Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:24][CH2:23][N:22]2[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:24][CH2:23][N:22]2[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN4S(C)(=O)=O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)N1CCC1c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[1-(methylsulfonyl)azetidin-2-yl]phenyl}-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aq. NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by prep-HPLC to give the title compound (20 mg, 13% yield) as a white solid. MS (ES+) 445.0 (M+CH3CN)+. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1 H), 7.95 (s, 1 H), 7.65 (s, 1 H), 7.50-7.30 (m, 4 H), 4.70 (m, 1 H), 3.10 (m, 2 H), 2.89 (s, 3 H), 1.90-1.80 (m, 2 H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]3[CH:15]=[CH:16][C:17]([C:19](OC)=[O:20])=[CH:18][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl.Cl.[NH:27]1[C:31]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][C:35]3=[O:47])=[N:30][N:29]=[N:28]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.CO.O.CN(C=O)C>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]3[CH:15]=[CH:16][C:17]([C:19]([N:40]4[CH2:41][CH2:42][C:37]5([CH2:36][C:35](=[O:47])[C:34]6[C:44](=[CH:45][CH:46]=[C:32]([C:31]7[NH:27][N:28]=[N:29][N:30]=7)[CH:33]=6)[O:43]5)[CH2:38][CH2:39]4)=[O:20])=[CH:18][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)nc(C1CC1)n2-c1ccccc1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C1CC2(CCN(C(=O)c3ccc4c(c3)nc(C3CC3)n4-c3ccccc3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 2-cyclopropyl-1-phenyl-1H-benzimidazole-5-carboxylate (194 mg, 0.664 mmol) was dissolved in THF (6 mL) and MeOH (6 mL), and aqueous 5 N sodium hydroxide solution (0.66 mL, 3.30 mmol) was added to it and stirred at 60° C. for 2 hours. This was restored to room temperature, 5 N hydrochloric acid (0.66 mL, 3.30 mmol) was added thereto, the solvent was evaporated away under reduced pressure, and the residue was azeotroped with toluene. DMF (4 mL) and water (1 mL) were added to it, and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (256 mg, 0.797 mmol), triethylamine (0.14 mL, 0.996 mmol), HOBT (135 mg, 0.996 mmol) and WSC hydrochloride (191 mg, 0.996 mmol) were added thereto. The reaction liquid was stirred at 90° C. for 2 hours, restored to room temperature, and water was added thereto. The precipitated solid was taken out through filtration, and dried under reduced pressure to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=8.8, 2.2 Hz), 7.69-7.59 (6H, m), 7.34 (1H, d, J=8.8 Hz), 7.23 (1H, dd, J=8.4, 1.6 Hz), 7.14 (1H, d, J=8.4 Hz), 4.50-3.29 (5H, m), 2.98 (2H, s), 2.06-1.77 (4H, m), 1.15-1.11 (2H, m), 1.04-1.00 (2H, m). MS [M+H]+=546.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:10]2)=[O:4].N1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:39]([C:33]3[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=3[Cl:31])(=[O:41])=[O:40])=[CH:20][C:21]=1[Cl:22])=[CH:10]2)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccc2cc(Oc3c(Cl)cc(N)cc3Cl)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc2cc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
To a solution of 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-8-carboxylic acid methyl ester (315) (1.26 mmol) in Pyridine (0.15 ml, 1.80 mmol) and CH2Cl2 (5 ml), was added 2,4-Dichlorobenzenesulfonyl chloride (381 mg, 1.55 mmol). The mixture was stirred at room temperature for 12 hr. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by Brine, dried over MgSO4, and concentrated. The crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 182 (506 mg, 70%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][F:59])[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][C@@H:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>CO.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][F:59])[C@@H:47]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.7 %

Procedure:
The compound (5.06 g, 5.47 mmol) synthesized in Example 4 (4a) was dissolved in methanol (75 mL) and tetrahydrofuran (15 mL) and palladium chloride (II) (190 mg, 1.09 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. After the reaction mixture was subjected to celite filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 4:1-3:1-2:1, V/V) to obtain the desired title compound (3.07 g, yield 63%) as pale yellow amorphous matter.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)=O.COC(=O)[CH2:29][N:30]([S:41]([NH:44][C:45]([O:47]CC[Si](C)(C)C)=O)(=[O:43])=[O:42])[CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][CH:36]=[CH:35]2.CC#N>O1CCCC1.Cl.CCOCC.O.CS(C)=O>[NH:37]1[C:38]2[C:34](=[CH:33][C:32]([CH2:31][N:30]3[S:41](=[O:43])(=[O:42])[NH:44][C:45](=[O:47])[CH2:29]3)=[CH:40][CH:39]=2)[CH:35]=[CH:36]1
Reactant: COC(=O)CN(Cc1ccc2[nH]ccc2c1)S(=O)(=O)NC(=O)OCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: O=C1CN(Cc2ccc3[nH]ccc3c2)S(=O)(=O)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Tetrabutylammonium fluoride trihydrate (252 mg, 0.80 mmol) and AcOH (0.057 mL, 1.0 mmol) are dissolved in tetrahydrofuran (4 mL) and this is used to dissolve the title A compound, N-(2-trimethylsilanyl-ethoxycarbonyl-aminosulfonyl)-N-(1H-indol-5ylmethyl)-glycine methyl ester (90 mg, 0.20 mmol) in a thick-walled round bottomed flask. This is sealed and stirred in an oil bath at 80° C. for 16 h. The reaction is allowed to cool, then diluted with 1N aqueous HCl (5 mL) and Et2O (25 mL). The organic layer is separated and washed with water (2×5 mL) and saturated aqueous NaCl (5 mL), then separated, dried over anhydrous MgSO4, filtered and evaporated, to yield the crude product as a brown oil. This is taken up in water (4.5 mL), MeCN (0.7 mL) and DMSO (1 mL). The resulting mixture is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro Cl 8, 50×20 mm I.D., particle size S-5 micron, 12 nM) in 3 aliquots and eluted at 30 mL/min with a gradient of 90:10 (water containing 0.1% TFA: MeCN) at 0 min to 10:90 at 5 min. Then held at 10:90 until 7 minutes. Fractions containing product are combined and concentrated on a Savant Speedvac to yield 5-(1H-indol-5-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a light tan foam: [M−1]−=264.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([OH:25])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.Br[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:23]([O:25][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(O)c2)ncn1)C1CC1
Reactant: CC(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)(C)C)c2)ncn1)C1CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-hydroxypyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (60 mg) in DMF (1.3 mL) were added 1-bromo-2,2-dimethylpropane (80 μL) and cesium carbonate (83 mg), and the mixture was stirred at 80° C. for 20 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20 mg) as a colorless amorphous solid.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[CH3:18][C:19]12[CH2:28][C:23]3([OH:29])[CH2:24][CH:25]([CH2:27][C:21]([CH3:30])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[CH3:18][C:19]12[CH2:28][C:23]3([O:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:24][CH:25]([CH2:27][C:21]([CH3:30])([CH2:22]3)[CH2:20]1)[CH2:26]2
Reactant: CC12CC3CC(C)(C1)CC(O)(C3)C2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(C)(CC(C)(C3)C1)C2
Yield: 96 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1,3-dimethyl-5-hydroxyadamantane was used instead of the 1,3-dimethyl-5,7-dihydroxyadamantane, and, as a result, a 1,3-dimethyl-5-acryloyloxyadamantane (yield: 96%, colorless liquid) was produced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31]C)=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(O)cc3C)cc12
Yield: 77.9 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (350.5 mg, 0.783 mmol) in DCM (8 mL). To this solution was then added, under nitrogen, a 1M solution of boron trichloride (3.92 mL, 3.92 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and 10 mL of methanol was slowly added. The solvent was removed under vacuum. The flask was again cooled, 25 mL of ice cold methanol was added and the resulting solid was filtered to give 264.5 mgs (78% yield) of methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-hydroxy-4-methylbenzoate as an ivory colored solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. 1H NMR (400 MHz, DMF-d7) δ ppm 2.30 (s, 3 H), 2.95 (d, J=4.77 Hz, 3 H), 3.98 (s, 3 H), 7.02 (s, 1 H), 7.38-7.48 (m, 3 H), 7.68-7.73 (m, 2 H), 7.76 (d, J=8.53 Hz, 1 H), 8.08-8.15 (m, 2 H), 8.33 (br. s., 2 H). LCMS Rt=3.636, m/z 434.3 (M+H), 100% purity.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.C(O)(=O)C.[O-:33][C:34]#[N:35].[K+]>C1COCC1.O>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][C:34]([NH2:35])=[O:33])[CH2:3][CH2:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: N#C[O-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCC3)s2)c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NC(N)=O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 61B-1, 50 mg, 0.123 mmol) and acetic acid (7 μL, 0.123 mmol) in THF/water (1.6:1, 2.1 mL), potassium cyanate (10 mg, 0.123 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was purified by column chromatography on silica (50-100% ethyl acetate in hexanes, 0-20% methanol in dichloromethane) and lyophilized to afford 1-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}urea (31.3 mg, 0.068 mmol, 54.9%) as a white powder. MS ESI: [M+H]+ m/z 449.1. 1H NMR (500 MHz, DMSO-d6 δ 10.23 (s, 1H), 8.82 (d, J=4.9, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.27 (d, J=4.9, 1H), 7.15-7.00 (m, 2H), 5.58 (s, 2H), 2.63-2.51 (m, 2H), 2.32 (m, 5H), 1.96 (m, 2H). rhSYK activity=+++
Reaction SMILES: C(Cl)CCl.Cl.[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][C:8]=1[C:18]([OH:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.[CH3:32][NH:33][CH2:34][C:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[O:37][C:36]=1[CH3:44].C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:33]([CH3:32])[CH2:34][C:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[O:37][C:36]=2[CH3:44])=[O:17])=[CH:9][C:8]=1[C:18]([OH:21])([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1cc(/C=C/C(=O)O)cnc1N
Reactant: CNCc1c(C)oc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc(N)c(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
EDC (0.13 g, 0.70 mmol) was added to a suspension of (E)-3-[6-Amino-5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-acrylic acid hydrochloride (0.15 g, 0.58 mmol), HOBt (0.09 g, 0.64 mmol), methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (0.11 g, 0.64 mmol) and (i-Pr)2EtN (0.60 mL, 2.48 mmol) in DMF (6 mL). The mixture was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. and diluted with H2O (15 mL) with rapid stirring. The resulting precipitate was filtered, washed with H2O (20 mL) then dried under high vacuum. The solid was then triturated with Et2O, and the resultant beige solid was collected, to yield 160 mg (73%) of product. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.67-7.47 (m, 4H), 7.26-6.99 (m, 3H), 6.58 (s, 2H), 5.49 (s, 1H), 4.80 and 4.74 (2×s, 2H), 3.04 and 2.85 (2×s, 3H), 2.52 (s, 3H), 1.53 (s, 6H); ESI MS m/z 380 [C22H25N3O3+H]+
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@@H:14]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26]([NH2:28])=[O:27])[C:15]1([CH3:33])[CH3:32]>ClCCl>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26](=[O:27])[NH2:28])[C:15]1([CH3:33])[CH3:32])(=[O:11])=[O:10]
Reactant: CC1(C)[C@H](O)CC[C@@H]1Nc1c(C(N)=O)cnn2cccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](OS(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cccc12
Reaction time: 15 h

Procedure:
Triethylamine (0.131 mL, 0.936 mmol) and methanesulfonyl chloride (0.029 mL, 0.375 mmol) were added to a solution of 4-((cis-3-hydroxy-2,2-dimethylcyclopentyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (90 mg, 0.312 mmol, from Intermediate 16) in dichloromethane (5 mL). After 15 h at room temperature, the mixture was diluted with dichloromethane (60 mL), washed with saturated sodium bicarbonate (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give crude cis-3-(3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylcyclopentyl methanesulfonate.
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[C:6]=1[NH2:7])([CH2:3][CH3:4])[CH3:2].[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].CC#N.C([O-])([O-])=O.[K+].[K+]>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>[CH:1]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]([CH3:15])[CH3:14])[C:6]=1[NH2:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cccc(Br)c1N
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(C)c1cccc(C(C)C)c1N

Procedure:
(−)-2-Sec-butyl-6-bromoaniline (2) (0.684 g, 3 mmol), isopropenylboronic acid pinacol ester (1 g, 6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol), MeCN 10 ml and K2CO3 (5 ml, 1M solution) were heated in a microwave at 160° C. for 400 sec. The reaction mixture was diluted with water (75 ml). Products were extracted with ethyl acetate (50 ml). The organic layer was washed with 5% NaHCO3, brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the compound purified by silica gel chromatography (CombiFlash, 30 g column, hexane-ethyl acetate). The reduction was then performed in MeOH (40 ml) over 5% Pd/C (˜0.3 g), hydrogen pressure 60 psi overnight (0.48 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:31][N:32]=[C:33]=[S:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH3:31])=[S:34])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2
Reactant: CN=C=S
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=S)NC)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman ##STR41## 4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman is prepared as described in Example 4 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-ethoxychroman and methyl isothiocyanate. Melting point: 202° C.
Reaction SMILES: [OH-].[Li+].[C:3]([C:6]#[C:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)([OH:5])=[O:4].[CH3:25]O>>[CH3:25][O:4][C:3]([C:6]#[C:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:5]
Reactant: Cc1c(-c2cccnc2)n(CC#CC(=O)O)c2ccccc12
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)C#CCn1c(-c2cccnc2)c(C)c2ccccc21

Procedure:
Treatment of 33 mg of 1-(3-methoxycarbonylprop-2-ynyl)-3-methyl-2-(3-pyridyl)indole in 1 ml of methanol with 0.3 ml of aqueous 1 N lithium hydroxide at room temperature yields 1-(3-carboxyprop-2-ynyl)-3-methyl-2-(3-pyridyl)indole; IR 1720 cm1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C(NC1SC(/C=C\C(OCC)=O)=C(CCC2C=CC(NC(OC(C)(C)C)=O)=CC=2)N=1)(=O)C.[H][H]>[Pd].C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)/C=C\c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1

Procedure:
A mixture of ethyl (2E)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylate and ethyl (2Z)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylate (200 mg), THF (7 ml) and 10% Pd/C (392 mg) were combined under nitrogen atmosphere. The mixture was stirred under 3 atm hydrogen atmosphere at 20° C. for 3 h. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give ethyl 3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]propanoate as a colorless amorphous.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:19]=O.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH3:19][N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 5.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of methanol was added 15 ml of 37% formaldehyde. After refluxing for 1 hour, the solution was cooled to ice bath temperature, treated (portionwise), with 2.5 g of sodium borohydride, and then stirred at ambient temperature for one hour. Evaporation of the volatiles yielded a residue which was taken up in ethyl acetate, washed with water followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Concentration afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% methanol/dichloromethane) to yield 4.2 g of 1-methyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil which was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate 2.34 g (39%) of the corresponding hydrochloride salt, m.p. 151°-153° C.