Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: C1COCCN1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCOCC1
Yield: 40 %

Procedure:
N-Cyclopropyl-N-[1-(3-morpholin-4-yl-hexanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide (42) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethylbenzene-sulfonamide (30) (250 mg, 0.56 mmol) and morpholine (2 mL) as described in Example 26 above. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 42 (120 mg, 40%) as a white solid. LC: 100%. MS: m/z=532.3, 533.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.15 (1H, s), 8.07 (1H, d, J=7.5 Hz), 7.88 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.75 (1H, d, J=15 Hz), 4.10 (1H, m), 3.96 (1H, d, J=15 Hz), 3.70 (4H, m), 3.09 (2H, m), 2.64-2.44 (6H, m), 2.20 (1H, dd, J=8.8 Hz), 1.99 (1H, m), 1.50-1.25 (4H, m), 1.02-0.70 (7H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([CH2:31][CH3:32])([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])=[C:18]([CH3:30])[CH:17]=3)[CH2:14][CH3:15])[S:10][C:9]=2[CH:33]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[CH2:14]([C:13]([C:11]1[S:10][C:9]2[CH:33]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[CH:12]=1)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([CH2:25][CH3:26])([OH:27])[CH2:28][CH3:29])=[C:18]([CH3:30])[CH:17]=1)[CH2:31][CH3:32])[CH3:15]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(C(=O)OC)cc3s2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(C(=O)O)cc3s2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
2-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}benzo[b]thiophene-6-carboxylic acid methyl ester (0.48 g, 1.02 mmol) is dissolved in MeOH (2 mL) and treated with H2O (0.5 mL) and NaOH (0.20 g, 5.12 mmol). The resulting mixture is heated at a reflux for 2 h, cooled to RT, and stirred overnight. The solution is diluted with H2O (10 mL), adjusted to pH 3-4 using 1 M HCl, and extracted with EtOAc (40 mL). The EtOAc layer is washed with brine (20 mL), dried with MgSO4, filtered, and concentrated to yield the title compound (0.42 g, 0.92 mmol, 89%). 1H NMR (CDCl3), δ 0.76 (t, J=7.5 Hz, 6H), 0.95 (t, J=7.5 Hz, 6H), 1.68 (q, J=14.8, 7.5 Hz, 4H), 2.25-2.27 (m, 7H), 3.82 (s, 2H), 6.74 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 7.09 (dd, J=8.5, 2.1 Hz, 1H), 7.24 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.3, 1.7 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H). Exact mass (m/z): calcd. for C27H35O4S (M+H)+: 454.2; found: 472.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cccc(O)c1
Reaction time: 3 h

Procedure:
3′-Hydroxyacetophenone (5.0 g) was dissolved in tetrahydrofuran (100 ml), and the solution was added dropwise with a 1 M solution of phenylmagnesium bromide in tetrahydrofuran (100 ml) at −30° C. Then mixture was further added with tetrahydrofuran (100 ml), and the mixture was stirred for 3 hours with gradually warming it. The mixture was added with saturated aqueous ammonium chloride under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain the title compound (7.55 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](O)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:45])=O>ClCCl>[Cl:45][C:32]([C:31]1[CH:35]=[CH:36][N:37]=[C:29]([C:18]2[CH:19]=[C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:17]=2[NH:16][C:14]([C:13]2[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])=[O:15])[CH:30]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)Cl)ccn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112.2 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid (170 mg, 0.30 mmol, 1.00 equiv) in dichloromethane (10 mL), and oxalyl dichloride (112 mg, 0.88 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum to yield 200 mg of crude product a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[C:21]([C:27]#[N:28])=[C:20]([OH:29])[C:19]=1[CH2:30][CH2:31][OH:32])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1.CO>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[C:21]([C:27]#[N:28])=[C:20]([OH:29])[C:19]=1[CH2:30][CH2:31][O:32][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(O)c(C#N)c3ccnn23)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO[Si](C)(C)C(C)(C)C)c(O)c(C#N)c3ccnn23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
tert-Butoxy-N-[4-cyano-5-hydroxy-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyridin-7-yl]-N-(4-ethoxyphenyl)carboxamide (42) (128 mg) was dissolved in dichloromethane (2.9 mL). To this solution, tert-butyldimethylchlorosilane (110 mg) and imidazole (50 mg) were added and the solution was stirred at room temperature for 3 h. To this reaction solution, methanol (2.9 mL) was added and the solution was further stirred at room temperature for 15 h. The reaction solution was diluted with ethyl acetate and washed with brine. After the organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure and the residue was purified with silica-gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (43) (107.3 mg, Yield 66%).
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH:25]([NH:33][C:34]([C:36]2[CH:44]=[C:43]3[C:39]([C:40]([Cl:45])=[CH:41][NH:42]3)=[CH:38][CH:37]=2)=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>>[Cl:45][C:40]1[C:39]2[C:43](=[CH:44][C:36]([C:34]([NH:33][CH:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:24][O:23][CH2:22][CH:19]3[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]3)=[O:35])=[CH:37][CH:38]=2)[NH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccc(F)cc2)CC1
Solvent: COc1ccccc1
Product: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using deprotection method B, but without addition of anisole, 4-{2-[(3-chloro-1H-indole-6-carbonyl)amino]-2-(4-fluorophenyl)ethoxymethyl}piperidine-1-carboxylic acid tert-butyl ester (2.3 g, 4.3 mmol) afforded, after purification (SiO2: 25% isopropyl amine in ethyl acetate), 1.0 g (54%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CC(C)=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a suspension of methyl valinate hydrochloride (10.0 g, 59.7 mmol) and sodium carbonate (15.8 g, 149 mmol) in acetone (200 ml)-water (100 mL) was added 4-bromobenzenesulfonyl chloride (12.7 g, 49.7 mmol) at 0° C., and the mixture was stirred at room temperature for 12 hr after addition. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with 0.1N hydrochloric acid, water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to give the title compound as a white powder (14.7 g, 84%).
Reaction SMILES: COC1C=CC(C[C:8]2[CH:16]=[CH:15][C:11]([C:12]([O-:14])=[O:13])=[C:10]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=CC=1>O1CCOCC1.[OH-].[Na+]>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:10]2[C:9]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[CH:8][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:24][CH:23]=1
Reactant: COc1ccc(COc2c(Cc3ccc(OC)cc3)ccc(C(=O)[O-])c2OCc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(COc2cccc(C(=O)O)c2OCc2ccc(OC)cc2)cc1

Procedure:
A solution of 19 (8.60 g, 16.71 mmol) in dioxane (84 mL) and 2N NaOH (42 mL) was stirred for 24 h at room temperature. The reaction mixture was concentrated in vacuo. The residue was stirred with H2O (100 mL) and then acidified to pH 2 with 1N HCl. The white solid was filtered, washed with hexane, and was recrystallised from EtOAc/hexanes to generate 5.93 g (90%) of 20 as a white crystalline solid, mp 129° C.: 1H NMR δ 3.8 (s, 3H), 3.85 (s, 3H), 5.12 (s, 2H), 5.20 (s, 2H), 6.83 (d, 2H, J=8.8), 6.96 (d, 2H, J=9.2), 7.18 (t, 2H, J=8.0), 7.22-7.27 (m, 2H), 7.41 (d, 2H, J=8.4), 7.73 (dd, 1H, J=1.2, 8.0); 13C NMR δ 55.36, 55.37, 55.44, 55.46, 71.42, 114.26, 119.12, 123.04, 124.37, 125.00, 126.87, 128.02, 129.73, 131.21, 147.17, 151.45, 159.94, 160.44, 165.45; HRMS m/z calcd for C23H22NaO6, 417.1332 (M+Na); found, 417.1332.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].BrP(Br)Br.CO>C(Cl)Cl>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1cccc(C(C)=O)c1Br
Agent: BrP(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cccc(O)c1Br
Temperature: -40 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, 1-(2-bromo-3-methoxy phenyl)ethanone (30.5 g, 229 mmol) which had been obtained in Reference example 3 (3b) was dissolved in methylene chloride (500 mL), and added dropwise with a 1.0 M solution of tribromo phosphine in dichloromethane (293 mL, 293 mmol) at −80° C. over 5 hours. Upon the completion of the dropwise addition, the mixture was stirred for 17 hours at −40° C. Subsequently, the reaction solution was cooled to −80° C. and added dropwise with methanol (500 mL). Upon the completion of the dropwise addition, the temperature was raised to −40° C. followed by stirring for 3 hours. The temperature of the reaction solution was raised to room temperature. The solvent was distilled off under reduced pressure until the solution turned green. After adding ethanol, the mixture was extracted with ethyl acetate/hexane (1:1, V/V). After neutralization with a saturated aqueous solution of sodium hydrogen carbonate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 100:0-55:45, V/V) to give the title compound as a colorless oily substance (13.5 g, yield 47%).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH3:46])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH3:46])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1
Reactant: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (806.9 mg, 1.20 mmol) (obtained as described in Reference Example 58(3)) in anhydrous tetrahydrofuran (40 ml) were added successively acetic acid (0.09 ml, 1.57 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.44 ml, 1.44 mmol) in an ice bath, and then the mixture was stirred in the ice bath for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (15:1) as the eluant to afford 3-hydroxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (428.2 mg, yield 84%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42](O)(=[O:50])[C:43]1[C:44](=[CH:46][CH:47]=[CH:48][CH:49]=1)[OH:45].CCN(C(C)C)C(C)C>CC#N>[OH:45][C:44]1[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=1[C:42]([NH:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:50]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)OCc1ccccc1)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
The HCl salt of benzyl 2-amino-2-methylpropylcarbamate (1.0 g, 3.87 mmol) was taken up in CH3CN (15 mL) along with HATU (1.60 g, 4.2 mmol), salicylic acid (535 mg. 3.87 mmol) and DIEA (2.0 mL, 11.6 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (30% EtOAc/pentane) to afford benzyl 2-(2-hydroxybenzamido)-2-methylpropylcarbamate (340 mg, 26%). Mass calculated for C19H22N2O4: 342.16; found: [M+H]+=343.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][C:11]([OH:13])=O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[S:8][CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCSc1ccccc1F
Agent: O=S(=O)(O)O
Product: O=C1CCSc2c(F)cccc21
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
3-[(2-Fluorophenyl)sulfanyl]propanoic acid (4.0 g, 20 mmol) was mixed with concentrated sulphuric acid (20 ml) at 0–5° C. The reaction solution was stirred at 0 to 5° C. for 3 h then allowed to warm up to room temperature overnight. The mixture was quenched dropwise into ice to give a white suspension. The aqueous phase was extracted with ethyl acetate (1×200 ml, 1×100 ml). The combined organic phases were washed with saturated sodium bicarbonate solution (1×50 ml), water (1×50 ml), 1M hydrochloric acid (50 ml) and water (2×50 ml). The organic phase was dried over magnesium sulphate, filtered and concentrated under vacuum. The title compound was isolated as a yellow solid (2.10 g, 11.5 mmol, 58%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1F)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][C:8]1([CH3:10])[O:7][C:6](=[O:12])[C:5]2[CH:13]=[CH:14][C:2]([O:1][C:23]3[C:16]([F:15])=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][C:22]=3[F:25])=[CH:3][C:4]=2[O:9]1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(Oc3c(F)cc(C=O)cc3F)cc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (I-1a: 12.9 g) and 3,4,5-trifluorobenzaldehyde (5.0 g) and potassium carbonate (27.6 g) were combined in dimethylformamide (100 mL) and stirred as the reaction mixture was heated to 80° C. After 24 hours, the reaction mixture was cooled to ambient temperature, combined with water, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography on silica gel eluting with 5-10% ethyl acetate in heptane to give the title compound (I-1b-2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].CC([O-])(C)C.[K+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:17])([F:16])[F:15])[CH2:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-(3-bromo-4-fluorophenyl)-4-(3,5-dichlorophenyl)-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrole (0.88 g) in THF (13 ml), t-BuOK (0.24 g) was added under ice cooling. The mixture was returned to room temperature and stirred for 16 hours. Water was added to the reaction mixture, and the aqueous layer was separated and extracted with ethyl acetate. The combined organic layers, were washed with saturated brine, and dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-(3-bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrole (0.88 g) at a yield of 100%.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C@H:13]([C@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[CH2:14][OH:15]>ClCCl>[CH3:12][C@H:13]([C@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[CH:14]=[O:15]
Reactant: CCC[C@@H](C)[C@@H](C)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC[C@@H](C)[C@@H](C)C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
Pyridinium chlorochromate (27.35 g, 126.9 mmol) and neutral alumina (96 g, 3.5 g per gram of pyridinium chlorochromate) in dry dichloromethane (200 mL) was stirred under nitrogen for 0.25 hours. (2R,3R)-2,3-Dimethyl-hexan-1-ol (5.0 g, 38.46 mmol) in dichloromethane (60 mL) was added and the resulting dark slurry was stirred at room temperature for 3 hours. The slurry was filtered through a short pad of silica eluting with excess dichloromethane. Evaporation of the solvent afforded the titled compound (4.1 g, 84% yield) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (m, 3H) 0.9 (d, J=6.6 Hz, 3H) 1.0 (d, J=6.6 Hz, 3H) 1.2 (m, 4H) 1.8 (m, 1H) 2.2 (m, 1H) 9.6 (s, 1H).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[N+:10]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:24]([CH3:26])=[C:18]([CH2:17][C:16]3[CH:27]=[CH:28][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=3)[C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2ccc([N+](=O)[O-])cc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.48 g) and ethyl 2-(4-nitrobenzyl)aceto-acetate (1.00 g) in ethanol (150 ml) was treated with dry HCl at 0° C. for 7.5 hours and the solution was kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water. Yield 0.63 g (51%). Melting point 280-285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(OCC)C>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]#[C:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCCCCCC#Cc1ccc(Cl)c(Cl)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Clc1ccc(C#CCCCCCCBr)cc1Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of 8-(3,4-dichlorophenyl)-oct-7-yn-1-ol (0.52 g) in diethyl ether (2.5 ml) was treated with phosphorous tribromide (0.23 g) at 0° C. (ice/salt bath). The solution was stirred at 0-5° C. for 2 h and allowed to warm to room temperature. Aqueous sodium hydrogen carbonate solution was added. The aqueous layer was extracted with further diethyl ether (2×5 ml) and the combined organic layers were washed with brine (5 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave an oil that was chromatographed on silica gel using dichloromethane as eluent. This gave 8-bromo-1-(3,4-dichlorophenyl)-1-octyne (0.25 g). 1H-NMR (CDCl3) δ 1.35-1.7 (6H, m), 1.75-1.95 (2H, m), 2.33 (2H, t), 3.35 (2H, t), 7.13 (1H, dd), 7.27 (1H, d) and 7.40 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[C:24]1([C:22]([C:21]2[C:14]3[C:13]([NH:1][C:2]4[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=4)=[N:18][CH:17]=[N:16][C:15]=3[NH:19][CH:20]=2)=[O:23])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1cccc2ccccc12)c1c[nH]c2ncnc(Cl)c12
Reactant: CC(=O)Nc1cccc(N)c1
Product: CC(=O)Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4cccc5ccccc45)c23)c1

Procedure:
N-(3-((5-(1-Naphthoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide was synthesized using N-(3-aminophenyl)acetamide and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(naphthalen-1-yl)methanone according to the general procedure A. A yellow solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.42 (s, 1H), 9.98 (s, 1H), 8.45 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.05-8.02 (m, 3H), 7.79-7.73 (m, 2H), 7.67 (s, 1H), 7.63-7.53 (m, 4H), 7.38-7.35 (m, 1H), 7.29-7.25 (m, 1H), 2.02 (s, 3H); LCMS [M+H] 422.