Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH2:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:34])[CH2:32][NH:33][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=2[NH:12][S:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])(=[O:11])=[O:10])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Product: CC(CNC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F)c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared from 2-(2,6-difluorobenzenesulfonylamino)-4-iodo-benzoic acid and 2-(3,4-dichloro-phenyl)-propylamine as in EXAMPLE 1, Part C. HPLC: RT=11.98 min. MS (ESI−): mass calcd. for C22H17Cl2F2IN2O3S, 625.3; m/z found, 624 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.63 (s, 1H), 8.02 (d, J=1.5, 1H), 7.54-7.45 (m, 1H), 7.39 (d, J=8.2, 1H), 7.34 (d, J=1.6, 1H), 7.32 (d, J=1.8, 1H), 7.09 (dd, J=8.3, 2.1, 1H), 7.02-6.94 (m, 3H), 6.34-6.32 (br m, 1H), 3.74-3.65 (m, 1H), 3.40 (ddd, J=13.7, 8.5, 5.6, 1H), 3.14-3.04 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCc1cccc(F)c1
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 73.2 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), 3-fluorobenzylamine (0.5 mL, 4.4 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 188 mg of the product 191. 1H NMR (CDCl3) δ 8.56 (s, 1 H), 7.45-7.20 (m, 3 H), 7.20-6.95 (m, 2 H), 5.20-4.95 (m, 2 H), 4.35-4.10 (m, 2 H), 2.75-2.55 (m, 1 H), 2.20-2.05 (m, 1 H), 1.80-1.05 (m, 15 H); MS: m/z 348 (M++1).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)=[O:14]
Reactant: O=C(Br)CBr
Reactant: Cc1onc(C(=O)c2ccccc2Cl)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(C(=O)c2ccccc2Cl)c1NC(=O)CBr
Reaction time: 1 h

Procedure:
Bromoacetylbromide (42 g, 210 mmoles) was added slowly to a mixture of (4-amino-5-methylisoxazol-3-yl)-2-chlorophenylmethanone of Example IIIb (24.8 g, 105 mmoles) in dichloromethane (300 ml) with 2N sodium carbonate (200 ml) and saturated sodium bicarbonate (500 ml) at 5° C. After stirring for 1 hour, the mixture was diluted with dichloromethane (400 ml) and water (400 ml). The organics were washed with water, saturated sodium chloride, dried (sodium sulfate) and evaporated to give 36 g of an oil. The residue (5.2 g) was flash chromatographed (25% ethyl acetate:hexane) to yield 4.5 g (85%) of an oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C=O)C>[CH3:8][C:7]1[C:2]2[N:3]([N:20]=[N:21][N:22]=2)[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cn2nnnc12

Procedure:
A mixture of 2-chloro-3-methyl-5-(4-(trifluoromethoxy)phenyl)pyridine prepared as described above (58 mg, 0.20 mmol), sodium azide (21 mg, 0.30 mmol), and pyridine 4-methylbenzenesulfonate (5 mg, 0.02 mmol) in anhydrous DMF (2.0 mL) was capped in a Biotage microwave reaction vial and subjected to irradiation at 160° C. for 30 min. Cooled, pressure released by opening the cap, additional sodium azide (65 mg, 1.00 mmol) and pyridine 4-methylbenzenesulfonate (52 mg, 0.20 mmol) were added, capped, and subjected to irradiation at 200° C. for 30 min. After cooling, the mixture was concentrated in vacuo, diluted with DMF (1.0 mL) and MeOH (2.0 mL), filtered, and subjected to preparative HPLC with a gradient MeCN/H2O (5% to 98 containing 0.1% TFA to afford 8-methyl-6-(4-(trifluoromethoxy)phenyl)tetrazolo[1,5-a]pyridine
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:24])[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].S(=O)(=O)(O)O>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:24][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC/C=C\C/C=C\CCO
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 8.7 g (45 mmoles) of p-toluenesulfonyl chloride in 60 ml pyridine was added dropwise at 0°-5° C., a solution of 5.8 g (31.8 mmoles) of (Z,Z)-3,6-dodecadienol (T. Kajiwara, J. Sekiya, Y. Odake and A. Hatanaka, Agric. Biol. Chem., 41, 1481 (1977)). The temperature was allowed to rise to 25° C., and the reaction mixture was stirred at room temperature overnight. The resulting suspension was slowly poured into a mixture of 1 N aqueous sulfuric acid and ice and the product extracted with ether. The ether extracts were combined, washed with 10% sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. The residue (8.0 g) was chromatographed on a silica gel column. Elution with 1:1 hexane-ether gave 4.9 g (14.6 mmoles) (45.8%) of (Z,Z)-3,6-dodecadienyl tosylate, which was dissolved in 20 ml of acetone.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[C:9]([C:10](=[O:12])[CH3:11])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)c1ccccc1
Product: CC(=O)C(=CN(C)C)C(=O)c1ccccc1

Procedure:
A stirred solution of benzoylacetone (16.2 g) and dimethylformamide dimethylacetal (16.2 ml) was heated on an oil bath at 80° C. for 40 minutes. Volatile materials were removed under vacuum and the residue was crystallised from ether to give 2-(dimethylaminomethylene)-1-phenyl-1,3-butanedione (mp 81°-83° C.).
Reaction SMILES: C([O:5][C@H:6]1[CH2:10][N:9]([C:11](=[O:32])[CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[C:40]([OH:42])=O)=[O:34])[CH2:7]1)(C)(C)C.[NH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][N:48](C(OC(C)(C)C)=O)[CH2:47][CH2:46]1>>[OH:5][C@H:6]1[CH2:10][N:9]([C:11](=[O:32])[CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:8]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[C:40]([NH:43][CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:42])=[O:34])[CH2:7]1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)O)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: O=C(NCC1CCNCC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by successively conducting procedures which were similar to Step 5 of Example 1 and Example 46, using (2R)-1-{(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxylic acid and 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine. The compound was obtained as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[C:22]([O:40][CH3:41])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:41][O:40][C:22]1[CH:21]=[C:20]([CH:39]=[CH:38][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:19][O:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate-layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (595 mg, yield 55%), which was then recrystallized from ethyl acetate-hexane. melting point: 107–108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C@@H:15]([CH3:23])[CH2:14]2)[C:9](=[O:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.C(Cl)CCl.[C:28](O)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:11][CH2:10][C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C@@H:15]([CH3:23])[CH2:14]1)=[O:12])(=[O:30])[CH3:29]
Reactant: C[C@H]1C[C@@H](N(C(=O)CO)c2ccc(Cl)cc2)c2ccccc2N1
Reactant: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)OCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.7 %

Procedure:
N-(4-Chlorophenyl)-2-hydroxy-N-[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (300 mg, 0.91 mmol, 1 equ.) was dissolved in methylene chloride (3 mL). To this solution was added EDC (464 mg, 2.7 mmol, 3 equ.) and acetic acid (164 mg, 2.7 mmol, 3 equ.) and the reaction mixture was stirred at room temperature for 20 h. Reaction mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride/methanol: 99/1 to 98/2 gradient) to afford 2-{(4-chlorophenyl)[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate (240 mg, 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[CH3:22]C1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.IC.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Solvent: CI
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and iodomethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (72%) as a white solid: mp 142-144° C.; MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-4-methylbenzenamine (0.82 g, 4.4 mmol) in anhydrous CH2Cl2 (40 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.72 ml, 4.85 mmol) and triethylamine (2.5 ml, 17.6 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCO3 (80 mL) was added and the mixture was stirred for 5 min. The organic layer was separated and aqueous was extracted with CH2Cl2 (3×20 mL). The combined organic solution was dried (Na2SO4). The solvent was removed in vacuo. The title compound was afforded as a yellow solid (1.48 g, 94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>O1CCOCC1.O.O1CCOCC1>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:24]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9 gm (42 millimols) of 4-[2-aminoethyl]-4'-hydroxy-biphenyl in a solution of 1.72 gm (43 millimols) of sodium hydroxide in 100 ml of a mixture of water/dioxane (1:1) was acylated at 0° C with a solution of 13 gm (76 millimols) of 2-methoxybenzoyl chloride in 50 ml of dioxane, while maintaining the pH at 10 by periodic addition of sodium hydroxide. After all of the acid chloride had been added, the mixture was stirred at room temperature for 2 hours, and then the pH of the resulting suspension was adjusted to between 4 and 5 by addition of 2 N hydrochloric acid. The suspension was now extracted with chloroform. After extraction with a dilute sodium bicarbonate solution, the chloroform phase was dried with sodium sulfate, evaporated, and the residue was recrystallized from ethyl acetate. Yield: 8.7 gm (59% of theory); m.p. 118° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([C:11]([CH2:13]Cl)=[O:12])([CH3:10])[CH3:9].[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31]([O:34][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])=[C:30]([CH3:42])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]>CC(C)=O>[CH3:7][C:8]([CH3:10])([CH3:9])[C:11](=[O:12])[CH2:13][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]([C:28]2[CH:33]=[CH:32][C:31]([O:34][S:35]([C:38]([F:41])([F:39])[F:40])(=[O:37])=[O:36])=[C:30]([CH3:42])[CH:29]=2)([CH2:18][CH3:19])[CH2:15][CH3:16])=[CH:21][C:22]=1[CH3:27]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Yield: 83.8 %

Procedure:
Potassium carbonate (59.7 mg, 0.43 mmol) and 1-chloropinacolin (42.0 mg, 0.31 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 0.1 g, 0.24 mmol) in acetone (1.2 mL), and the mixture was heated under reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (6% ethyl acetate/hexane) to give the title compound (103.5 mg, 83%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][CH:14]([NH2:16])[CH3:15]>>[CH:14]([NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])([CH3:15])[CH3:13]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and propan-2-amine (0.420 g, 67%).
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17]=[CH:18][C:19](=[CH2:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH2:21][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:16][CH2:17][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(=C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1=CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 11 h
Yield: 56 %

Procedure:
To a rapidly stirred solution of 70% aqueous triflic acid (2.10 g, 0.01 mol) and benzaldehyde (106.1 g, 1.0 mol) in 100 ml toluene was added isoprene (150 cm3, 1.5 mol) over 4 hrs. at 25° C. The mixture was stirred at room temperature for a further 11 hours after which the reaction mixture was quenched by the addition of Polyrad* (2 g) and solid sodium carbonate (5 g). The crude mixture was distilled under reduced pressure to give pure rosyrane (56% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:18])[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1ccc2c(N)ncnn12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(Br)c2c(N)ncnn12
Reaction time: 96 h
Yield: 154.3 %

Procedure:
To a solution of butyl 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (225.0 mg, 0.96 mmol) in DMF (7.5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (137.3 mg, 0.48 mmol) in two portions. The solution was stirred for 4 days and then quenched by addition of saturated aqueous sodium sulfate solution (20 mL) and water (20 mL). The solid was filtered, washed with water and air-dried. The crude material was purified by HPLC using a gradient of 30-80% of MeCN in water to afford 232.0 mg (77%) of the title compound as an off-white solid. 1H-NMR (DMSO-d6) δ 8.42 (bs, 1 H), 8.03 (s, 1 H), 7.35 (s, 1 H), 7.03 (bs, 1 H), 4.23 (t, J=6.4 Hz, 2 H), 1.69-1.62 (m, 2 H), 1.46-1.36 (m, 2 H), 0.92 (t, J=7.3, 3H); MS [M+H]+=313.0; LCMS RT=2.83 min.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:1]([O:11][CH2:22][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@H](O)c1ccccc1
Yield: 9528.3 %

Procedure:
A solution of 85.1 g (559 mmol) of D-mandelic acid, 65 ml(628 mmol) of benzyl alchohol, and 1.01 g (5.35 mmol) of p-toluenesulfonic acid in 700 ml of benzene was refluxed for 6.5 hours. The mixture was washed with water and concentrated. The residue was recrystallized from ether to give 123.5 g of the aimed compound D-2 in 91% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([CH3:19])[CH3:18])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)cc1Cl
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-2-chlorophenol (50 g) in N,N-dimethylformamide (DMF) (250 mL) stirred under nitrogen at room temperature was added K2CO3 (100 g) and 2-bromopropane (136 mL) in one charge. The reaction mixture was stirred at 85° C. for 16 h. After cooling the reaction, the reaction mixture was filtered, the solvent of the filtrate was removed in vacuo. The residue was dissolved in diethyl ether (300 mL), washed with water (6*100 mL), the organic phase was dried over MgSO4 and concentrated to give 4-bromo-2-chlorophenyl 1-methylethyl ether (D68) (56 g) as a yellow oil. δH (CDCl3, 400 MHz): 1.37 (6H, d), 4.52 (1H, m), 6.82 (1H, d), 7.29 (1H, m), 7.50 (1H, d).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:10]([OH:12])=[O:11].[OH-].[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCOCC1>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C@@H:2]2[C:10]([OH:12])=[O:11])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)[C@H]1Cc2ccccc2N1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (R)-2,3-dihydro-1H-indole-2-carboxylic acid (2.89 g, 14.5 mmol) and 1N sodium hydroxide (37.7 mL, 37.7 mmol) in water (79 mL) stirring at room temperature is added dropwise a solution of 4-benzyloxybenzenesulfonyl chloride (4.1 g, 14.5 mmol) in dioxane (104 mL). Upon completion of the addition, the pH of the reaction mixture is monitored and maintained between 7–8 by slow addition of 1N aqueous sodium hydroxide over the next 2 hours. The reaction mixture is stirred overnight at room temperature. The solution is poured into crushed ice and the resulting mixture is acidified to pH 2–3 with 1N aqueous hydrochloric acid (15 mL). The product is extracted into dichloromethane (2×150 mL). The extract is washed with water (150 mL), brine (150 mL), dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated to give 5.5 g of (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid as an oil: [M+1]+=410.32, [M−1]−=408.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.S([CH2:20][N+:21]#[C-:22])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:22][N:21]=[CH:20]1
Reactant: O=Cc1ccc(Br)cn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1ccc(-c2cnco2)nc1

Procedure:
In 5.4 ml of methanol was dissolved 200 mg of 5-bromo-2-formyl pyridine (5-bromo-2-pyridinyl aldehyde) which was then reacted with 231 mg of tosylmethylisocyanide for 3 hours in the presence of 178 mg of potassium carbonate under reflux. After completion of the reaction, the same post-treatment as in Preparation Example 13 was carried out to obtain the title compound. 204 mg.