Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[NH2:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])=[O:49])=[O:45])[CH3:43].Cl>CN(C=O)C>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53])=[O:49])=[O:45])[CH3:43])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of Boc-Gly-Ala prepared as in Example 33B (10.2 g, 41.5 mmol) in anhydrous DMF (300 ml), was added HOBT.H2O (6.21 g, 46.0 mmol), EDC.HCl (8.81 g, 46.0 mmol) and DAla-Gly-Gly-OBzl.HCl (13.7 g, 41.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (40 ml). The resulting solution was extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and concentrated to half volume. The product crystallized out upon standing at RT for 30 min. Collection of the crystals by filtration and drying at high vacuum afforded 17.4 g (80% yield) of the pure product: 1H NMR (DMSO-d6) δ 1.21 (d, J=7.4 Hz, 3 H), 1.23 (d, J=7.3 Hz, 3 H), 1.38 (s, 9 H), 3.56 (d, J=6.3 Hz, 2 H), 3.75 (d, J=5.7 Hz, 2 H), 3.93 (d, J=6.0 Hz, 2 H), 4.24-4.34 (m, 2 H), 5.14 (s, 2 H), 6.98 (t, J=5.7 Hz, 1 H), 7.34-7.40 (m, 5 H), 7.93 (d, J=7.2 Hz, 1 H), 8.17-8.24 (m, 3 H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:24])([F:23])[CH2:21]I>CN(C=O)C>[I:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:21][C:20]([F:24])([F:23])[F:19])[CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: Cn1cc(I)c2c(=O)[nH]cnc21
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(I)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 90 °C
Yield: 77 %

Procedure:
To a stirred suspension of 5-iodo-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (13.7 g, 49.8 mmol) in anhydrous DMF (137 ml) was added potassium carbonate (13.8 g, 100 mmol) and 1,1,1-trifluoro-2-iodoethane (7.36 ml, 74.7 mmol). The resulting mixture was heated at 90° C. for 24 h. The reaction mixture was partitioned between brine/water (1:1, 1.41) and ethyl acetate (350 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×350 ml). The combined organic phase was washed with brine/water (1:1, 4×350 ml), dried and concentrated. The residue was purified by flash chromatography (0-45% ethyl acetate/cyclohexane) to give the title compound (13.7 g, 77%). LCMS RT=1.05 min, M+H+=358.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[N:18][N:17]=1.C[N:27](C=O)C.C1N=CN(C(N2C=NC=C2)=O)C=1.C([O-])(=O)C.[NH4+]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[O:20][C:19]([NH:21][CH2:22][C:23]([NH2:27])=[O:24])=[N:18][N:17]=1
Reactant: O=C(O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Product: NC(=O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of {5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-acetic acid (75 mg, 0.16 mmol, 1 eq) in DMF CDI (35 mg, 0.21 mmol, 1.3 eq) was added. The reaction mixture was stirred at RT under argon for 3 hrs and then amoniumacetate (30 mg, 0.41 mmol, 2.5 eq) was added. The mixture was stirred for another 2 hrs. The resulting mixture was directly purified by preparative HPLC to afford the desired product (35 mg). LC/MS (Method A) [4.57 min; 455(M+1)]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13](Br)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2].[O:18]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]=[C:13]([C:28]3[CH:29]=[CH:30][C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:26][CH:27]=3)[S:14][CH:8]2[C:7]1=[O:16])[CH3:2]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CN1C(=O)C2C=C(Br)SC2C1=O
Product: CCOC(=O)CN1C(=O)C2C=C(c3ccc(Oc4ccccc4)cc3)SC2C1=O

Procedure:
The title compound was prepared from (2-bromo-4,6-dioxo-3a,4,6,6a-tetrahydro-thieno[2,3-c]pyrrol-5-yl)-acetic acid ethyl ester, example 1-d, and 4-phenoxy-phenyl boronic acid under conditions analogous to experimental example 3-a. NMR (CDCl3, 200 MHz): δ=7.58-7.54 (d, J=8.97 Hz, 2H), 7.41-7.34 (m, 3H), 7.20-7.0 (m, 4H), 4.35 (s, 2H), 4.27-4.17 (q, J=7.0, 2H), 1.32-1.25 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:3]=1.C([Li])CCC.N#N.Cl.C1C[O:27][CH2:26]C1>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:26]=[O:27])=[CH:10][CH:11]=1
Reactant: Fc1ccc(Oc2cccc(Br)c2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a cooled (-75° C.), stirred solution of 1-bromo-3-(4-fluorophenoxy)benzene (38.5 g; 0.1442M) in dry THF (80 ml) was added n-butyllithium (1.63M in n-hexane, 68 ml; 0.11M) dropwise at under N2. After stirring for 30 min at -73° C., DMF (11.38 g; 0.1557M) was added dropwise to the mixture at -73° C. The mixture was stirred for further 30 min, and then allowed to warm to room temperature. 2M aqueous HCl (200 ml) was added to the mixture and the whole was extracted with Et2O (100 ml×3). The combined organic layers were washed with water (150 ml), brine (150 ml), dried over MgSO4, and concentrated in vacuo. The residual oil was purified by flash column (SiO2) eluting with ethyl acetate-n-hexane (1: 10) to give 21.6 g of the subtitle compound [B] as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:31][N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cc(-c2ccccc2)ccn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cc(-c5ccccc5)ccn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:29]#[N:30])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.O1CCCC1.[CH3:36][NH2:37]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:29]#[N:30])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:37][CH3:36])[N:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nccc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)n1
Solvent: C1CCOC1
Product: CNc1nccc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
4-(2,4-dichlorophenyl)-2-[2-(methylsulfonyl)pyrimidin-4-yl]-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.047 g, 0.10 mmol) was dissolved in 2.0 M of Methylamine in Tetrahydrofuran (1.74 mL, 0.00349 mol) and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo and the residue was purified using ISCO chromatography on silica gel, elution 30% ethyl acetate in hexanes to ethyl acetate to afford the title compound (0.037 g, 81%). LCMS: (FA) ES+, 428, 430. 1H NMR (400 MHz, d4-methanol) δ: 8.07-8.01 (m, 1H), 7.99 (s, 1H), 7.24-7.21 (m, 1H), 7.09-7.02 (m, 2H), 6.97 (d, J=5.04 Hz, 1H), 2.62 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].Cl>CN(C)C=O.O>[C:19]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:15][C:14]3[N:13]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Reactant: C[Si](C)(C)CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C(=O)O)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid in 100 cm3 of dimethylformamide is added dropwise to a suspension of 1.45 g of sodium hydride (at 60% in oil) in 25 cm3 of dimethylformamide cooled to a temperature in the region of 0° C. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is cooled to a temperature in the region of 0° C. and 4.18 cm3 of (2-chloromethoxyethyl)trimethylsilane are added dropwise. The mixture is stirred for about 20 hours at a temperature in the region of 20° C. After cooling this mixture to a temperature in the region of 0° C., 100 cm3 of water and 16 cm3 of aqueous 1N hydrochloric acid solution are added. The mixture is extracted three times with 100 cm3 of ethyl acetate. The combined organic phases are washed with three times 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (98/2 by volume)], 1.8 g of 6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid are thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[C:12]([F:14])[C:5]2[N:6]([CH2:10][CH3:11])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:15][O:16][C:17]([C@@H:19]1[O:21][CH2:20]1)=[O:18].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[CH2:10]([N:6]1[C:5]2[C:12]([F:14])=[CH:13][C:2]([NH:1][CH2:20][C@@H:19]([OH:21])[C:17]([O:16][CH3:15])=[O:18])=[CH:3][C:4]=2[O:8][C:7]1=[O:9])[CH3:11]
Reactant: COC(=O)[C@H]1CO1
Reactant: CCn1c(=O)oc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CCn1c(=O)oc2cc(NC[C@@H](O)C(=O)OC)cc(F)c21

Procedure:
Prepared from 6-amino-3-ethyl-4-fluoro-1,3-benzoxazol-2(3H)-one (Step 2, 0.90 g, 4.59 mmol), methyl (2R)-glycidate (0.469 g, 4.59 mmol) and lithium trifluoromethanesulfonate (0.716 g, 4.59 mmol) in acetonitrile (10 ml) according to the method of EXAMPLE 86, Step 8 (1.11 g, 81%); MS for C13H15FN2O5 m/z 299 (M+H)+.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O>[C:7]1([NH:13][C:14]([NH:5][C:3](=[NH:6])[CH3:4])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(=N)NC(=O)Nc1ccccc1

Procedure:
Following a procedure similar to that described in Example 23 but using 4.6 g. sodium in 500 ml. dry acetone, 18.8 g. acetamidine hydrochloride and 23.8 g. phenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from isopropyl alcohol 27.1 g. 1-phenyl-3-(acetimidoyl)urea hydrochloride; m.p. 204°-206°C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12]Br)=O.[NH3:14]>>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]2[S:12][N:14]=[CH:1][C:3]=2[CH:8]=1)([O-:11])=[O:10]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SBr
Reactant: N
Product: O=[N+]([O-])c1ccc2sncc2c1

Procedure:
Angewandte Chemie, 36 (1923), 159 and Berichte der deutschen Chemischen Gesellschaft, 58 (1925), 2,095 disclose that thionaphthene-2,3-dione may be reacted with ammonia and hydrogen peroxide to give 3-carbamyl-1,2-benzisothiazole and that 1,2-benzisothiazole may be obtained from the latter by hydrolysis and decarboxylation. Berichte, 56 (1923), 1,630 and Liebigs Annalen der Chemie, 454 (1927), 264 describe the reaction of 2-formyl-4-nitrophenylsulfenyl bromide with ammonia to give 5-nitro-1,2-benzisothiazole. Benzisothiazoles can also be synthesized by cyclizing o-mercapto-phenyl-carbonyl compounds in the presence of polyphosphoric acid (Annali di Chimica, 53 (1963), No. 5, 577-587). German Laid-Open Application DOS No. 1,670,196 discloses the reaction of dihalomethylaryl compounds with ammonia and sulfur to give benzisothiazoles. All these processes are unsatisfactory in respect to ease of access to the starting materials, economy, and simplicity of operation coupled with a good yield of end product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.[Si]([C:20]([F:23])([F:22])[F:21])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:14]([OH:15])[C:20]([F:23])([F:22])[F:21])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=Cc1ccc(Br)cc1-c1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-[1,1′-biphenyl]-2-carbaldehyde (1.9 g, 7.3 mmol) and was added TMSCF3 (1.2 g, 8.7 mmol) in THF (20 mL) and cooled to 0° C. To this solution was added TBAF (1.46 mL, 1M in THF) and the reaction mixture was warmed to RT for 3 h. After this time, the mixture was treated with 3 N HCl (5 mL) and stirred for 12 h. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE=1:10) to afford 1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Si:17]([O:1][CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1nc2cnccc2[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1nc2cnccc2[nH]1

Procedure:
A procedure similar to that described in Preparation 49 was repeated, except that 5.00 g of 2-hydroxymethyl-1H-imidazo[4,5-c]pyridine, 6.85 g of imidazole, 7.58 g of t-butyldimethylsilyl chloride and 100 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.40 g of the title compound, melting at 53-55° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[N:12]1([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[S:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[C:27]=3[C:35]([C:37]3[CH:42]=[CH:41][C:40](F)=[CH:39][CH:38]=3)=[O:36])=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.[Cl-].[Na+].O>[O:11]=[C:7]1[CH2:8][CH2:9][CH2:10][N:6]1[CH2:5][CH2:4][O:3][C:40]1[CH:41]=[CH:42][C:37]([C:35]([C:27]2[C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[S:30][C:26]=2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:25][CH:24]=2)=[O:36])=[CH:38][CH:39]=1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reactant: O=C1CCCN1CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(OCCN2CCCC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil dispersion, 50 mg) was suspended in DMF (2.0 mL) and stirred at ambient temperature for 15 min under argon before 1-(2-hydroxyethyl)-2-pyrrolidinone (87 μL) was added. After stirring for 15 min, 4-fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl ketone (223 mg) in 1 mL of DMF was introduced and the resulting solution was stirred at ambient temperature for 3.5 h. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5-10:90-85) afforded the product as a colorless oil (210 mg).
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10])(=[O:5])=[O:4]>CO>[CH3:15][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[S:3](=[O:5])(=[O:4])[NH2:1]
Reactant: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: N
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ammonia in methanol (40 mL, 2 M) is added to the crude 3-chlorosulfonyl-4-methyl-benzoic acid and the solution stirred at room temperature for 16 hours. The volume is reduced by 50% by heating under reduced pressure, the solution is filtered to remove the precipitate and the precipitate washed with additional methanol. The sulphonamide precipitate is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:17]=2)=[C:10]([CH3:32])[CH:9]=1)=[O:6]>CCO.CCOC(C)=O.[Ni]>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH3:32])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:31])[CH:17]=2)=[C:12]([CH3:14])[CH:13]=1)=[O:6]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(O)c3ccc(F)cc3)c2)c(C)c1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of N-{4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester (222 mg, 0.49 mmol) in a mixture of EtOH/EtOAc (4:1, 25 mL) was added nickel catalyst (2 mL, water and methanol washed). The mixture was hydrogenated under 50 psi at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound of Step A (159 mg) as a white solid. MS (APCl−) Calc.: 453.2. Found: 452.2 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 5.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.4 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[CH3:10][O:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:17]2[C:12]([O:11][CH3:10])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=1
Reactant: COc1ncccc1B(O)O
Reactant: Nc1nnc(Cl)cc1Br
Product: COc1ncccc1-c1cc(Cl)nnc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 4-bromo-6-chloropyridazin-3-amine (CAS RN 446273-59-2) and 2-methoxypyridine-3-boronic acid (CAS RN 163105-90-6) after a reaction time of 18 hours. Brown solid (49%). MS (ESI+): m/z=237.054 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:18]/[C:17](=[N:19]\[O:20][C:36](=[O:37])[CH2:35][CH2:34][N:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH2:29][CH2:30]1)/[C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:9])=[O:10]
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCC(=O)O/N=C(\N)[C@@H]2CCCCN2S(=O)(=O)CC2CCCCC2)CC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28] and 3-[4-(tert-butoxycarbonyl)piperazino]propanoic acid [see Preparation 90] to afford tert-butyl 4-(3-[((Z)-amino(2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidylmethylidene)amino]oxy-3-oxopropyl)-1-piperazinecarboxylate as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C)C=O>O>[O:23]=[C:21]1[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:28])[N:22]1[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccccc1CN1C(=O)c2ccccc2C1=O)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.1 %

Procedure:
A mixture of diethyl [2-(bromomethyl)benzyl]phosphonate (11.2 g), potassium phthalimide (6.46 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was ashed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave diethyl {2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzyl}phosphonate (11.3 g, 83%) as colorless prism crystals. melting point: 91-92° C.