Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[NH2:46][C:47]1[S:48][C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:46][C:47]2[S:48][C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=2)=[O:44])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C(F)(F)F)s4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (68 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the react-ion solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 70 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4](Cl)=[CH:5][C:6]=1[CH3:7].C[O:10]C(Cl)Cl.[CH2:14]([Cl:16])Cl>>[Cl:1][C:2]1[S:3][C:14]([Cl:16])=[C:5]([CH3:4])[C:6]=1[CH:7]=[O:10]
Reactant: ClCCl
Reactant: Cc1cc(Cl)sc1Cl
Reactant: COC(Cl)Cl
Product: Cc1c(Cl)sc(Cl)c1C=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,5-dichloro-3-methylthiophene [prepared according to the method of J. Amer. Chim. Soc., 1971, 333.] (11.8 g) in CH2Cl2 (200 mL) was added TiCL1 (37.94 g) and dichloromethyl methyl ether (12.6 g) at -10° C. After stirring for 4 hours, the reaction mixture was poured into ice-water and the whole was stirred vigorously for 30 minutes. The resulting mixture was extracted with CH2Cl2 (200 ml×1), and the organic layers was washed with saturated NaHCO3 solution(100 mL×1), brine (100 mL×1), dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by distillation (bp : 140-145° C./10 mmHg) to provide the subtitle compound (11.75 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:22][C:23](=[O:25])[CH3:24])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>>[CH2:28]([O:27][P:26]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:22][C:23](=[O:25])[CH3:24])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:30][CH2:31][CH3:32])=[O:33])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccccc1CCBr)(NC(C)=O)C(=O)OCC
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)C(Cc1ccccc1CCP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Yield: 86 %

Procedure:
A solution of 5 g (1.2 mmol) of ethyl 3-[2-(2-bromoethyl)phenyl]-2-acetamido-2-carboethoxypropanoate in 10 mL of P(OEt)3 was stirred at reflux for 4 h. The excess P(OEt)3 and the volatile by-products were removed from the mixture by distillation under vacuum. The remaining viscous oil was initially purified by column chromatography (C-18, MeOH:H2O; 4:1), then by preparative HPLC (C-18, MeOH:H2O, 7:3) giving 0.48 g (86%) of the product as a clear viscous oil. IR(Nujol) 1745.9, 1676.5 cm-1 (C=O); 1H NMR(CDCl3) δ 1.1-1.5 (m, 12H); 1.8-3.1 (complex, m, 7H); 3.7 (s, 2H); 3.8-4.4 (m, 8H); 6.6 (s, 1H), 7.0-7.3 (m, 4H) Anal. Calcd. for C22H34NO8P: C, 56.04; H, 7.27; N, 2.97. Found: C, 55.91; H, 7.31, N, 2.84.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[S:16](Cl)(=[O:19])(=[O:18])[NH2:17].C(N(C(C)C)CC)(C)C>C(#N)C>[N:2]1[N:1]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][O:13][S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:15]=2)[CH:5]=[N:4][CH:3]=1
Reactant: OCCOc1ccc(-n2cncn2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)OCCOc1ccc(-n2cncn2)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of 8.2 g (0.04 mole) of 2-[4-(1H-1,2,4-triazol-1-yl)phenoxy]ethanol in 100 ml of acetonitrile was treated with a solution of 1.3 equivalents of sulfamoyl chloride in 19 ml of acetonitrile. One equivalent, 5.2 g (0.04 mole), of diisopropylethylamine was also added in one portion. The mixture was stirred for 2 hr. The precipitate was collected and partitioned between ethyl acetate and a dilute potassium carbonate solution. The organic layer was separated and concentrated to a white powder. The powder was triturated with ethyl ether, collected and dried to give 6.3 g (55%) of white powder, mp 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][O:11][CH3:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][O:11][CH3:12])[CH2:9][CH2:8][N:7]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:6]1)=[O:4]
Reactant: COCC1(C(=O)OC)CCNC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC1(C(=O)OC)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
To a stirred mixture of 3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (140 mg, 0.81 mmol), triethylamine (112 μl, 0.82 mmol) and cesium carbonate (263 mg, 0.81 mmol) in acetonitrile (2 ml) was added tert-butyl bromoacetate (119 μl, 0.81 mmol) slowly. The mixture was stirred for 15 minutes, filtered and concentrated. The residue was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate and hexanes (1:2) provided 118 mg (51%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:38])([F:39])([F:35])([F:36])[F:37])[CH:33]=1)[C:28]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:2]=1[CH3:1])=[O:29])#[N:24]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1c(N)cccc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cccc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
100 mg (0.346 mmol) of the compound of Example 69A and 111 mg (0.346 mmol, 85% pure) of the compound from Example 23A were dissolved in 1.9 ml of anhydrous DMF and 158 mg (0.415 mmol) of HATU and 72 μl (0.415 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT overnight (about 15 h) and then stirred into about 10 ml of water. The resulting precipitate was filtered off with suction, dissolved in dichloromethane and washed successively with semisaturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, filtration and removal of the solvent on a rotary evaporator, the residue obtained in this manner was purified by preparative HPLC (Method 33). After evaporation of the product fractions, the solid was re-dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution to convert the product into the form of the free base. After drying of the organic phase over anhydrous magnesium sulphate, filtration and evaporation, the product was finally triturated with 3 ml of pentane to which a few drops of diisopropyl ether had been added. Filtration with suction and drying of the solid under high vacuum gave 66 mg (35% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].[C:15]1([CH2:21][CH2:22]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:22][CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1ccc(=O)n2CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (7.5 g), lithium hydride (0.59 g), and dimethylformamide (300 ml) was stirred for 3 hrs at 25° C., under nitrogen. 2-Phenylethyl bromide (9.36 g) was added and the mixture was stirred for an additional eighteen hrs. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with petroleum ether to afford 3.0 g (24%) of 5,6,7,8-tetrahydro-5-oxo-1-(2-phenylethyl)-2(1H)-quinolinone.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([Cl:21])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:22].[Na+]>CC(C)=O>[I:22][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([Cl:21])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 37.3 g. (0.1 moles) of ethyl α-bromo-β-(3-chloro-4-cyclohexylphenyl)propionate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-β-(3-chloro-4-cyclohexylphenyl)propionate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH:1][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[Cl:30])(=[O:39])=[O:38])[CH2:10]3)[CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=S(=O)(N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
(R)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.064 mmol, 20 mg) was dissolved in tetrahydrofuran (1 mL) and triethylamine (0.128 mmol, 17.8 μL) followed by 2-chlorobenzenesulfonyl chloride (0.064 mmol, 13.6 mg) and the solution stirred at room temperature overnight. The reaction was concentrated to dryness to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give the title compound (9.8 mg, 0.02 mmol, 31.5%) MS (ESI): m/z [M−H]− 484.4.
Reaction SMILES: Br[C:2]1[C:3](=[O:27])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:5]=2.[CH3:28][N:29](C)C=O>[Cu+]>[O:27]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[C:28]#[N:29]
Reactant: CN(C)C=O
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Agent: [Cu+]
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2-Bromo-3-phenyl-6-(3-phenyl-propoxy)-indene-1-one (1.0 g, 2.3 mmol) obtained in Step 2 was dissolved in N,N-dimethyl formamide (10 mL), copper(I) cyamide (617 mg, 6.9 mmol) was added thereto, and the mixture was stirred for 3 hrs at 150° C., followed by cooling. The resulting mixture was washed with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate:hexane=1:3) to obtain 700 mg of the titled compound (yield: 80%) as a red solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[C:20]([O-:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.O1CC[CH2:31][CH2:30]1>CS(C)=O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:30]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([OH:28])=[O:27])=[CH:22][N:23]=3)[CH3:31])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C([O-])c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4′-(trifluoromethyl)biphenyl-4-ol (263 mg, 1.1 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (44.2 mg, 60 wt % in mineral oil, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. A solution of the crude methyl 641-(methylsulfonyloxy)ethyl)nicotinate prepared above in DMSO (6 mL) was added. The mixture was heated to 60° C. for 48 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(1-(4′-(trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinic acid (60 mg). 1H NMR (400 MHz, CD3OD, δ): 8.98 (m, 1H), 8.19-8.21 (m, 1H), 7.54-7.61 (m, 4H), 7.42-7.44 (m, 3H), 6.86-6.89 (m, 1H), 5.42-4.43 (q, 1H), 1.58 (d, 9H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22](N)=[CH:21][CH:20]=3)([CH3:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:30].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>O.CC(C)=O>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:33][CH:32]([Cl:30])[C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21][CH:20]=3)([CH3:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)Oc1ccc2c(c1C)OC(C)(COc1ccc(N)cc1)CC2
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3ccc(OC(C)=O)c(C)c3O2)cc1

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 1.3 g of 7-acetoxy-2-(4-aminophenoxymethyl)-2,8-dimethylchroman (prepared as described in Preparation 40), 340 mg of sodium nitrite, 1.3 ml of concentrated aqueous hydrochloric acid, 4 ml of ethyl acrylate, 60 mg of cuprous oxide, 10 ml of acetone and 0.5 ml of water were reacted, to afford 1.0 g of the title compound as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[F:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([CH2:23][O:24][C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)=[N:20][C:19]=2[CH:32]=1.O>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([CH2:23][O:24][C:25]3[CH:31]=[CH:30][C:28]([NH:29][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:27][CH:26]=3)=[N:20][C:19]=2[CH:32]=1
Reactant: Nc1ccc(OCc2nc3cc(F)ccc3s2)cc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(OCc2nc3cc(F)ccc3s2)cc1
Reaction time: 1 h
Yield: 55 %

Procedure:
0.09 ml of triethylamine and 0.07 ml of butyryl chloride were added to a solution of 150.8 mg of 4-(5-fluorobenzothiazol-2-ylmethoxy)aniline [prepared as described in step (b) above] in 3 ml of methylene chloride cooled in an ice-water bath. The temperature of the resulting mixture was then elevated to room temperature and the mixture was stirred for 1 hour. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was recrystallized from a mixed solvent of methylene chloride and hexane to give 104.5 mg (yield 55%) of the title compound as a solid having a melting point of 201° to 202° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:7]=1)[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[3-(4-Bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.15 g, 0.35 mmol) and 2-pyrrolidinone (0.05 g, 0.53 mmol) were combined in 1,4-dioxane (10 mL). Sodium hydride (60% in mineral oil; 0.03 g, 0.7 mmol) was added, and the reaction was stirred at room temperature for 2 hours to give the title compound, which was used as a crude solution in the hydrolysis step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([O:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[OH:1])[S:10][C:11]=3[CH:17]=2)=[N:27][CH:28]=1
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: Clc1ncnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Oc3ncnc4ccccc34)cc2s1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.1 %

Procedure:
To a reaction mixture of 2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (15.1 mg, 0.057 mmol; see Example 3 above) in 0.4 mL of NMP was added cesium carbonate (47 mg, 0.143 mmol) and stirred for 1-3 min at room temperature. To this mixture was added 4-chloroquinazoline (18.8 mg, 0.114 mmol). The reaction mixture was stirred at room temperature for 5 hours or until done by LC. The crude reaction mixture was filtered, purified by preparative HPLC, freebased, concentrated under reduced pressure and lyophilized to give the title compound (7.4 mg) as a solid. ES/MS m/z 393.2 (MHS, Rt=2.10 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=1.[C:28]1([C@@H:34]([NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:27][C:23]1[N:22]=[C:21](/[CH:39]=[CH:38]/[C:37]([NH:36][C@H:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:35])=[O:40])[CH:26]=[CH:25][CH:24]=1
Reactant: C=CC(=O)N[C@@H](C)c1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)/C=C/c1cccc(Br)n1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To the solution of triphenylphosphine (0.496 mmol) in DMF (10 mL), a palladium acetate (0.245 mmol) was added at room temperature under argon atmosphere. The mixture was stirred for 5 min then 2,6-dibromopyridine (12.7 mmol) followed by N-((S)-1-phenylethyl)acrylamide (14.0 mmol) and triethylamine (35.9 mmol) were added and the reaction mixture was stirred at 140° C. for 7 hr. The majority of the solvent was removed under diminished pressure. Diluted HCl was added and the product was extracted with ethyl acetate. Organic layers were combined, washed with brine, dried over sodium sulfate. Drying agent and solvent was removed and product was purified by column chromatography using hexanes and hexanes:ethyl acetate 2:1 as eluents, to give pure product with a good yield.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9].[OH-].[Na+]>CC(C)=O>[CH3:7][C:8]1([CH3:10])[O:13][C@@H:12]([C@H:14]2[O:15][C@@H:7]3[O:6][C:14]([CH3:16])([CH3:12])[O:9][C@@H:8]3[C@H:16]2[OH:17])[CH2:10][O:11]1
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Reaction time: 24 h
Yield: 112.5 %

Procedure:
Sulfuric acid (40 ml) is added dropwise to a solution of α-D-glucose (41) (50 g. 0.28 mol) in acetone (1 l) at 0° C. The reaction mixture is stirred for 24 h and then it is neutralized using sodium hydroxide (6 M). The acetone is evaporated and the aqueous layer is extracted with chloroform (×2). The chloroform is dried (MgSO4) filtered and evaporated. Crystallization from cyclohexane yielded the di-isopropylidene glucose (42) (41 g. 57%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(=O)C.[Br:16]Br.C([O-])(O)=O.[Na+]>CCOCC>[Br:16][C:9]1[CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(O)c(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 4-(methylsulfonyl)phenol (5 g, 29.1 mmol) in ether (100 mL) at −15° C. was slowly added acetic acid (5 mL). To this cold solution was slowly added Br2 (5.1 g, 32.0 mmol) and the reaction was stirred at −10° C. for 1 h and then warmed to r.t. and stirred for further 10 h. After the reaction was completed, 100 mL of sat. NaHCO3 aq. was added and the mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, 2-bromo-4-(methylsulfonyl)phenol (3.2 g, 43.6%) was obtained as a white solid.
Reaction SMILES: C1C(O)=CC=CC=1C.C1C(O)=CC=C(C)C=1.C[O:18][CH3:19].[CH3:20][C:21]1[C:26](C)=[CH:25][CH:24]=[C:23]([CH3:28])[C:22]=1O>CO>[CH3:24][C:25]1[CH:26]=[C:21]([CH3:20])[CH:22]=[C:23]([CH3:28])[C:19]=1[OH:18]
Reactant: COC
Reactant: Cc1ccc(C)c(O)c1C
Agent: Cc1ccc(O)cc1
Solvent: Cc1cccc(O)c1
Solvent: CO
Product: Cc1cc(C)c(O)c(C)c1

Procedure:
methylating meta-cresol and para-cresol in the ortho position by reacting the meta-cresol and para-cresol with methanol, dimethyl ether or a mixture thereof at a temperature of 270° to 450° C., at a pressure of atmospheric to 100 bar and in the presence of a catalyst bed without a residence time of 0.01 to 10 seconds, whereby a mixture of 2,3,6-trimethylphenol and 2,4,6-trimethylphenol is produced;