Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:8]1=[O:25])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCc2ccc3cccnc3n2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A mixture of 6-3 (380 mg, 0.8 mmol) and 10% Pd/carbon (200 mg) in EtOH (20 mL) was stirred under a balloon of hydrogen for 6 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 to 70:20:10 chloroform/ethyl acetate/MeOH) to give 6-4 as a yellow oil.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]=1[CH2:21][CH3:22].[H-].[Na+].[CH3:25][C:26]1([CH3:34])[O:31][CH2:30][CH:29]([CH2:32][OH:33])[CH2:28][O:27]1>C(OCC)(=O)C>[CH3:25][C:26]1([CH3:34])[O:31][CH2:30][CH:29]([CH2:32][O:33][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH2:21][CH3:22])[CH2:28][O:27]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: CCc1c(Cl)ccnc1C(=O)N(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1c(OCC2COC(C)(C)OC2)ccnc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 36.9 %

Procedure:
To a dimethylsulfoxide (20 ml) solution of the 4-chloro-3-ethyl-N,N-diisopropylpyridine-2-carboxamide (1 g, 3.72 mmol) obtained in the step (92b) above, oily sodium hydride, in oil (195 mg, 4.46 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, the (2,2-dimethyl-1,3-dioxan-5-yl)methanol (598 mg, 4.09 mmol) obtained in Example (11a) was added and the mixture was stirred at room temperature for 16.5 hours. Ethyl acetate was added to the reaction mixture. The mixture was washed twice with a saturate saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated. The residue was washed with diethyl ether to obtain the title compound (520 mg, yield: 36.9%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([NH:17][NH2:18])=O)=[N:12][CH:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+]>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)=[CH:11][N:12]=2)[N:24]=1
Reactant: NNC(=O)c1ncc(-c2ccc(OC(F)(F)F)cc2)o1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)n[nH]1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 5-(4-(trifluoromethoxy)phenyl)oxazole-2-carbohydrazide (4.6 g, 16 mmol), acetimidamide hydrochloride (2.27 g, 24 mmol) and NaOH (1.1 g, 27.2 mmol) in dry THF (100 mL) was stirred at reflux for 16 h. The mixture was then cooled to RT, concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1 to 1:1) to afford the title compound as a yellow solid (4.0 g, 80%). MS (ES+) C13H9F3N4O2 requires: 310. found: 311 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J=9.0 Hz, 2H), 7.51 (s, 1H), 7.28 (d, J=9.0 Hz, 2H), 3.79 (s, 1H), 2.65 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15]O)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>ClCCl.O>[C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]=1[CH2:14][CH2:15][Br:50])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl{6-[(2,2-dimethylpropanoyl)amino]-4-(2-hydroxyethyl)pyridin-3-yl}acetate (2.30 g, 6.84 mmol) with imidazole (0.558 g, 8.20 mmol) in dichloromethane (50 mL) was treated with triphenylphosphine (1.79 g, 6.84 mmol) and carbon tetrabromide (2.72 g, 8.20 mmol). The reaction mixture was allowed to stir at room temperature for 2 h, then was diluted with water and the layers separated. The organic layer was washed successively with 5% hydrochloric acid, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4), filtered and concentrated. The residue was filtered through a short silica plug (20% EtOAc:hexanes eluent) to afford tert-butyl{4-(2-bromoethyl)-6-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}acetate which was used immediately in the next step. LC/MS (M+1)+=398.9;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH:32]=O)[NH:24][C:23]=1[CH3:34])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH:32]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:34])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCC(=O)O
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c1CCC(=O)O

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-(2-carboxyethyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester to give the title compound.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2.CCOCC>COCCOCCOC>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][C:2]3[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1Oc1cccc2[nH]ccc12

Procedure:
Methyl 2,4-difluorobenzoate (1.53 g), K3PO4 (1.89 g) and 4-hydroxyindole (1.08 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M aqueous NaOH solution, and brine, and dried over Na_SO4. The solution was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: [O:1]([CH2:8][CH2:9]CCBr)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=O>CC(O)C>[O:1]([CH2:8][CH2:9][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCOc1ccccc1
Reactant: O=CN1CCNCC1
Solvent: CC(C)O
Product: c1ccc(OCCN2CCNCC2)cc1

Procedure:
The procedure of Example 2 was repeated in entirety substituting 57.0 g (0.27 moles) of 2-bromoethyl phenyl ether for 4-phenoxybutyl bromide, using 61.6 g (0.54 moles) of 1-formylpiperazine in 300 ml of 2-propanol and refluxing the mixture for 8 hours. Evaporation of the final dried chloroform extracts gave 35 g of 1-[2-phenoxyethyl]piperazine as an oil.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[C:33]([O:42][CH3:43])(=[O:41])[C:34]1[C:35](=[CH:37][CH:38]=[CH:39][CH:40]=1)O.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:28]([N:17]1[C:16](=[O:32])[C:15]([NH:14][CH2:13][CH2:12][O:11][C:40]2[CH:39]=[CH:38][CH:37]=[CH:35][C:34]=2[C:33]([O:42][CH3:43])=[O:41])=[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:18]1(=[O:26])=[O:27])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 120 °C
Yield: 6.3 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. Methyl salicylate (52 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 20 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (9 mg, 6%). 1H NMR (CDCl3, 500 MHz): δ 1.74 (s, 9H), 3.27 (q, 2H), 3.97-4.00 (m, 5H), 6.17 (t, 1H), 6.86 (d, 1H), 7.05 (t, 1H), 7.44-7.48 (m, 4H), 7.52-7.56 (m, 2H), 7.85 (dd, 1H); 13C NMR (CDCl3, 125 MHz): δ 27.85, 43.53, 52.52, 61.69, 67.49, 107.84, 114.40, 121.12, 121.69, 125.42, 129.00, 129.85, 131.69, 132.27, 133.85, 135.56, 158.01, 159.56, 166.79; Mass Spectrum: M+H+ 459.0.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([C:10](=O)[CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=1.[S-:14][C:15]#[N:16].[K+]>O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:16][C:15](=[S:14])[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(C(=O)CN)ccn1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cc(-c2c[nH]c(=S)[nH]2)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a stirred solution of crude 1-(2-methyl-pyridin-4-yl)-2-amino-ethanone dihydrochloride (8.50 g, 35.8 mmol) in water (60 ml) was added at room temperature potassium thiocyanate (16.4 g, 168 mmol) and the reaction mixture was heated under reflux conditions for 3 h and at 0° C. for 2 h. The precipitated solid was collected by filtration, saturated sodium bicarbonate solution (100 ml) was added and the mixture was stirred at room temperature for 2 h. The product was collected by filtration to give 4-(2-methyl-pyridin-4-yl)-1,3-dihydro-imidazole-2-thione (5.44 g, 79%) as a light brown solid; MS (ISP) 192.2 [(M+H)+].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:17](=[O:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH2:4][CH2:3]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:2]3[CH2:7][CH2:6][CH:5]([N:8]4[C:17](=[O:18])[CH2:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[CH2:9]4)[CH2:4][CH2:3]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: O=C1Cc2ccccc2CN1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4CC3=O)CC2)C1=O
Yield: 35 %

Procedure:
Title compound was prepared from 2-(piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as yellow solid in 35% yield. MS m/e (M+H)+=576.2. 1H NMR (500 MHz, DMSO-D6): δ=13.55 (s, 1H), 8.37 (s, 1H), 7.29 (s, 1H), 7.23 (dd, J1=7.63, J2=6.10, 4H), 5.37 (dd, J1=16.48, J2=7.63, 1H), 4.64 (d, J=17.70, 2H), 4.48 (s, 1H), 4.38 (s, 2H), 4.09 (m, 1H), 3.57 (m, 1H), 3.54 (s, 2H), 3.11 (m, 3H), 3.00 (m, 2H), 2.89 (m, 1H), 2.61 (m, 1H), 2.36 (m, 1H), 1.54 (m, 2H), 0.74 (d, J=28.08, 9H).
Reaction SMILES: [OH-].[Na+].O[N:4]=[C:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[C:10]([C:15]([NH2:17])=[O:16])[CH:11]=2)[CH2:6]1.C1(C)C=CC(S(Cl)(=O)=[O:27])=CC=1>O>[C:5]([CH2:6][C:7]1[C:12]([C:13]([OH:14])=[O:27])=[CH:11][C:10]([C:15]([NH2:17])=[O:16])=[C:9]([O:18][CH3:19])[CH:8]=1)#[N:4]
Reactant: COc1cc2c(cc1C(N)=O)C(=O)C(=NO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CC#N)c(C(=O)O)cc1C(N)=O
Temperature: 50 °C
Yield: 88.7 %

Procedure:
To a solution of NaOH (0.97 g, 19.2 mmol) in H2O (20 ml) was added 2-Hydroxyimino-6-methoxy-3-oxo-indan-5-carboxylic acid amide (1.5 g, 6.4 mmol). The mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (1.6 g, 8.32 mmol) was added in portions to the mixture. The mixture was heated at 80° C. for 15 min. After cooling carefully to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and the precipitate was collected and dried to give product as a solid (1.33 g, 89%). LC-MS: m/e 233 (M−1).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.N([O-])=O.[Na+].[CH:16](=[O:22])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>O.C(#N)C>[CH3:2][CH:1]([C:4]1[CH:10]=[CH:9][C:7]([C:20]2[O:21][C:17]([CH:16]=[O:22])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1ccc(-c2ccc(C=O)o2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
& B. A mixture of 100 g (0.74 mole) of 4-isopropylaniline (Aldrich Chemical Co.), 100 ml of water, and 200 ml of concentrated hydrochloric acid, was cooled at 5° C. and treated dropwise with a solution of 52 g (0.75 mole) of sodium nitrite in 150 ml of water. The mixture was kept at 5° C. for 1 hour. A solution of 90 g (0.94 mole) of furfural in 150 ml of acetonitrile was added all at once followed by a solution of 30 g of CuCl2.×H2O in 125 ml of water. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was warmed at 45° C. for 30 minutes and then cooled, and extracted with ether (3×400 ml). The combined ethereal extracts were washed with water (3×200 ml), saturated NaHCO3 solution (2×200 ml) and water (2×200 ml). The ethereal extract was dried over MgSOr and the solvent removed in vacuo (water pump). The residual oil was distilled under high vacuum using a flame. The product, 5-[4-(1-methylethyl)phenyl]-2-furancarboxaldehyde (B), was obtained as an oil (26 g, 16% yield); b.p. 160-175° C./0.5 mm Hg.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1>C(Cl)Cl.[Cl-].[Na+].O>[Br:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([Cl:3])=[N:9][CH:8]=1
Reactant: CCOc1cncc(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
As shown in step 2-iv of Scheme 2, phosphorous oxychloride (48.02 g, 403.6 mmol) was added to 3-bromo-5-ethoxypyridine, 1-oxide (4.4 g, 20.18 mmol) in 700 mL of DCM at RT. The reaction mixture was stirred at RT overnight. After the addition of brine, the organics were partitioned, dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The product was purified by filtering the concentrate through a pad of silica gel and eluting the pad with ethyl acetate. The volatiles were removed under reduced pressure to provide 5-bromo-2-chloro-3-ethoxypyridine (Compound 1003, 4.3 g, 85.6%): 1H NMR (CDCl3) δ 8.1 (s, 1H), 7.32 (s, 1H), 4.15 (q, 2H), 1.6 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:38][CH2:39][OH:40])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)c1ccccc1
Reaction time: 6 h
Yield: 75.2 %

Procedure:
To a stirred solution of 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-phenylpyrimidine-4-carboxamide (47) (287 mg, 427 μmol, Eq: 1.00) in tetrahydrofuran (10 ml) was added HCl (1N) (640 μl, 640 μmol, Eq: 1.5) at room temperature and the reaction mixture was stirred for 6 hrs, neutralized with 1N NaOH aqueous solution, extracted with ethyl acetate, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient, 0 to 5% methanol-dichloromethane) to obtain 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-phenylpyrimidine-4-carboxamide (48) (white foam, 179 mg, 321 μmol, 75.1% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[CH2:28][CH2:29][NH:30][CH3:31]>O1CCCC1>[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[CH2:28][CH2:29][N:30]([CH3:31])[C:17](=[O:19])[C:16]1[CH:20]=[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)[C:13]([Cl:22])=[CH:14][C:15]=1[Cl:21]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: CNCCC1OCCO1
Solvent: C1CCOC1
Product: CN(CCC1OCCO1)C(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
After a solution of 1 g (2.7 mmol) of 5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-2,4-dichlorobenzoic acid and 0.66 g (4.1 mmol) of 1,1-carbonyldiimidazole had been stirred for 1 hour in 20 ml of tetrahydrofuran, 0.55 g (4.1 mmol) of N-[2-(1,3-dioxolan-2-yl)-ethyl]-N-methylamine were added. The mixture was subsequently stirred for a further 16 hours at approximately 20° C. The reaction mixture was then concentrated. The crude product was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=1:1). Yield: 0.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH:24]=O)[CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:36]2[CH2:37][CH2:38][C:33]([OH:39])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:34][CH2:35]2)[CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=CCC(CC(=O)N1CCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
1-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1,2,3,4-tetrahydroquinoline (900 mg), in MeOH/THF (1:1, 20 mL) was treated sequentially with molecular sieves 3A (767 mg), 4-phenyl-4-hydroxypiperidine HCl (767 mg) and NaBH3CN (150 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (750 mg). Mass spectrum (FAB): 537.2081.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([N:12]1[CH2:41][CH2:40][CH2:39][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C@@H:2]([C:10]([N:12]1[CH2:41][CH2:40][CH2:39][C@H:13]1[C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Br
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
450 mg (0.44 mmole) of Boc-D-Phe-Pro-Arg-Phe-pNa.HBr are dissolved in 4 ml of trifluoroacetic acid, with the addition of 0.1 ml of anisole, and the solution is stirred at room temperature for 45 minutes. The product is precipitated with ether, centrifuged off and triturated with ether and centrifuged off again several times. The dried substance is triturated with NaHCO3 solution, the mixture is extracted with n-butanol, the organic phase is dried with K2CO3 and filtered and the filtrate is evaporated to dryness. The solid residue is triturated with ether and centrifuged off.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.Cl.Cl[CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:23]([NH2:25])=[NH:24])[S:20][CH:21]=1>>[NH:22]([C:19]1[S:20][CH:21]=[C:17]([CH2:16][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)[N:18]=1)[C:23]([NH2:25])=[NH:24]
Reactant: N=C(N)Nc1nc(CCl)cs1
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1

Procedure:
When a solution of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] is reacted with 4-chloromethyl-2-guanidinothiazole hydrochloride and a strong base, the title compound is thereby produced, which is identical to the product obtained in Example 31.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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:9][C:10]1[S:14][C:13]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: Oc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Oc1cccc(-c2ccc(Cl)s2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
To a solution of 3-iodophenol (1.0 g, 4.55 mmol) in DME (10 ml) was added Pd(PPh3)4 (263 mg, 0.227 mmol) at ambient temperature under N2. After stirring for 20 min., 5-chlorothiophene-2-boronic acid (886 mg, 5.45 mmol) and a solution of Na2CO3 (723 mg, 6.82 mmol) in H2O (3 ml) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (30 ml) and H2O. The organic layer was washed with saturated NaHCO3 aqueous solution, H2O and then brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (15 g) chromatography eluting with hexane/ethyl acetate (10:1) to give 3-(5-chloro-2-thienyl)phenol (0.88 g, 91.9%).