Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[Si:18]([O:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
(±)-2-Hydroxy-3-phenylpropanoic acid (Sigma, 3.0 g, 18 mmol) was dissolved in 13 mL of DMF and chilled to 0° C. Imidazole (2.5 g, 36 mmol) and tert-butyldimethylsilylchloride (10 g, 69 mmol) were added. The mixture was allowed to warm to room temperature. After 12 hours, the mixture was diluted with 450 mL of 1:1 EtOAc:hexanes. The mixture was washed with 300 mL of 1M citric acid, 300 mL of water, and 150 mL of sat. Na2SO4, and the organic layer was evaporated. The residue was taken up in 170 mL of MeOH. The resulting mixture was chilled to 0° C. and potassium carbonate (5.7 g, 42 mmol) and 60 mL of water were added. The mixture was warmed to room temperature and stirred for 4 hours. The solvent was evaporated under reduced pressure. The residue was taken up in 5 mL of water and 1 M citric acid was added until the mixture reached pH 4.0. The mixture was extracted with EtOAc (3×100 mL), and the combined organic extracts were dried over MgSO4. The mixture was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with a gradient of 10% to 30% EtOAc in hexanes) to afford (±)-2-(tert-butyldimethylsilyloxy)-3-phenylpropanoic acid (2.0 g, 40%) as a clear oil. 1H NMR (400 MHz, CDCl3): ppm 7.49-7.37 (m, 5H), 4.60 (dd, J=3.7 Hz, 7.6 Hz, 1H), 3.30 (dd, J=3.7 Hz, 13.7 Hz, 1H), 3.12 (dd, J=7.8 Hz, 13.6 Hz, 1H), 1.03 (s, 9H), 0.12 (s, 3H), 0.00 (s, 3H). Carboxyl H was not detected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:29][CH3:30])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[C:25]([N+:26]([O-:28])=[O:27])[C:19]([F:18])=[CH:20][C:21]=2[O:29][CH3:30])=[N:3][CH:4]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 125 °C

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 11, 391 mg, 1.48 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 289 mg, 1.55 mmol) and p-toluenesulfonic acid monohydrate (310 mg, 1.63 mmol) in 2-pentanol (25 mL) was heated at 125° C. for 18 h. The mixture was cooled and used in the next step without further purification; m/z: ES+ MH+ 414.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:20]1[S:24][N:23]=[CH:22][N:21]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:9])=[O:8].[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)[CH:33]=1.ClC1C=CC(B(O)O)=C(C2N(C)N=CC=2)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>[Cl-].[NH4+].O.C1COCC1>[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:13]2[CH:14]=[CH:15][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:3]=3[O:2][CH3:1])[C:20]3[S:24][N:23]=[CH:22][N:21]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[C:34]([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)[CH:33]=1
Reactant: Cn1nccc1-c1cc(Cl)ccc1N
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c([N+](=O)[O-])c2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cn1nccc1-c1cc(Cl)ccc1B(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Nc3ccc(Cl)cc3-c3ccnn3C)c([N+](=O)[O-])c2)c(OC)c1
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (INTERMEDIATE M) (189 mg, 0.416 mmol), 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)aniline (the product of STEP 1 in the preparation of INTERMEDIATE F) (95 mg, 0.457 mmol), and THF (2079 μl) to give a brown solution. The flask was cooled in an ice bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (1248 μl, 1.248 mmol) was added dropwise over 1 minute to give a dark maroon mixture. After 10 min, the mixture was diluted with a saturated aq. ammonium chloride solution and water, then extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (20 to 70% EtOAc/heptane) give 4-((4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)amino)-N-(2,4-dimethoxybenzyl)-3-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (197.46 mg, 0.308 mmol, 73.9% yield) as a bright orange solid. m/z (ESI) 642.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:12]=[C:13](OB(O)O)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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.C1(C)C=CC=CC=1>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[C:13]1[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=1
Reactant: OB(O)Oc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: Oc1ccc(-c2cc(F)c(F)c(F)c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
At first, 75.0 g of 4-bromo-3-fluorophenol (S3-1), 82.9 g of 3,4,5-trifluorophenyl-boric acid (S3-2), 13.6 g of tetrakis(triphenylphosphine)palladium, 108.5 g of sodium carbonate and 1100 ml of a mixed solvent of dimethoxyethane/water=2/1 (volume ratio) were added into a reactor under nitrogen atmosphere, and the mixture was heated to 80° C. and stirred for 4 hr. Next, the reaction solution was cooled to room temperature, added with toluene and then washed with 1N hydrochloric acid and water. Afterwards, the solution was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. Subsequently, the product was purified by silica-gel column chromatography with a mixed solvent of heptane/ethyl acetate=4/1 as the eluent and then dried under reduced pressure. The obtained residue was recrystallized in heptane to obtain 77.5 g of 3-fluoro-4-(3,4,5-trifluorophenyl)phenol (S3-3). The yield of (S3-3) from (S3-1) was 81.5%.
Reaction SMILES: [CH3:1][CH:2]1[CH:12]=[C:11]([CH3:13])[CH2:10][CH2:9][C:3]21[CH:7]([OH:8])[O:6][CH2:5][CH2:4]2.[CH3:14]O>>[CH3:14][O:8][CH:7]1[C:3]2([CH2:9][CH2:10][C:11]([CH3:13])=[CH:12][CH:2]2[CH3:1])[CH2:4][CH2:5][O:6]1
Reactant: CC1=CC(C)C2(CCOC2O)CC1
Reactant: CO
Product: COC1OCCC12CCC(C)=CC2C

Procedure:
The title compound was prepared from 6,8-dimethyl-2-oxaspiro[4.5]dec-7-en-1-ol and methanol according to Example 1, producing 2 isomers in a ratio of 7:3.
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][C:18]=1[Cl:30])=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:30][C:18]1[CH:19]=[C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:21]=[CH:22][C:17]=1[CH2:16][NH2:15]
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CN)c(Cl)c1
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Add 4N hydrogen chloride in dioxane (6 mL, 24 mmol) to a solution of N-(tert-butoxycarbonyl)-2-chloro-4-(3,3-dimethyl-butyryl)-benzylamine (700 mg, 2.06 mmol) in dichloromethane (25 mL) and stir overnight. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid into saturated aqueous NaHCO3 and stir for 30 min. Extract twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (477 mg, 97%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[CH2:15][CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[N:21]([CH3:46])[C:22]4[C:27]([N:28]=3)=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:25]=[C:24]([N:35]3[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]3[CH2:44][CH3:45])[N:23]=4)[CH2:17][CH2:18]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)CC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)C4(N)CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
A mixture of (1-{4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperazine-1-carbonyl}cyclopropyl)carbamic acid tert-butyl ester (0.123 g, 0.19 mmol) in DCM/TFA (5 mL/5 mL) was stirred for 4 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 432 as a white solid (0.066 g, 64%). LCMS (Method I): RT=2.47 min, [M+H]+ 462.3. 1H NMR (400 MHz, DMSO-d6): δ 8.04-8.00 (m, 1 H); 7.66-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.18-4.22 (m, 4 H); 3.85 (s, 3 H); 3.82 (s, 2 H); 3.78 (t, J=4.6 Hz, 4 H); 3.58-3.53 (m, 4 H); 3.27 (q, J=7.4 Hz, 2 H); 2.55-2.45 (m, 4 H); 1.34 (t, J=7.4 Hz, 3 H); 0.92-0.87 (m, 2 H); 0.82-0.75 (m, 2 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(Cl)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
Trans-methyl 2-(4-chlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (155 mg, 0.46 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 3.63 mL, 20.71 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-chlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (23.5 mg, 18%). 1H NMR (600 MHz, dmso) δ 1.74-1.83 (m, 2H), 1.84-1.91 (m, 1H), 1.96-2.03 (m, 1H), 2.70 (dt, 1H), 2.79-2.86 (m, 1H), 3.09-3.15 (m, 1H), 3.69 (dd, 1H), 5.89-5.98 (m, 1H), 7.32-7.36 (m, 2H), 7.36-7.41 (m, 2H). HRMS Calculated for [C14H15ClN2O2+H]+: 279.0900. Found: 279.0889
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:11]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16]3[C:22]4=[C:23]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=6)=[C:30]([Cl:43])[CH:29]=5)[N:24]=[CH:25][N:26]=[C:21]4[S:20][C:17]=32)=[N:12]1)[CH:9]=[CH2:10]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:43][C:30]1[CH:29]=[C:28]([NH:27][C:23]2[N:24]=[CH:25][N:26]=[C:21]3[S:20][C:17]4[C:18]5[C:13]([CH2:14][CH2:15][C:16]=4[C:22]=23)=[N:12][N:11]([CH2:8][CH2:9][CH3:10])[CH:19]=5)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1
Reactant: C=CCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.7 %

Procedure:
To a solution of 2-allyl-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine trifluoroacetate (25.0 mg, 0.05 mmol) in ethyl acetate (1.50 mL) was added Pd/C (2.0 mg, 10%) under nitrogen. The reaction was stirred at rt under hydrogen atmosphere (balloon, 1 atm) for 4 h. The Pd/C residue was removed by filtering through a pad of celite and pad was washed with EtOAc (2×3 mL). The combined EtOAc layers were dried over sodium sulfate and the solvent was removed in vacuo. The residue was then separated by preparative HPLC to give (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-propyl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine trifluoroacetate (salt) (3.4 mg, 15%) as a yellow solid. 1H NMR (CD3CN) δ 8.33 (s, 1H), 7.82 (d, J=2.6 Hz, 1H), 7.65 (s, 1H), 7.49 (dd, J=2.3, 8.9 Hz, 1H), 7.45 (m, 1H), 7.33 (t, 1H), 7.28 (d, J=10 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 7.12 (dt, 1H), 5.23 (s, 2H), 4.08 (t, 2H), 3.40 (t, 2H), 3.04 (t, 2H), 1.88 (m, 2H), 0.94 (t, 3H); LCMS RT=3.91 min, [M+H]+=520.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=O)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:29]=[CH:30][CH:31]=1)#[N:22]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1cccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)c1

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-cyanobenzoic acid: MS (ESI): m/z 392 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])=[CH:24][CH:25]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: CC(C)(C)c1ccc(N)cc1
Product: COc1cccc2cc(C(=O)Nc3ccc(C(C)(C)C)cc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 4-t-butylaniline to give N-(4-t-butylphenyl)-7-methoxybenzofuran-2-carboxamide (Compound 389a). Successively, it was formylated to give N-(4-t-butylphenyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 389b), then compound 389b was reacted with cyclobutylamine to give compound 389 as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl.[CH3:28][O:29][C:30](=[O:42])[C@H:31]([CH2:40]O)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCl>[CH3:28][O:29][C:30](=[O:42])[CH:31]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:40][Cl:20]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of triphenylphosphine (65.8 g, 0.251 mol)) and hexachloroethane (59.4 g, 0.251 mol) in dichloromethane (850 mL) was added in one portion to a solution of N-Boc-serine methyl ester (50 g, 0.228 mol) in dichloromethane (170 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and then the reaction was quenched with a saturated solution of NaHCO3 (150 mL). The organic product was extracted with dichloromethane (2×300 mL) and the combined organic layers was washed with brine (300 mL) and dried over anhydrous sodium sulphate. The solution was concentrated under reduced pressure and then triturated with Et2O (500 mL). After filtration and evaporation of the solvent, the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet ether) which gave the title compound (42 g, 78%).
Reaction SMILES: [NH2:1][C:2](=[S:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(OCC)C>[C:4]([C:3]1[N:1]=[C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:9][CH:2]=1)([OH:6])=[O:5]
Reactant: CCOC(=O)CC(N)=S
Solvent: CCOCC
Product: CCOC(=O)Cc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 106.3 %

Procedure:
A solution of ethyl 3-amino-3-thioxopropionate (73.5 g) in diethyl ether (100 ml) was added to a solution of bromopiruvic acid (88.5 g) in diethyl ether (300 ml) and stirred for 15 hours at ambient temperature. The precipitates were collected by filtration and added to a mixture of water (500 ml) and diethyl ether (300 ml) and then adjusted to pH 7.5 with 20% aqueous sodium carbonate. The separated aqueous solution was adjusted to pH 1.0 with conc. hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was dried over magnesium sulfate and evaporated. The residue was washed with diisopropyl ether to give ethyl 2-(4-carboxythiazol-2-yl)acetate (57.1 g).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.[C:29]([N:36]1[CH2:41]CCC[C:37]1=O)(OC(C)(C)C)=[O:30].C1(N)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C.CN(C)C(Cl)=O>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:29](=[O:30])[N:36]([CH3:41])[CH3:37])[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:28])=[CH:8][N:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCNCC2)s1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CN(C)C(=O)Cl
Solvent: NC1CCCCC1
Product: CN(C)C(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
{2-[3-Cyclohexyl-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was pre-pared in a similar manner to the synthesis of example 12 from N-Boc piperidone, cyclohexyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester, Boc deprotection, reaction with dimethylcarbamoyl chloride and hydrolysis of the ester moiety as described in general procedure (I) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22].B(Br)(Br)Br.C(Cl)(Cl)Cl.C(O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2c(F)cccc2F)ccc2cc(O)ccc12
Reaction time: 1 h
Yield: 41 %

Procedure:
Dissolve [2-(2,6-difluorophenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-ylethoxy)-phenyl]-methanone (1.5 g, 3.0 mmol) in 500 mL methylene chloride and chill in ice. To this solution add boron tribromide (6.0 mL, 63 mmol) in portions with swirling between additions. Allow to come to room temperature and stir for one hour. Pour into a two-phase system consisting of an organic layer of 3/1 chloroform/isopropanol and an aqueous layer of saturated sodium bicarbonate. Separate the phases and dry the organic layer using 3 Å molecular sieves. Purify on a silica column eluting with a 0-10% methanol/methylene chloride gradient to give 600 mg (44%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C@@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][N:18]2[C:19](=[O:33])[N:20]3[O:25]CC2C=CC=CC=2)=[O:16])[C@H:10]([F:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C@@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][N:18]2[C:19](=[O:33])[N:20]3[OH:25])=[O:16])[C@H:10]([F:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)[C@H](F)C1
Reaction time: 8 h

Procedure:
To a solution of the product of Step 1 (3.0175 g, 6.33 mmol) in methanol (80 mL) and ethyl acetate (20 mL), was added 10% palladium on carbon (0.73 g, 6.86 mmol) and the reaction mixture was stirred under an atmosphere of hydrogen (balloon) overnight. LC/MS analysis showed reaction was complete. The reaction mixture was filtered through a microfilter and the collected solid was washed well with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene to afford the title compound as a yellow foam which was used directly in the next step without purification
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]2[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[Cl:9]>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:11]2[CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CC(C(Oc2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CO
Product: Clc1ccc(C(Oc2ccccc2)C2CNC2)cc1Cl
Temperature: 60 °C
Yield: 97 %

Procedure:
1N HCl (3 mL) was added to 10 mL of tertiary butyl 3-((3,4-dichlorophenyl)(phenoxy)methyl)azetidine-1-carboxylate (150 mg, 0.352 mmol) dissolved in a methanol solution, and heated to reflux at 60° C. for one day. Thereafter, the solvent of the reaction mixture was removed by reduced pressure evaporation to obtain the title compound.