Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:48]([CH3:49])=[CH:47][S:46][C:45]=2[S:50]([C:52]2[S:53][CH:54]=[C:55]([CH3:67])[C:56]=2[C:57]2[CH:62]=[CH:61][C:60]([NH2:63])=[C:59]([N+:64]([O-])=O)[CH:58]=2)=[O:51])=[CH:40][C:39]=1[N+:68]([O-])=O>>[NH2:64][C:59]1[CH:58]=[C:57]([C:56]2[C:55]([CH3:67])=[CH:54][S:53][C:52]=2[S:50]([C:45]2[S:46][CH:47]=[C:48]([CH3:49])[C:44]=2[C:41]2[CH:42]=[CH:43][C:38]([NH2:37])=[C:39]([NH2:68])[CH:40]=2)=[O:51])[CH:62]=[CH:61][C:60]=1[NH2:63]
Reactant: Cc1csc(S(=O)c2scc(C)c2-c2ccc(N)c([N+](=O)[O-])c2)c1-c1ccc(N)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Cc1csc(S(=O)c2scc(C)c2-c2ccc(N)c(N)c2)c1-c1ccc(N)c(N)c1

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (4-amino-3-nitrophenyl)-4-methylthiophenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[ClH:10].[CH3:11]O>O1CCOCC1>[ClH:10].[CH3:11][O:8][C:7](=[O:9])[C@H:5]([CH2:4][CH2:3][O:2][CH3:1])[NH2:6]
Reactant: COCC[C@H](N)C(=O)O
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COCC[C@H](N)C(=O)OC
Reaction time: 84 h

Procedure:
A solution of 13.3 g of O-methyl homoserine in 370 ml of methanol and 180 ml of a 6 N solution of hydrogen chloride in dioxane is allowed to stand at room temperature for 3 to 4 days. The solvent is removed under reduced pressure and the residue lyophilized to give O-methyl homoserine methyl ester hydrochloride which is represented by the following formula ##STR51## Substitution of an equivalent quantity of O-methyl homoserine methyl ester hydrochloride for the methyl D-methioninate hydrochloride of Example 35 and substantial repetition of the procedures described in Examples 35 through 39 provides methyl DL-2,6-dimethyltyrosyl-DL-O-methylhomoseryl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR52##
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:66]=[CH:65][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:64])[CH2:25][N:26]3[CH2:33][CH2:32][C:31](=[O:34])[N:30]([CH2:35][C:36](=[O:62])[N:37]4[CH2:42][CH2:41][N:40]([C:43]([NH:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([CH2:53][NH:54]C(OC(C)(C)C)=O)=[CH:49][CH:48]=5)=[O:44])[CH2:39][CH2:38]4)[CH2:29][CH2:28][C:27]3=[O:63])[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:74]>ClCCl.O1CCOCC1>[ClH:74].[ClH:74].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:64])[CH2:25][N:26]3[CH2:33][CH2:32][C:31](=[O:34])[N:30]([CH2:35][C:36](=[O:62])[N:37]4[CH2:42][CH2:41][N:40]([C:43]([NH:45][CH2:46][C:47]5[CH:48]=[CH:49][C:50]([CH2:53][NH2:54])=[CH:51][CH:52]=5)=[O:44])[CH2:39][CH2:38]4)[CH2:29][CH2:28][C:27]3=[O:63])[CH2:20][CH2:19]2)=[O:17])=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)N2CCN(C(=O)CN3CCC(=O)N(CC(=O)N4CCN(C(=O)NCc5ccc(CNC(=O)OC(C)(C)C)cc5)CC4)CCC3=O)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(CNC(=O)N2CCN(C(=O)CN3CCC(=O)N(CC(=O)N4CCN(C(=O)NCc5ccc(CN)cc5)CC4)CCC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 g of 1,5-bis-{2-[4-(4-tert-butyloxycarbonylaminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione (starting material A1) is suspended in 2 ml of dichloromethane and then admixed with 2 ml of trifluoroacetic acid. The mixture is stirred at RT overnight, and 2 ml of a solution of HCl in dioxane are then added. The mixture is concentrated to dryness using a rotary evaporator. The residue is twice triturated with ether and the solvent decanted off. The residue is then dried under high vacuum. This gives 0.17 g of the title compound of m.p. from 90° C. (decomposition). The mass spectrum shows the molecular peak MH+ at 719 Da.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:25](CC)CC)C>CN(C=O)C>[NH2:25][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)N1CCC[C@H]1C#N

Procedure:
(S)-1-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (title compound of Reference Example 2, 60.7 g) and triethylamine (30.1 mL) were dissolved in DMF (300 mL). Methanesulfonyl chloride (16 mL) was added thereto under ice-cooling. After stirring at room temperature for 3 hr, the reaction mixture was washed with water and dried. The solvent was evaporated under reduced pressure. Ethanol was added to the residue to give (S)-1-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (64.1 g) as a white solid.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.N([O-])=O.[Na+].[I-:20].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>S(=O)(=O)(O)O>[I:20][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1
Reactant: [I-]
Reactant: CCOC1=NS(=O)(=O)c2cc(N)ccc21
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Product: CCOC1=NS(=O)(=O)c2cc(I)ccc21

Procedure:
6-Amino-3-ethoxybenzoisothiazole-1,1-dioxide (D.3b) (0.25 g) was diazotised with sodium nitrite (0.21 g) in conc. sulphuric acid (5 ml) at 0°-10° C. for 2 h. After pouring into an aqueous (50 ml) solution of potassium iodide (1 g), the black suspension was treated with sodium metabisulphite until an orange precipitate remained. The solid was collected, washed with water and dried (0.26 g, mp 185°-90°)
Reaction SMILES: [F:1][CH:2]([F:17])[S:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[F:17][CH:2]([F:1])[S:3]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)=[O:26]
Reactant: Cn1cc(SC(F)F)c(=O)c2ccc(F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(S(=O)C(F)F)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
To a stirred solution (a part remained undissolved) of crude 3-difluoromethylthio-7-fluoro-1-methyl-4-quinolone (4) (3.43 g, 13.23 mmol) in DCM (200 ml) at 0° C. was added ˜80% MCPBA (2.50 g, 11.59 mmol) in a few portions over a period of approximately 1 min. The stirred mixture was allowed to warm to room temperature and was stirred for 30 min. An additional amount of MCPBA (640 mg) was added in 5 portions in approximately 1 h intervals, and the progress of the oxidation was monitored by 1H NMR 30 min after each addition. The mixture was washed with 5% aqueous Na2CO3 (70 ml), the aqueous layer was extracted with DCM (2×200 ml), the combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel with DCM and then with hexane-ethyl acetate (gradient 2:1,1:1,1:2) to give 980 mg (20.7%; two steps) of the product. The product was further purified by recrystallization from absolute ethanol to give 620 mg (13.1%) of 3-difluoromethylsulfinyl-7-fluoro-1-methyl-4-quinolone (5) as off-white crystals. 1H NMR, CDCl3; δ=3.94 s, 3H, N—CH3; 7.050, 6.870, 6.866, 6.686 (4 lines, X part of ABX), 1H, CHF2; 7.21 dd, 1H, J=10.2 & 2.4 Hz, H at C8, 7.27 ddd, 1H, J=8.9, 7.9 & 2.2 Hz, H at C6; 7.99 s, 1H, H at C2; 8.44 dd, 1H, J=9.0 & 6.3 Hz, H at C5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:34][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56](Br)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH2:46][CH:45]2[CH:43]1[CH2:44]2)=[O:41])([CH3:38])([CH3:37])[CH3:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:56]4[CH:55]=[CH:54][C:53]([C:50]5[NH:49][C:48]([CH:47]6[CH2:46][CH:45]7[CH:43]([CH2:44]7)[N:42]6[C:40]([O:39][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:41])=[N:52][CH:51]=5)=[CH:58][CH:57]=4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:34][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C(c2ncc(-c3ccc(Br)cc3)[nH]2)CC2CC21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)CC2CC21
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a solution of 3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.19 g, 0.41 mmol) in DME (2.0 mL) was added 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.16 g, 0.41 mmol), Tetrakis(triphenylphosphine)Palladium (0.05 g, 0.04 mmol) and aqueous potassium phosphate (2 M, 0.60 mL, 1.2 mmol). The solution was degassed with argon for 15 min and heated to 80° C. for 18 h with stirring. The solution was cooled diluted with EtOAc and filtered. The filtrate was washed with H2O and brine. The organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 30→100% EtOAc (10% MeOH) in Hexanes to 80% MeOH in EtOAc). The desired fractions were concentrated and combined with the filtered solid to provide 3-(5-{4′-[2-(2-tert-Butoxycarbonyl-2-aza-bicyclo[3.1.0]hex-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.17 g, 62%). LCMS-ESI+: calc'd for C39H46N6O4: 662.36 (M+); Found: 663.39 (M+H+).
Reaction SMILES: Cl.NC[CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.COC1C(OC)=CC=CC=1C=O.C(N(CC)CC)C.B.[Na]>CO>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[CH2:4][OH:15]
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: B
Agent: COc1cccc(C=O)c1OC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(CO)cc1OC
Temperature: 25 °C

Procedure:
1.0 g of α-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride was suspended in 5 ml of methanol, and after adding thereto 0.85 g of 2,3-dimethoxybenzaldehyde, 0.63 ml of triethylamine was added dropwise to the mixture while stirring at room temperature. The mixture was heated under reflux for 30 minutes, and 0.24 g of sodium boron hydride was added slowly to the mixture while stirring under ice cooling. After the foaming stopped, the mixture was concentrated. The residue was subjected to a separating procedure with chloroform and water, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 1.07 g of α-[[2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 96°-97° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.Br[C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][C:23]1[CH:31]=[CH:32][C:20]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:21][CH:22]=1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Yield: 64.2 %

Procedure:
A mixture of 4-(4-trifluoromethoxyphenoxy)piperidine (30.3 g, 0.116 mol) prepared in Reference Example 190, 2-(4-bromophenoxy)tetrahydropyran (30 g, 0.116 mol), palladium acetate (1.0 g, 4.64 mmol), BINAP (4.3 g, 6.96 mmol) and cesium carbonate (49 g, 0.151 mol) in toluene (300 ml) was refluxed under a nitrogen atmosphere for 30 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenoxy)piperidine (32.6 g, yield 64%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[CH:8][C:9]=2[CH2:11][CH2:12][CH3:13])[S:4][C:3]=1[C:21]#[N:22].[CH:23]([NH2:25])=O>O>[NH2:22][C:21]1[C:3]2[S:4][C:5]3[N:6]=[C:7]([N:14]4[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]4)[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[C:10]=3[C:2]=2[N:1]=[CH:23][N:25]=1
Reactant: NC=O
Reactant: CCCc1cc(N2CCC(O)CC2)nc2sc(C#N)c(N)c12
Solvent: O
Product: CCCc1cc(N2CCC(O)CC2)nc2sc3c(N)ncnc3c12
Yield: 35 %

Procedure:
The above nitrile (316 mg, 1.0 mmol) and formamide (3 μL) were heated in a SmithSynthesizer™ (Personal Chemistry) at 150° C. for 16 h. The reaction mixture was poured into water and the resulting solid was collected by filtration. The solid was further purified with HPLC (Shimadzu, Thermohypersil PEP 100-C18, 254 nM, acetonitrile/water 15-70% in 25 minutes, retention time=12.61 min) to give the title compound as a white solid (120 mg, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:6]([CH2:12]Cl)=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Si]([O:36][C:37]1[CH:38]=[C:39]([C:43]2[C:51]3[C:46](=[N:47][CH:48]=[N:49][C:50]=3[NH2:52])[NH:45][N:44]=2)[CH:40]=[CH:41][CH:42]=1)(C(C)(C)C)(C)C>CN(C=O)C>[NH2:52][C:50]1[N:49]=[CH:48][N:47]=[C:46]2[N:45]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:44]=[C:43]([C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([OH:36])[CH:38]=3)[C:51]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
To a stirred mixture of compound (8) (100 mg, 0.25 mmol) and potassium carbonate (42 mg, 0.30 mmol) in DMF (2.5 mL) was added a solution of compound (3) (94 mg, 0.28 mmol) in DMF (2.5 mL) and the reaction mixture was stirred at RT for 18 hr. Potassium carbonate (3×35 mg, 0.75 mmol) was added in three portions over 30 hr. The solvent was removed in vacuo and the crude material was purified by flash column chromatography, eluting with 4.5% methanol in DCM, to afford the title compound (Intermediate B) (94 mg, 64%) as a off-white solid: m/z 588/590 (M+H)+ (ES+) (Method B).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.1 %

Procedure:
0.78 g of ethyl pyrazole-4-carboxylate was dissolved in 15 ml of methylene chloride and 1.56 g of trityl chloride and 0.86 ml of triethylamine were added thereto and then the resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was washed with 10% aqueous solution of citric acid and SSC and then dried with sodium sulfate. The solvent was distilled off to give 2.45 g of ethyl 1-tritylpyrazole-4-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:21]([C:28]1[CH:32]=[CH:31][NH:30][C:29]=1[CH2:33]O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:33][C:29]3[NH:30][CH:31]=[CH:32][C:28]=3[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1[nH]ccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (0.95 g, 3.95 mmol), thionyl chloride (0.342 ml, 4.74 mmol) and DMF (several drops) in 50 ml benzene is stirred at RT for 2 days. The solvent and excess thionyl chloride are evaporated under reduced pressure. The resulting acid chloride is dissolved in 50 ml benzene, and 3-benzylpyrrolylmethyl alcohol (3.95 mmol) and 0.482 g 4-dimethtylaminopyridine (3.95 mmol) are added. The mixture is left at 25° for 18 hours and then heated under reflux for 2 hours. The mixture is then poured into water and extracted with ether. The organic phase is washed with dilute HCl, sat. NaHCO3, water and brine, dried and concentrated under vacuum. The crude product is purified by preparative TLC developing with 20% ethyl acetate/hexane to yield 3-benzylpyrrolylmethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate (A; R is hydrogen, X=X' is methyl, W is oxygen, R1 is 4-chlorophenyl).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
To a vial containing 7-chloro-6-nitrothieno[3,2-b]pyridine (128.7 mg, 0.5996 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 297.6 mg, 1.486 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA (179.9 mg, 1.392 mmol). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as a yellow solid (210.1 mg, 93%). LCMS calc. for C17H23N4O4S (M+H)+: m/z=379.1. found 379.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:28][C:27]3[CH2:26][CH2:25][NH:24][CH2:23][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Br:1][C:2]1[C:3]([C:20]2[S:28][C:27]3[CH2:26][CH2:25][N:24]([CH:30]([CH3:32])[CH3:29])[CH2:23][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3c(s2)CCNC3)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCc2sc(-c3nc(NCCN4C(=O)NC(=O)C4(C)C)ncc3Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-(5-Bromo-4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (0.15 g, 032 mmol) was treated with acetone (1 mL), sodium triacetoxyborohydride (0.136 g, 0.64 mmol) in dicholoethane (5 mL). The reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and water. The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The mixture was dried with sodium sulfate and purified by preparative HPLC. Yield=0.05 g. MS (M+H)+ 507/509.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:30][CH3:31])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Zn](CC)[CH2:39][CH3:40]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:7]1[C:2]([CH2:39][CH3:40])=[CH:3][C:4]([O:30][CH3:31])=[C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:20]3)[CH2:17][CH2:18]2)=[O:12])[CH:6]=1
Reactant: CC[Zn]CC
Reactant: COc1cc(Br)c(Cl)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCc1cc(OC)c(NCC(=O)N2CCN(C3CN(C(=O)OC(C)(C)C)C3)CC2)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 110.9 %

Procedure:
To a mixture of tert-butyl 3-(4-(2-(4-bromo-5-chloro-2-methoxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate (100 mg, 0.193 mmol), Pd(dppf)2Cl2 (29 mg, 0.04 mmol) and K2CO3 (55 mg, 0.386 mmol) in DMF (10 mL) at RT, Et2Zn (0.8 mL, 0.8 mmol, 1.0 M in hexane) was added. The resulting mixture was stirred at 80° C. for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the crude product (100 mg). ESI-MS m/z: 467.5[M+1]+.