-bromoacetophenone in 25 ml of ethanol was stirred at room temperature. After 18 hours the resultant solid was collected, washed with ethano, and dissolved in water. The solution was made basic with aqueous potassium carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether, collected by filtration, washed with diethyl ether, and air dried to yield 1.4 g of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C14H12N2O2 : C, 74.98; H, 5.39; N, 12.49. Found: C, 74.68; H, 5.39; N, 12.40.] A mixture of 871 mg (5.8 mmole) of 2-mercaptobenzimidazole and 1.3 g (5.8 mmole) of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine was dissolved in 10 ml of 47% aqueous hydrobromic acid and 10 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water, made alkaline with potassium carbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Trituration of the residue with diethyl ether yielded 1.8 g of the analytically pure title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br[CH:12](C(OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A mixture of 5-bromosalicylaldehyde (10 g, 50 mmol), diethyl bromomalonate (13.1 g, 55 mmol), potassium carbonate (6.9 g, 50 mmol), and 2-butanone (80 mL) was stirred at 90° C. for 16 hrs. The solvent was removed under reduced pressure at 45° C., and the residue was acidified with 1M HCl, extracted, washed, dried, and evaporated. The residue was purified by chromatography to give about 3.6 g of ethyl 5-bromo-benzofuran-2-carboxylate, mp. 59-60° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:33]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]([CH2:24][C:23]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]2=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(F)cc2)ccc1OCCc1ccccn1
Reaction time: 48 h

Procedure:
4-fluorobenzenesulfonyl chloride (0.22 mmol) is added to a room temperature solution of triethylamine (0.9 mmol) and 3-[3-Methoxy-4-(2-pyridin-2-yl-ethoxy)-benzylamino]-azepan-2-one (3) (0.22 mmol) in methylene chloride (0.2 M). After stirring for 48 hours, the reaction mixture is concentrated and the resulting residue is purified by reverse phase HPLC, to afford the desired product (4).