Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li][CH2:12]CCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:12]
Reactant: COc1cccc(OC)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc(OC)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a solution of 1,3-dimethoxybenzene (2.00 g, 14.5 mmol) in THF (30 mL) at 0° C. was added n-BuLi (6.40 mL, 15.9 mmol, 2.5 M in hexanes) slowly over a 2 min period. The solution was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. The solution was re-cooled to 0° C., iodomethane (2.70 mL, 43.5 mmol) was added slowly (the solution warmed up) and the solution was stirred at 0° C. for 10 min and then at room temperature for 1.5 h. The reaction was quenched with water, most of the solvent was removed in vacuo, and extraction was done in EtOAc (2×75 mL) with water (50 mL). Flash chromatography with silica gel (gradient to 6% ethyl ether/hexanes) afforded the title compound as a colorless liquid (1.98 g, 90% yield): 1H NMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 3.82 (s, 6H), 6.54 (d, 2H, J=8.3 Hz), 7.12 (t, 1H, J=8.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=C(O)Cc1ccc(Cl)cc1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(Cl)cc1Br
Yield: 88.2 %

Procedure:
28.3g (0.113 mol) of 2-bromo-p-chlorophenylacetic acid was mixed with 26.9g (0.226 mol) of thionylchloride and the mixture was refluxed for 2.5 hours. After the excess thionylchloride had been distilled off, the reaction mixture was distilled under reduced pressure to give 26.7g of 2-bromo-p-chlorophenylacetyl chloride as yellow-orange oil. (b.p. 148° - 152°C/15 mmHg)
Reaction SMILES: [CH2:1]([S:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]#[CH:3].[O-][C:15]#[N:16].[K+]>C(O)C.C(N(CC)CC)C.O>[C:15]([CH:3]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[S:4][CH2:1][CH2:2]1)#[N:16]
Reactant: N#C[O-]
Reactant: C#CCSc1cc2ccccc2[nH]1
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: N#CC1CCSc2[nH]c3ccccc3c21
Yield: 69 %

Procedure:
The product of the above (2) (13.2 g) is dissolved in a mixture of ethanol (300 ml) and triethylamine (20 ml). The solution is refluxed for 1 hour and further 2 hours after addition of a solution of potassium cyanate (25 g) in a mixture of ethanol (170 ml) and water (80 ml) and evaporated to remove the solvent. The residue is extracted with ether after addition of water. The extract is washed with water, dried and evaporated to remove the solvent. The oily residue (15 g) is chromatographed on an column of silica gel (450 g) and eluted with benzene. The eluate is condensed to give the title compound as crystals melting at 125°-126° C. Yield: 69%
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21]C(OCC2C=CC=CC=2)=O)[C:16]1=[O:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:33])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]1=[O:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
To a solution of (S)-2-(3-benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid tert-butyl ester (4 g, 8.92 mmol) in a mixture of MeOH (40 mL) and EtOAc (10 mL) was added 10% Pd/C (500 mg). The mixture was degassed and stirred at room temperature for 4 hours under an atmosphere of hydrogen (balloon pressure). The reaction mixture was filtered through a short pad of celite which was then flushed with MeOH. The combined filtrates were evaporated under reduced pressure to afford the title compound as a white solid (2.6 g, 92%); 1H NMR (400 MHz, CDCl3) δ 1.48 (9H, s), 3.32 (1H, dd), 3.52 (1H, dd), 3.95 (2H, br s), 5.55 (1H, dd), 6.00 (1H, t), 6.55 (1H, d), 6.72 (1H, d), 7.18-7.35 (5H, m).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1>>[CH2:35]([O:34][C:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)=[O:33])[CH3:36]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(N/C(CC)=C2\C(=O)Nc3cc(OC)c(OC)cc32)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and ethyl 4-aminophenylacetate
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:13][CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]=[CH:8]2)#[N:2].[OH-:37].[Na+].OO>CS(C)=O>[F:27][C:26]([F:29])([F:28])[O:25][C:22]1[CH:21]=[CH:20][C:19]([CH:18]2[CH2:17][NH:16][CH2:15][CH:14]2[NH:13][C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:12]3[C:7]=2[CH:8]=[N:9][CH:10]=[N:11]3)=[CH:24][CH:23]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc(C#N)c3ncncc23)C(c2ccc(OC(F)(F)F)cc2)C1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(NC2CNCC2c2ccc(OC(F)(F)F)cc2)c2cncnc12
Yield: 69.5 %

Procedure:
Tert-butyl 3-(8-Cyano-quinazolin-5-ylamino)-4-(4-trifluoromethoxy-phenyl)-pyrrolidine-1-carboxylate (100.00 mg; 0.20 mmol; 1.00 eq.) was stirred with aqueous 2.0M NaOH (1 ml; 2.00 mmol; 10.00 eq.) and aqueous 35% H2O2 (0.19 ml; 2.00 mmol; 10.00 eq.) in DMSO (8 ml) at 40° C. overnight. The crude was purified by pre-HPLC to yield the title compound (58 mg, 56.0%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1cccnc1
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: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cccnc1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3-pyridylboronic acid (0.153 g) in ethanol (1 ml). The mixture was heated under reflux for 5 hours, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:methanol (100:1). Combination and evaporation of suitable fractions followed by recrystallisation from ether gave the title compound as an off-white solid, m.p. 265-7° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)[C:16]1=[O:27]>CC(C)=O.[I-].[Cs+]>[CH3:26][O:25][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][CH2:24][CH:15]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]2=[O:27])=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)C(=O)C(Br)CC2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(=O)C(Oc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
A mixture of 2.95 g (31.4 mmol) of phenol, 25.5 g (78.2 mmol) of cesium carbonate and 320 mg (1.23 mmol) of cesium iodide in 64 ml of acetone was heated at reflux for 40 minutes and then cooled to 0° C. To this 0° C. mixture was added 8.00 g (31.4 mmol) of 2-bromo-3,4-dihydro-7-methoxy-1(2H)-naphthalenone. The resultant reaction mixture was stirred 3 hours at 0° C. and 15 hours at 25° C., then filtrated. The filtrate was evaporated to an oil which was purified via column chromatography on 400 g of silica gel, eluting with 25% ether-hexane, to give 5.14 g (61%) of present title product as an oil, crystallized from ether-hexane, m.p. 94.5-96.5° C.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[C:21]([O:23][CH3:24])=[O:22]>CO.O>[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C@@H:8]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.9 %

Procedure:
0.15 g of sodium borohydride was added in one portion, at a temperature in the region of 20° C. and under an inert atmosphere, to a stirred solution of 1.6 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]-piperidine-3-carboxylate in 15 cm3 of methanol. The mixture was subsequently stirred for 2.5 hours at a temperature in the region of 25° C. 15 cm3 of distilled water were then added dropwise over approximately 10 minutes while maintaining at a temperature in the region of 15° C. The mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 20 cm3 of distilled water. The mixture was extracted with a total of 100 cm3 of dichloromethane. The organic phases were combined, dried over sodium sulfate, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The solid obtained was purified by chromatography under argon pressure (50 kPa) on a column of silica gel (particle size 20-45 μm; diameter 3 cm; height 35 cm), elution was carried out with a mixture of ethyl acetate and cyclohexane (8/2 by volume), and 15-cm3 fractions were collected. Fractions 38 to 59 were combined and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.3 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylate were thus obtained in the form of a foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C@@H:10]([NH:15]C(OC(C)(C)C)=O)[C:11]([CH3:14])([CH3:13])[CH3:12].FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C@@H:10]([NH2:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccn1)C(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](N)C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 2-pyridylmethylamide (16 g, 50 mmol) in dichloromethane (25 mL) cooled at 0° C. is added trifluoroacetic acid (150 mL). The resulting solution is allowed to warm to 25° C. and is stirred for 18 h. The reaction mixture is diluted with toluene, concentrated, brought to pH=10 with 2 M sodium hydroxide, and extracted with 3:1 dichloromethane/isopropanol (200 mL). The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2S)-2-Amino-3,3-dimethylbutanoic acid 2-pyridylmethylamide (11 g, 100% yield) as a white solid.
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:19])=[C:16]([CH2:17][OH:18])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@H:6]([O:25]C(=O)C(C)(C)C)[C@H:5]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>NC(O)C>[OH:18][CH2:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C@H:6]([OH:25])[C@@H:5]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:19]
Reactant: COCCO[C@@H]1c2ccn3c(CO)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Agent: CC(N)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCO[C@@H]1c2ccn3c(CO)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of 0.60 g (1.10 mmol) of (7R,8R,9R)-10-acetyl-3-hydroxymethyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine and 0.30 g (2.10 mmol) potassium carbonate in aminoethanol is stirred at 90° C. for 2 h. The reaction is quenched by adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (dichloromethane/methanol: 13/1) to give 0.20 g (0.52 mmol/47%) of the title compound as a colourless solid with a melting point of 180-183° C. (diethyl ether).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]([C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][N:16](C)[CH2:17]C=C)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]>ClCCl.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>[F:38][C:2]([F:1])([F:37])[C:3]([C:12]1[CH:13]=[C:14]([CH2:15][NH:16][CH3:17])[CH:21]=[CH:22][C:23]=1[Sn:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: C=CCN(C)Cc1ccc([Sn](CCCC)(CCCC)CCCC)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 35 °C
Yield: 78.5 %

Procedure:
Compound 13 (270 mg, 409 μmol) was dissolved in dichloromethane (5 mL) and the solution was degassed by nitrogen bubbling over 15 min. The solution was then added to N,N-dimethylbarbituric acid (191 mg, 1.23 mmol) and Tetrakis(triphenylphosphine)palladium(0) (19 mg 16.4 μmol) placed in a two necked flask under nitrogen atmosphere and the resulting mixture was warmed 4 h at 35° C. The solvent was removed under vacuum, the residue dissolved in diethylether (10 mL), and washed with a 0.1M sodium carbonate solution (2×5 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified over silica gel using chloroform/methanol (9/1) to give 199 mg (321 μmol, 78% yield) of a yellowish oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])[NH2:23])=[C:13]([CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:12]=1[OH:37])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])=[C:13]([CH2:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:12]=1[OH:37])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Br)c(CCC(F)(F)F)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.36 ml (3.57 mmol) of methyl chlorooxalate in 5 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 1.75 g (3.57 mmol) of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-aniline (Example 1) and 0.55 ml (3.57 mmol) of triethylamine in 15 ml of methylene chloride in the course of 5 minutes. The reaction mixture is subsequently stirred at room temperature for 90 minutes and poured onto ice-water and the organic phase is separated off. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate of melting point 139°-140°.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:18]2=[S:19])[CH:16]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C)C1=S
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methylphenyl-isothiocyanate (9.18 g), triethyl amine (12 g) and chloroform (200 mL) was heated at reflux for 5 hours. The mixture was cooled to ambient temperature, washed with 1N HCl (2×200 mL), then with water (200 mL) The organic phase was evaporated to dryness. The residue was crystallized from ethanol to give the title compound (9.2 g) as a tan solid, m.p. 132°-134° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N, 11.00. Found: C, 51.79; H, 4.12; N, 10.73. Mass spectrum (El, M.+) m/z 254/256.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH3:25])=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:10]([CH3:25])=[C:9]1[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc3c(c2)c(C)c(C)n3Cc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 1-benzyl-5-(4-methoxy-phenyl)-2,3-dimethyl-1H-indole (0.925 g, 2.709 mmol) was reacted with BBr3 (3.3 ml of a 1M solution in CH2Cl2) to give the product (0.608 g, 1.857 mmol, 69%) as a brown glass. 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 2.27 (s, 3H), 5.38 (s, 2H), 6.81 (d, J=8.4 Hz, 2H), 6.98 (d, J=7.5 Hz, 2H), 7.19-7.23 (m, 2H), 7.27 (t, J=7.3 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.57 (s, 1H), 9.32 (s, 1H); [ESI(+)], m/z 328 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](O)(=O)[CH:12]([CH3:14])[OH:13].Cl.[OH-].[NH4+]>>[OH:13][CH:12]([C:14]1[NH:1][C:2]2[C:3]([O:9][CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1)[CH3:11]
Reactant: CC(O)C(=O)O
Reactant: COc1cccc(N)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cccc2nc(C(C)O)[nH]c12
Temperature: 100 °C

Procedure:
2,3-Diaminoanisole (5.88 g) and lactic acid (5.6 ml) were combined, treated with concentrated hydrochloric acid (45 ml) and heated at 100° C. for 18 h. The reaction was cooled to 0° C., neutralised with ammonium hydroxide solution and extracted with ethyl acetate (3×45 ml). The combined organic layers were dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo and the residue purified by flash chromatography on silica eluting with ethyl acetate to yield the desired product as a reddish-brown solid (4.91 g).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:15])[C:5]1[CH:14]=[CH:13][C:8]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].[Br:21]Br>C(O)(=O)C>[ClH:1].[ClH:1].[Br:21][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[N:4]([CH3:3])[CH3:15])[CH2:9][CH:10]([NH2:12])[CH3:11]
Reactant: BrBr
Reactant: CC(N)Cc1ccc(N(C)C)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(N)Cc1ccc(N(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.51 g of 4-dimethylamino-α-methylphenethylamine dihydrochloride and 5.0 g of anhydrous sodium acetate in 50 ml of acetic acid is added dropwise with stirring a solution of 0.51 ml of bromine in 50 ml of acetic acid. The mixture is stirred at room temperature for 2 hours. The solvent is evaporated and the residue dissolved in 200 ml of water. The solution is alkalized with sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous sodium sulphate and acidified with hydrogen chloride in ether. The precipitate is filtered off and recrystallized from ethanol-ethyl acetate. Yield: 2.3 g, m.p. 190°-191°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28])[CH:20](O)[C:21](O)=[O:22]>C(O)(=O)C.CS(O)(=O)=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:20]2[C:7]3[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=3[O:15][C:21]2=[O:22])[CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28]
Reactant: Cc1cc(C(O)C(=O)O)cc(C)c1O
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1O
Temperature: 95 °C
Reaction time: 0.07 h
Yield: 88.1 %

Procedure:
1.5 ml (23 mmol) of methanesulfonic acid are added to a mixture of 154.8 g (0.75 mol) of 2,4-di-tert-butylphenol and 98.1 g (0.50 mol) of 3,5-dimethyl-4-hydroxymandelic acid in 500 ml of acetic acid which is stirred at 95° C. under nitrogen. After about 4 minutes, crystallisation of the product in the form of fine, white crystals begins. The reaction mixture is refluxed for another hour, then cooled to about 15° C., and the precipitated product is filtered off. The residue is washed with 250 ml of acetic acid and with 1500 ml of water. Drying gives 161.5 g (88%) of 3-(3,5-dimethyl-4-hydroxyphenyl)-5,7-di-tert-butylbenzofuran-2-one, melting point 225°-228° C. (compound (107), Table 1).