Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:30]([O:29][C:27]([NH:26][CH:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)NC(CN)Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)Cc1ccccc1
Yield: 39 %

Procedure:
Using an analogous procedure to that described in the second paragraph of the portion of Example 2 which is concerned with the preparation of starting materials, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-amino-2-(tert-butoxycarbonylamino)-3-phenylpropane to give N-[2-(tert-butoxycarbonylamino)-3-phenylpropyl]-1-(4-pyridyl)piperidine-4-carboxamide in 39% yield.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)([OH:3])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCCl.C(Cl)(Cl)Cl>[O:3]=[C:1]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc2c(CCCC(=O)O)c[nH]c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc2c3c([nH]c2c1)C(=O)CCC3
Yield: 44.8 %

Procedure:
A mixture or methyl 3-(3-carboxypropyl)indole-6-carboxylate (173 mg), triphenylphosphine (191 mg) and carbon tetrachloride (1.0 ml) in 1,2-dichloroethane (10 ml) was heated at 80° C. for 2 hours. The resulting mixture was diluted with chloroform and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel thin layer chromatography with a mixture of hexane and ethyl acetate (4:1) and recrystallized from a mixture of hexane and ethyl acetate to give methyl 8-oxo-5,6,7,8-tetrahydrocarbazole-2-carboxylate (72.2 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33].[F-].[K+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:24]3[CH:29]=[CH:28][C:27]([C:38]4[CH:39]=[CH:40][C:35]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:36][CH:37]=4)=[CH:26][CH:25]=3)=[CH:9][CH2:10][S:11][C:12]3[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=3)=[CH:4][CH:3]=2)=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc(SCC=C(c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an evaporated schlenk flask kept under nitrogen atmosphere were added {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid (208 mg, 0.38 mmol, example 1, step A–B), 4-(methansulfonyl)phenylboronic acid (280 mg, 1.4 mmol), KF (77 mg, 1.33 mmol), Pd2(dba)3 (21 mg, 23 mmol) and Pd(P(t-BU)3)2 (23 mg, 46 mmol). THF (5 ml) was added to the solid mixture keeping the mixture under nitrogen. The reaction mixture was stirred at room temperature for 1 h, followed by 4 h at 50° C. A saturated solution of ammonium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (2×20 ml). The organic phases were dried and evaporated. The residue was purified by column chromatography (eluent: ethyl acetate:methanol (9:1)) to give the title compound in 95 mg (36%) yield.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37](O)=[O:38].ON1C(=O)CCC1=O.CN1CCOCC1>CN(C)C=O>[NH:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C:37]([NH:12][C@H:13]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Yield: 65.5 %

Procedure:
A mixture of p-toluenesulfonic acid salt of Phe-Gly-OBzl (3.06 g), Boc-Gly-OH (1.10 g), N-hydroxysuccinimide (941 mg), N-methylmorpholine (0.725 ml), and N,N-dimethylformamide (40 ml) was cooled to 4° C., and added with N,N′-dicyclohexylcarboduimide (1.56 g). The mixture was allowed to react overnight at room temperature with stirring, and then evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=98:2 solution) to give Boc-Gly-Phe-Gly-OBzl (1.93 g).
Reaction SMILES: [N:1]1([CH:6]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)/[CH:7]=[CH:8]/[C:9]2[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](=O)([O-])O.[Na+]>CO>[CH3:27][O:18][C:17](=[O:19])/[CH:16]=[CH:15]/[C:13]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:8]=[CH:7]/[CH:6]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:14]=1
Reactant: Cc1ccc(C(/C=C/c2cccc(/C=C/C(=O)O)n2)N2CCCC2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1cccc(/C=C/C(c2ccc(C)cc2)N2CCCC2)n1
Temperature: 25 °C
Reaction time: 144 h
Yield: 93 %

Procedure:
A solution of (E)-3-(6-[3-pyrrolidin-1-yl-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-acrylic acid (2.04 g, 5.9 mmol) in methanol (50 ml) was treated with concentrated HCI (10 ml) and stirred at room temperature for 6 days. The reaction was neutralised with a saturated solution of sodium hydrogen carbonate and solvent removed under reduced pressure. DCM was added to the residue and inorganic solids removed by filtration. Concentration of the filtrate under reduced pressure yielded methyl-(E)-3-(6-[3-pyrrolidin-1-yl-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-acrylate as a pink foam (1.98 g, 93%). 1H-NMR; δ (CDCl3), 7.70 (1H, d, J=15.7 Hz), 7.57 (1H, t, J=7.7 Hz), 7.30 (1H, t, J=7.6 Hz), 7.25 (2H, d, J=8.3 Hz), 7.17 (1H, d, J=7.2 Hz), 7.10 (2H, dt, J=8.2, 1.8 Hz), 6.96 (1H, d, J=15.6 Hz), 6.93 (1H, d, J=7.9 Hz), 3.83 (3H, s), 3.65 (2H, bs), 2.85 (4H, bm), 2.41 (3H, s) and 2.04 (4H, bm).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C(NC(C)C)(C)C.[Li].[CH2:24]=[O:25]>C1COCC1.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([CH2:15][CH2:24][OH:25])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[N:6][CH:7]=1
Reactant: C=O
Reactant: Cc1cc(NC(=O)C(C)(C)C)ncc1Br
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)C(=O)Nc1cc(CCO)c(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(5-bromo-4-methylpyridin-2-yl)-2,2-dimethylpropanamide (30.0 g, 111 mmol) in THF (80 mL) was cooled in an ice bath and treated dropwise with a solution of lithium diisopropylamine in heptane/tetrahydrofuran/ethylbenzene (2.0 M, 138 mL) After stirring 1 h, the solution was treated with paraformaldehyde (24.9 g, 277 mmol) and allowed to warm gradually to room temperature while stirring 12 h. The mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by MPLC (eluent 6-50% ethyl acetate/hexanes) afforded N-[5-bromo-4-(2-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide. 1H NMR (500 MHz, CDCl3), δ 8.33 (s, 1H), 8.30 (s, 1H), 8.02 (br s, 1H), 3.98 (dd, J=6.5, 6.5 Hz, 2H), 3.04 (dd, J=6.5, 6.5 Hz, 2H), 1.34 (s, 9H); LC/MS (M+1)+=300.87;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[N:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[N:17]=[C:16]([N:24]3[CH2:48][CH2:47][C:27]4([CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:33])[CH:29]([C:42]([O:44]CC)=[O:43])[CH2:28]4)[CH2:26][CH2:25]3)[CH:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:49]2[CH:53]=[CH:52][C:51]([CH3:54])=[N:50]2)[CH:3]=1.C1COCC1.[Li+].[OH-]>O>[CH2:35]([O:34][C:32]([N:30]1[CH:29]([C:42]([OH:44])=[O:43])[CH2:28][C:27]2([CH2:26][CH2:25][N:24]([C:16]3[CH:15]=[C:14]([O:13][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[N:49]4[CH:53]=[CH:52][C:51]([CH3:54])=[N:50]4)[C:9]([F:10])([F:11])[F:12])[N:19]=[C:18]([S:20]([CH3:23])(=[O:21])=[O:22])[N:17]=3)[CH2:48][CH2:47]2)[CH2:31]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)C1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(S(C)(=O)=O)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(S(C)(=O)=O)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 2-benzyl 3-ethyl 8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.10 g, 2.65 mmol) in 2:1 THF:H2O (90 mL) was added LiOH (127 mg, 5.3 mmol), and the reaction was stirred at RT for 21 h, after which additional LiOH (65 mg, 2.6 mmol) was added, and the reaction was stirred for 8 h longer. The reaction was then quenched with 1 N HCl to pH<1, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid which was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.C12NC(CC1)CCC2>>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]#[N:6]
Reactant: C1CCCNCC1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: C1CC2CCC(C1)N2
Agent: Cl
Product: N#Cc1cc(F)c(N2CCCCCC2)c(F)c1

Procedure:
The title compound was prepared using the procedure described in Example 325A except using 3,4,5-trifluorobenzonitrile and azepane instead of 3,4-difluorobenzonitrile and 8-aza-bicyclo[3.2.1]octane hydrochloride. 1H NMR (DMSO-d6) δ 7.62 (d, 2H), 3.39 (m, 4H), 1.73 (m, 4H), 1.61 (m, 4H); MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14](OCC)=[O:15])=[C:12]([C:19]([CH3:21])=[CH2:20])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:19]([CH3:21])=[CH2:20])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=C(C)c1snc(-c2ccc(CC)cc2)c1C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: C=C(C)c1snc(-c2ccc(CC)cc2)c1CO
Temperature: -78 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 3-(4-ethylphenyl)-5-(prop-1-en-2-yl)-1,2-thiazole-4-carboxylate (280 mg, 0.93 mmol, 1.00 equiv) in toluene (6 mL). DIBAL-H (1.32 g, 2.50 equiv) was added at −78° C. The resulting solution was stirred for 4 h at −78° C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 200 mL of ethyl acetate. The organic layer was washed with 1×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by TLC method with petroleum ether/ethyl acetate (3:1). This resulted in 305.3 mg (crude) of [3-(4-ethylphenyl)-5-(prop-1-en-2-yl)-1,2-thiazol-4-yl]methanol as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C15H17NOS, 260.4 (M+H). found 260.4.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:13][CH2:14][P:15]([CH2:20][N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:19])[O:16][CH2:17][CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CCCCCC.C1COCC1.CCOCC>[C:29]1([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:21][CH2:20][P:15]([CH:14]([N:13]=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:19])[O:16][CH2:17][CH3:18])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A 1.53 N butyllithium solution (0.3 ml; 0.46 mmol) in hexane is added dropwise to a stirred solution of the ethyl phosphinate 3 (200 mg; 0.42 mmol) in THF (10 ml) at -78° C. under an atmosphere of argon. After 5 minutes benzyl bromide (0.06 ml; 0.51 mmol) is added dropwise to the deep-red reaction solution. After 2 hours the reaction solution is warmed to room temperature and after 15 hours diluted with ether. The solution is extracted with saturated aqueous ammonium chloride solution (2×20 ml). The organic phase is dried over Na2SO4 and evaporated under reduced pressure. The monoalkylated phosphinate 4 (187 mg, 79% of theory) is obtained after purification on silica gel using column chromatography (ethyl acetate/heptane=2/3).
Reaction SMILES: [OH:1][N:2]=[CH:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1.[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C:34]#[CH:35].C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl>[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][C:34]1[O:1][N:2]=[C:3]([CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9](=[O:28])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[O:19])=[CH:15][CH:16]=2)[CH:35]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2C=NO)cc1
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1cc(C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)no1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A solution of 1-(4-{2-[2-(hydroxyimino-methyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-phenyl)-3-o-tolyl-urea (300 mg, 0.789 mmol), 2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (359 mg, 1.182 mmol, crude mixture) and triethyl amine (12.9 μL) in dichloromethane (2 mL) was stirred 5 minutes. A sodium hypochlorite solution (5.25%, 2 mL) was added. The reaction was stirred at room temperature overnight. The aqueous portion was extracted 4 times with dichloromethane. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated. Chromatography of the crude mixture on a Biotage Flash 40S column eluting with ethyl acetate/hexane 1:5 gave the title compound (66 mg, 14%). MS (CI) m/z 604.5 (M−1), 505.9 (M-99)
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[CH3:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[CH3:40][O:41][C:42]1[N:47]=[C:46]([C:48](=[O:50])[CH3:49])[CH:45]=[CH:44][CH:43]=1>>[OH:39][C:29]1([CH2:49][C:48]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([O:41][CH3:40])[N:47]=2)=[O:50])[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([CH3:25])[CH:27]=2)[N:31]([CH2:35][CH2:36][CH3:37])[C:30]1=[O:38]
Reactant: COc1cccc(C(C)=O)n1
Reactant: CCCN1C(=O)C(=O)c2cc(C)ccc21
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2cccc(OC)n2)c2cc(C)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-methyl-1-propylindoline-2,3-dione and 1-(6-methoxypyridin-2-yl)ethanone (commercially available from Fisher Scientific). 1H-NMR δ 7.74 (m, 2H), 7.19 (s, 1H), 7.11 (d, 1H), 6.98 (d, 1H), 6.77 (d, 1H), 5.27 (bs, 1H), 4.03 (s, 3H), 3.65 (m, 3H), 3.49 (d, 1H), 2.30 (s, 3H), 1.74 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12](N(CC)CC)C.IC>C(Cl)Cl>[CH3:12][S:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1ccc2nc(S)sc2c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CI
Product: CSc1nc2ccc(O)cc2s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To the ice cooled solution of 2-mercapto-benzothiazol-6-ol from step 1 (3.80 g, 20.76 mmol, 1.0 eq) in DCM (40 mL, 0.5M) at 0° C., was added triethylamine (7.29 mL, 51.91 mmol, 2.5 eq) followed by iodomethane (1.93 mL, 31.14 mmol, 1.5 eq). The reaction was stirred from 0° C. to −10° C. for 3 hours. The solvent was removed in vacuo. Water (ca. 200 mL) was added and the aqueous layer was extracted with ethyl acetate (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to yield 2-methylsulfanyl-benzothiazol-6-ol as light green powder (3.76 g, 92%). The crude product was used in the next step without purification. M+H=198.0
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12](O)=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[NH:21]1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C(OC(=O)C)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]#[N:21])[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(C#N)nc12
Reaction time: 5 h

Procedure:
In accordance with scheme 6, to a solution of 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (for R1=morpholinyl, XII) and imidazole in pyridine was added at 0° C. phosphoroxychloride. After about 5 hours, the cold solution was diluted with ethylacetate and worked up in conventional manner to obtain 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonitrile (IXX), which was dissolved in triethylamine and in pyridine and was then stirred for 4 hours with hydrogen sulfide at room temperature. Solvent and excess hydrogen sulfide were removed. The obtained 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbothioic acid amide (XX) was dissolved in tetrahydrofurane and was reacted with iodomethane at 50° C. for about 4 hours. All volatile components were distilled off under vacuum and the residue was dissolved in a solution of 4,4-diethoxy-tetrahydro-pyran-3-ylamine in tetrahydrofurane. The mixture was stirred at 50° C. overnight, the solvent was distilled off and the residue was suspended in hydrochloric acid and stirred for about 3 hours at room temperature. It was obtained (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3,4,6,7-tetrahydro-pyrano[3,4-d]imidazole Id1).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH2:10]1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][CH:9]([NH:7][CH3:6])[CH2:10]3)[N:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC(N(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(CCc2nc(-c3ccc(Br)cc3)oc2C)C1

Procedure:
Stir (1-{2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester (see Intermediate 10) with a 1:1 solution of trifluoroacetic acid and dichloromethane (0.30M) for 30 minutes at room temperature. After this time, quench the reaction with 1N sodium hydroxide and extract with dichloromethane. Extract from the organic layer with 1N hydrochloric acid. Basify the aqueous layer with 1N sodium hydroxide and extract with dichloromethane. Dry the organics with sodium sulfate, decant and concentrate in vacuo to yield the pure title compound, MS (m/e) (79Br/81Br): 364.1/366.0 (M+1)
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=1.[OH-].[Na+].CO.O>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=1
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCc4ccc(C(=O)OC)cc4)ccc3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCc4ccc(C(=O)O)cc4)ccc3c2)o1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of methyl 4-[({1-bromo-6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)methyl]benzoate (77.2 mg, 0.126 mmol), prepared in the previous step, and 1 N NaOH (200 μL, 0.200 mmol) in 15 mL of THF, plus 15 mL of methanol, plus 5 mL of water was refluxed under nitrogen for 21 h. After cooling to room temperature the reaction was filtered and acidified by the addition of 300 μL of 1 N HCl. The reaction was concentrated under reduced pressure to remove most of the THF and methanol. The solid present was collected by filtration and dried under reduced pressure to give the title compound (61 mg, 81%) as a white solid, mp 281-283° C. Elemental Analysis for C33H26BrNO5. 0.05 H2O Calc'd: C, 66.35; H, 4.40; N, 2.34. Found: C, 66.50; H, 4.34; N, 2.18.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH:28](O)=O>>[Cl:27][C:25]1[CH:26]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[C:9]([O:21][CH3:22])[CH:8]=3)[CH:28]=[N:1]2)=[CH:23][CH:24]=1
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2N)ccc1OCCN1CCCC1
Reactant: O=CO
Product: COc1cc(-n2cnc3cc(Cl)ccc3c2=O)ccc1OCCN1CCCC1
Yield: 91 %

Procedure:
2-Amino-4-chloro-N-{3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]phenyl}benzamide (11.6 mmol, 4.5 g) was dissolved in 90 mL 88% formic acid and was heated to reflux for 3 h. The solvents were removed by rotary evaporation and the residue was purified by silica gel column chromatography affording the lo product (4.2 g, 91%). 1H NMR (DMSO-D6): δ 1.82 (4H, m), 2.65 (4H, m), 2.88 (2H, t, J=6.2 Hz), 3.88 (3H, s), 4.20 (2H, t, J=6.4 Hz), 6.89-6.91 (2H, overlapping), 7.01 (1H, d, J=10.1 Hz), 7.49 (1H, d, J=8.6 Hz), 7.76 (1H, s), 8.12 (1H, s), 8.29 (1H, d, 8.7 Hz). LCMS m/z=400 (m+H+).