Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
1.44 parts of 4-(2-chloro-4-trifluoromethylphenoxy)phenol, 0.84 part of ethyl bromoacetate, and 1.38 parts of anhydrous potassium carbonate were refluxed for 3 hours in 20 parts by volume of methyl ethyl ketone in an atmosphere of nitrogen. After the reaction, the reaction mixture was filtered. The filtrate was concentrated, and water was added. The mixture was then extracted with ethyl acetate. The extract was washed with a 1N aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.5 parts of ethyl 4-(2-chloro-4-trifluoromethylphenoxy)phenoxyacetate.
Reaction SMILES: CC(OC([N:8]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9]1)=O)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].C(Br)C1C=CC=CC=1>CN(C)C=O>[NH:8]1[CH2:9][CH2:10][CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)C1CCCNC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 202.3 %

Procedure:
(S)-Nip.(S)-CSA 1.1. (1S)-(+)-10-Camphorsulfonic acid (11.62 g, 0.05 mol) was added to a stirred solution of racemic nipecotic acid (6.46 g, 0.05 mol) in acetone (100 mL). The solution was heated to reflux, and H2O (15 mL) was added until all solids dissolved. The solution was cooled to room temperature and allowed to stir overnight. The precipitate that formed was isolated by filtration and recrystallized three times with acetone/H2O (6/1, v/v) to afford 1.99 g (11% yield) of the desired product as a white solid: m.p. 221-223° C.; {a}D+25.3° (c 1.0, MeOH). Boc-(S)-Nip-OH 1.2. (S)-Nip.(S)-CSA (1.90 g, 5.3 mmol) was dissolved in methanol (12 mL). Triethylamine (2.2 mL, 15.8 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.3 mmol) were added and the solution was stirred at 50° C. for 12 h. The solution was then concentrated, and the residue was dissolved in H2O. The aqueous solution was washed with diethyl ether, and the organic layer was discarded. The aqueous layer was acidified to pH 3 with 1 M HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to afford 1.24 g (quantitative yield) of the desired product as a white solid: m.p. 166-168° C.; FAB-MS m/z (M+Na+) calcd for C11H19NO4Na 252.3, obsd 252.5. Boc-(S)-Nip-OBn 1.3. Boc-(S)-Nip-OH (0.70 g, 3.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (14 mL). Cs2CO3 (1.0 g, 3.1 mmol) and benzyl bromide (0.41 mL, 3.5 mmol) were added, and the solution was stirred at room temperature for 24 h. The solution was then concentrated, and the residue was dissolved in H2O. The aqueous solution was then extracted with CH2Cl2. The organic solution was dried over MgSO4 and concentrated to give an oil. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (1/3, v/v) to afford 0.81 g (82% yield) of the desired product as a white solid. 2. Oligomer Synthesis
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:30](=[O:29])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33]
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCCNC(=O)C(F)(F)C(F)(F)F)c(=O)c1n23
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 4 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 2.04 g of the desired compound (50.4%, a pale yellow solid).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1([CH3:33])[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:16]2[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([CH3:30])=[C:28]([CH3:29])[C:15]=2[O:14]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[OH-].[Na+]>O1CCCC1>[CH3:12][C:13]1([CH3:33])[CH:17]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[C:16]2[C:25]([CH3:32])=[C:26]([N:31]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[C:27]([CH3:30])=[C:28]([CH3:29])[C:15]=2[O:14]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2c3c(C)c(N4C(=O)c5ccccc5C4=O)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of phthalic anhydride (566.4 mg, 3.82 mmol) in tetrahydrofuran (5 ml) was added a solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (987.3 mg, 3.38 mmol) in tetrahydrofuran(10 ml) and the resulting mixture was refluxed with heating for 11 hours. The reaction mixture was cooled down to room temperature and then concentrated under reduced pressure. Sodium acetate (314.6 mg, 3.84 mmol) and acetic anhydride (20 ml) were added into the residue and the resulting mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled down to room temperature and then an 8 N aqueous solution of sodium hydroxide was added into the mixture until it became basic. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1.16 g (81% yield) of the title compound. Melting point: 222-224° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>C(O)C.O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stiffed mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. RecrystaIlization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C.
Reaction SMILES: [CH3:1]CC([O-])(C)C.[Na+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:29][C:30]1[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=1[CH2:32][CH:33]1[C:42](=O)[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Br:29][C:30]1[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=1[CH2:32][CH:33]1[C:42](=[CH2:1])[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34]1
Reactant: O=C1CCC2(CC1Cc1ccccc1Br)OCCO2
Reactant: CCC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: C=C1CCC2(CC1Cc1ccccc1Br)OCCO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium tert-pentoxide (70 ml of a 1M solution), prepared for immediate use, is added to a suspension of methyl(triphenyl)phosphonium iodide (25 g, 61.8 mmol) in 50 ml of toluene, and the mixture is stirred at room temperature under nitrogen for 20 minutes. The compound obtained in Step 1 (6.70 g, 20.6 mmol) dissolved in 50 ml of toluene is added dropwise and the reaction mixture is refluxed for 3 hours. After cooling, the reaction mixture is hydrolysed with a saturated NH4Cl solution and extracted with ether. The organic phase is washed with a saturated NaCl solution, H2O, dried over MgSO4 and concentrated in vacuo. The title product is purified by flash chromatography over a column (SiO2, toluene/cyclohexane:60/40).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([OH:18])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[OH:32])[CH2:27][NH2:28]>>[C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:31]([OH:32])=[C:24]([OH:23])[CH:25]=3)=[O:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: NCc1ccc(O)c(O)c1
Reactant: COc1cc(O)c(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COc1cc(O)c(C(=O)NCc2ccc(O)c(O)c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.17 g of the target compound is obtained as white solid in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2-hydroxy-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 3,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([O:39]CC)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:35])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 70 °C
Yield: 67.9 %

Procedure:
To a mixture of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol) in methanol (4 mL) was added a solution of NaOH (24 mg, 0.6 mmol) in water (2 mL). The mixture was heated at 70° C. for 3 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (80 mg). m/z (M+H)+: 619
Reaction SMILES: [CH:1]([P:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:7][CH2:8][OH:9])([CH2:3][CH3:4])[CH3:2].[OH:14]CCCP(C(CC)C)C(CC)C.OO.C=CCC>C(O)(C)C.C(=S)=S>[CH:1]([P:5](=[O:14])([CH2:6][CH2:7][CH2:8][OH:9])[CH2:10][CH2:11][CH2:12][OH:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)P(CCCO)CCCO
Reactant: CCC(C)P(CCCO)C(C)CC
Agent: C=CCC
Agent: OO
Solvent: CC(C)O
Solvent: S=C=S
Product: CCC(C)P(=O)(CCCO)CCCO

Procedure:
The residual product is believed to contain both s-butyl bis(3-hydroxypropyl) phosphine and 3-hydroxypropyl di-s-butyl phosphine. It is dissolved in an equal volume of isopropanol and oxidized with 30% hydrogen peroxide in an equal volume of isopropanol as described above in Example 1 until a negative carbon disulfide reading is obtained. The solution of oxidized phosphine is concentrated under reduced pressure to yield a syrupy yellow liquid weighing 555.6 g (99.2% yield on oxidation or a yield of 62.5% based on the starting butene).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(C)C)=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[CH:15]([Cl:20])[N:14]1[CH:21]([F:23])[F:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[CH:15]([Cl:20])[N:14]1[CH:21]([F:23])[F:22]
Reactant: CC(C)Oc1cc(N2C(=O)N(C)C(Cl)N2C(F)F)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: CN1C(=O)N(c2cc(O)c(Cl)cc2Cl)N(C(F)F)C1Cl
Yield: 93.5 %

Procedure:
Hydrolysis of 2.6 g (0.0067 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-chlorodifluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one in 10 mL of concentrated sulfuric acid produced 2.17 g of 1-(2,4-dichloro-5-hydroxyphenyl)-3-chlorodifluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one as a solid (mp 146°-148° C.).
Reaction SMILES: C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH:24]1[C:32]([O:34][CH3:35])=[O:33].[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][CH3:49])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][CH3:49])[C:45]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][C@H:24]1[C:32]([O:34][CH3:35])=[O:33])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1Cc2ccccc2N1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OC
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Triethylamine (3.15 ml) and bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (5.75 g, 22.6 mmol) were added to a solution of methyl indoline-2-carboxylate (2 g, 11.3 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (2.6 g, 13.6 mmol) in methylene chloride (15 ml), at 0° C. under nitrogen. The reaction was stirred for 2 h at 5° C. and then at room temperature overnight. The mixture was filtered, the filtrate was washed with water (2×40 ml) and the combined aqueous fractions were extracted with methylene chloride. The combined organic fractions were dried and concentrated to give a residue, which was purified by chromatography on a column of silica gel, using a 7/3 petroleum ether/ethyl acetate mixture as eluent. The product was obtained in the form of a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.CC(N1[C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])=[CH:15][C:14](C)=N1)(C)C.CC(N1C(C(NCC2C=CC(B(O)O)=CC=2)=O)=CC(C)=N1)(C)C>>[CH:16]1([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:46])=[O:47])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])[CH2:15][CH2:14][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5cc(C)nn5C(C)(C)C)cc4)cc23)CC1
Agent: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)C5CCCC5)cc4)cc23)CC1
Yield: 47 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (4-{[(cyclopentylcarbonyl)amino]methyl}phenyl)boronic acid (119 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 30 mg of the title compound (47%).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:8]=[C:9]2[CH:15]=[N:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[N:11][CH:12]=1)[C:3](O)=[O:4].[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O>CN(C=O)C>[CH3:28][C:2]([CH3:1])([CH:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:8]=[C:9]2[CH:15]=[N:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[N:11][CH:12]=1)[C:3]([NH:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[O:4]
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1cnc2c(cnn2-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a stirred solution of 2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)propanoic acid (8 mg, 0.022 mmol), 2-aminothiazole (9 mg, 0.09 mmol), and diisopropylethylamine (0.015 mL, 0.09 mmol) in anhydrous DMF (0.3 mL) was added HATU (33 mg, 0.09 mmol) under argon. After stirred at rt overnight and 80° C. for 30 min, the mixture was concentrated. HPLC purification gave 2,2-dimethyl-3-phenyl-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(thiazol-2-yl)propanamide (Example 162, 5 mg, 0.009 mmol, 41% yield) as a trifluoroacetic acid salt. MS found: (M−H)−=452.11. 1H-NMR (400 MHz, Acetone) δ ppm 8.56 (1 H, d, J=2.54 Hz) 8.39 (1H, d, J=2.03 Hz) 8.24 (2H, d, J=7.63 Hz) 8.18 (1H, s), 7.37-7.47 (4H, m) 7.27 (1H, d, J=3.56 Hz) 7.16-7.23 (3H, m) 7.11 (1H, t, J=7.38 Hz) 6.95 (1H, d, J=3.56 Hz) 4.98 (1H, s) 1.42 (6H, d, J=7.63 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:3]=1[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[C:2]([OH:1])=[CH:13][CH:12]=[CH:11][C:10]=1[O:14][C:21]1[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=1)[CH:8]=[CH2:9]
Reactant: C=CCOC(=O)c1c(O)cccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(O)cccc1Oc1nc(OC)cc(OC)n1
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
2.0 g of allyl 2,6-dihydroxybenzoate (V) was added to the suspension of 0.4 g of sodium hydride in 50 ml of dimethylformamide and the mixture was stirred for 10 minutes. To this mixture was added 2.2 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine. The reaction mixture was stirred for 5 hours and 50 ml of saturated ammonium chloride solution was added thereto. The reaction solution was then extracted with 200 ml of ethylacetate. The extract was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (hexane:ethylacetate=2:1 v/v) on silica gel to obtain 3.0 g (Yield 90%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][OH:13]>O>[Cl:1][C:2]1[C:3]([O:13][CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: O
Product: COc1ncc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,6-Dichloro-nicotinic acid (1.00 g, 5.21 mmol) is added to a solution of Na (252 mg, 10.9 mmol) in methanol (50 mL). The mixture is refluxed overnight before another portion of Na (252 mg, 10.9 mmol) is added. Refluxing is continued for 2 h. The mixture is cooled to rt, diluted with water and concentrated. The remaining solid is dissolved in water and the solution is neutralised by adding 2 N aq. HCl. The resulting suspension is extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give 5-chloro-6-methoxy-nicotinic acid (976 mg) as a white solid; LC-MS: tR=0.77 min; [M+1]+=189.90; 1H NMR (D6-DMSO): δ 4.03 (s, 3H), 8.22 (d, J=1.8 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:17])/[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1.[CH3:18][C:19]1([CH3:27])[CH2:25][C:24](=O)[O:23][C:21](=[O:22])[CH2:20]1>O1CCOCC1>[CH3:18][C:19]([CH3:27])([CH2:25][C:24]1[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH2:6][C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][NH:10][C:9]=3[N:8]=2)[N:17]=1)[CH2:20][C:21]([OH:23])=[O:22]
Reactant: N/C(CCCc1ccc2c(n1)NCCC2)=N\O
Reactant: CC1(C)CC(=O)OC(=O)C1
Solvent: C1COCCO1
Product: CC(C)(CC(=O)O)Cc1nc(CCCc2ccc3c(n2)NCCC3)no1
Temperature: 100 °C

Procedure:
A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 3,3-dimethylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting mixture was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.12 (6H, s); 1.96 (2H, p); 2.14 (2H, p); 2.36 (2H, s); 2.80 (6H, m); 3.05 (2H, s); 3.50 (2H, t); 6.63 (1H, d); 7.57 (1H, d).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([CH2:17]C(=O)C)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:15][C:14](=[O:16])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ICCCCCCc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
6-Iodo-1-phenylhexane (17.43 g, 0.061 mol), acetyl acetone (6.66 g, 0.067) and potassium carbonate (8.41 g, 0.061 mol) were dissolved in dry absolute ethanol (75 ml) and the solution was refluxed for 18 hours. After cooling to room temperature the solution was filtered and evaporated under reduced pressure to an oil. This was partitioned between ethyl acetate (80 ml) and water (80 ml), and the organic layer was washed with brine, dried and evaporated to an orange oil (15.27 g). This was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate to give 9-phenylnonan-2-one as a colourless oil (7.12 g, 54%).