Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:16]4[N:17]=[N:18][N:14]([CH2:13][C:12]5[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:27][CH:26]=5)[N:15]=4)[CH:20]=3)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: COc1ccc(Cn2nnc(-c3cccc(O)c3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.60 g, 1.83 mmol), 3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenol (0.38 g, 1.35 mmol) (from Example 26 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.41 g, 1.22 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 26%).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[C:18](OC(=O)C)(=[O:20])[CH3:19].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]#[N:19])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[C:18]#[N:19])[CH:12]=1
Reactant: N#CCc1cccnc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#CC(=Cc1ccc(Cl)cc1Cl)c1cccnc1
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a stirred solution of 2,4-dichlorobenzaldehyde (5.0 g, 29 mmole) and 3-pyridylacetonitrile (3.05 ml, 29 mmole) in 150 ml absolute ethanol were added 3.95 g K2CO3. After stirring for about 15 minutes, a white solid precipitated out of the reaction mixture. The reaction mixture was stirred overnight and filtered. The filter cake was washed with absolute ethanol and dissolve in CH2Cl2. The CH2Cl2 solution was filtered and concentrated in vacuo. The resulting white solid was recrystallized from 3:2 hexane/ethyl acetate to give 6.0 g (76%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH2:11]([S:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=O)[CH3:12].CCN=C=NCCCN(C)C.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:11][CH3:12])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)cc1N
Reactant: CCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 5-bromo-N2-methylpyridin-2,3-diamine (0.70 g), 2-ethylsulfanylbenzoic acid (0.66 g), WSC (0.80 g), HOBt (23 mg), and pyridine (20 ml) was stirred under reflux at 120° C. for 30 minutes. After the reaction mixture was allowed to stand overnight, the mixture was stirred under reflux at 120° C. for 9.5 hours again. Into the reaction mixture cooled to room temperature, water was poured under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with wafer and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. A mixture of the resulting residue and acetic anhydride (7 ml) was stirred under reflux at 140° C. for 1 hour. Aqueous sodium hydroxide solution was added to the reaction mixture cooled to room temperature to neutralize, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.60 g of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 42).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>C1COCC1>[Cl:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[OH:1])[O:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2cc(Cl)c(O)cc2O1
Reaction time: 40 h
Yield: 52 %

Procedure:
A solution of ethyl 7-hydroxychroman-2-carboxylate (5.0 g, 22.5 mmol) in THF is treated with N-chlorosuccinimide (NCS) (3.6 g, 27 mmol), stirred for 40 hr and concentrated in vacuo. The resultant residue is purified chromatographically (silica gel/20% EtOAc in hexanes as eluent) to give the title product, 3.0 g (52% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: Br[CH:2]1[C:11](=O)[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[S:34])=[CH:28][C:27]=2[O:36][CH3:37])[CH:25]=1>C(O)C.CCOC(C)=O>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]3[S:34][C:2]4[CH2:3][C:4]5([O:8][CH2:7][CH2:6][O:5]5)[CH2:9][CH:10]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[C:11]=4[N:35]=3)=[CH:28][C:27]=2[O:36][CH3:37])[CH:25]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Reactant: O=C1C(Br)CC2(CC1c1ccc(F)cc1)OCCO2
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CC2(CC3c3ccc(F)cc3)OCCO2)ccc1-n1cnc(Cl)c1
Yield: 57 %

Procedure:
A mixture of 7-bromo-9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-on (50 mg, 0.177 mmol, preparation AAC) and 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (91 mg, 0.276 mmol, from step 4 of preparation A) was heated in ethanol (0.25 mL) at 80° C. for 45 min. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (50% acetone/hexanes) to give 54 mg (57% yield) of the titled compound as a white solid. LC-MS (M+H)+ 513.2. 1H NMR (400 MHz, chloroform-d) δ ppm 7.49 (dd, J=11.21, 1.89 Hz, 2 H) 7.15-7.24 (m, 2 H) 7.08 (d, J=8.31 Hz, 1 H) 6.93-7.04 (m, 3 H) 6.58 (dd, J=8.56, 2.27 Hz, 1 H) 4.16-4.33 (m, 1H) 3.89-4.15 (m, 4H) 3.49 (s, 3 H) 3.13 (dd, J=16.37, 3.02 Hz, 1 H) 2.82-2.98 (m, 1H) 1.98-2.32 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:30])[CH:10]2[CH2:19][CH2:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[OH:22])=[CH:17][CH:16]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: BrCc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccccc3CBr)cc2)N1c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-hydroxyphenyl)-azetidin-2-one (11) was reacted with 1,2-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (15) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCCN1CCCC1
Product: Cc1ccccc1N1C(C)N(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=597.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([CH3:16])([CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:7][OH:8])=[O:4].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([NH:5][C:6]([CH3:16])([CH2:9][CH2:10][C:11]1[S:12][C:13]([Br:17])=[CH:14][CH:15]=1)[CH2:7][OH:8])=[O:4]
Reactant: COC(=O)NC(C)(CO)CCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(CO)CCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butan-1-ol (11.7 g, 48.0 mmol) obtained in Example 1(d) was dissolved in dimethylformamide (120 ml), and N-bromosuccinimide (10.8 g, 60.8 mmol) was added thereto in an ice bath followed by stirring for 4 hours at room temperature under a nitrogen atmosphere. The reaction mixture was poured into ice-cold 10% hydrochloric acid (300 ml), and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4:1-1:3); to afford the title compound (12.4 g, 80% yield) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:31]2[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:7]=1
Reactant: CCOC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Product: CCOC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cccc32)c1

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and ethyl 3-(4-amino-1H-indazol-1-yl)benzoate (Intermediate 6).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[CH:35]=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[C:35]([OH:6])=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C=O)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of sodium chlorite (1.19 g; 13.13 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.03 g; 8.59 mmol; 3.6 eq.) in water (7 mL) was added dropwise to a mixture of 2-methyl-2-butene (2.39 mL) and 3-(5-fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (705 mg; 2.39 mmol; 1 eq.) in 1,4-dioxane (7 mL). The reaction mixture was stirred at room temperature for 16 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The precipitate was filtered off and dried to afford the title compound (625 mg, 84%) as a white solid. 1H NMR (CDCl3) δ 8.17 (dd, J=8.8, 6.7 Hz, 1H), 6.85 (ddd, J=8.9, 7.6, 2.3 Hz, 1H), 6.35 (dd, J=9.9, 2.3 Hz, 1H), 5.25-4.87 (m, 1H), 4.41 (ddd, J=10.1, 6.4, 1.2 Hz, 2H), 4.11 (ddd, J=10.0, 4.0, 1.1 Hz, 2H), 1.45 (s, 9H). HPLC (max plot) 96.4%; Rt 3.60 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18]>C(#N)C>[CH3:14][P:15]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])(=[O:19])[O:16][CH2:17][CH3:18]
Reactant: CCOP(C)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CC#N
Product: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-1,2-dinitrobenzene (3.31 mmol) and diethyl methylphosphonite (5.30 mmol) in 3 ml of acetonitrile is stirred at RT overnight. The mixture is then concentrated and the residue is purified by preparative TLC to yield ethyl P-methyl-2-nitro-5-chlorophenylphosphinate.
Reaction SMILES: CCCC[N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])(CCCC)CCCC.[F-].O1C2C=CC=CC=2C=C1[C:28]1[C:29](=[O:64])[NH:30][C:31](=[O:63])[C:32]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=1>C1COCC1>[OH:45][CH2:44][CH2:43][CH2:42][N:35]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:41]2[C:33]([C:32]2[C:31](=[O:63])[NH:30][C:29](=[O:64])[C:28]=2[C:16]2[CH:15]=[CH:14][NH:5][CH:17]=2)=[CH:34]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](OCCCn1cc(C2=C(c3cc4ccccc4o3)C(=O)NC2=O)c2cccnc21)(c1ccccc1)c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1cc[nH]c1
Yield: 84 %

Procedure:
TBAF (0.12 mL, 1 M solution in THF, 0.12 mmol) as added dropwise to a solution of 3-benzofuran-2-yl-4-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyrrole-2,5-dione Compound 16a (0.044 g, 0.06 mmol) in THF (1 mL) under nitrogen. After 18 hours the mixture was concentrated and purified by column chromatography (SiO2) to give Compound 24 (0.017 g, 84%) as an orange solid. 1H NMR (300 MHz, Acetone-d6) δ 10.47 (s, 1H), 9.57 (s, 1H), 8.3 (dd, J=4.7, 1.5 Hz, 1H), 7.9 (s, 1H), 7.56 (m, 1H), 7.49 (dd, J=7.9, 1.5 Hz, 1H), 7.01 (dd, J=7.9, 4.7 Hz, 1H), 6.75 (m, 1H), 6.22 (m, 1H), 4.55 (t, J=6.6 Hz, 2H), 4.02 (t, J=5.7 Hz, 1H), 3.56 (q, J=5.8 Hz, 2H), 2.11 (m, 2H); MS (ES) m/z: 388 (M+H+).
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:23][CH3:24])([CH3:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:24][O:23][C:17]([C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)([CH3:22])[C:18]([F:19])([F:20])[F:21]
Reactant: [H][H]
Reactant: COC(C)(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(C)(c1ccc(O)cc1)C(F)(F)F

Procedure:
At 50° C. and a hydrogen pressure of 5 bar, 24.5 g of 1-benzyloxy-4-(1-methoxy-1-methyl-2,2,2-trifluoroethyl)benzene in 150 ml of glacial acetic acid were hydrogenated in the presence of 1.4 g of palladium (10% on carbon). The catalyst was filtered off and the mixture was concentrated to give the title product as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CS(C)=O.Br[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[Br:25]>C1(C)C=CC=CC=1>[Br:25][C:24]([F:27])([F:26])[C:23]([F:29])([F:28])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[Br:25])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Reactant: FC(F)(Br)C(F)(F)Br
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC(=Cc1ccc(OC(F)(F)C(F)(F)Br)cc1)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Temperature: 24 °C
Yield: 42 %

Procedure:
4,4'-bis(hydroxy)-α-methylstilbene (100.0 g, 0.442 mole) is added to a 3 liter, 4 necked round bottomed flask along with DMSO (dimethylsulfoxide) (1150 ml) and toluene (350 ml). The resulting mixture is deoxygenated with nitrogen for 15 minutes, then KOH (58.4 g, 0.884 mole as 85 percent pellets, the remaining 15 percent being water) is added all at once. The mixture is stirred and heated to reflux, and water is removed azeotropically by distillation of the water/toluene azeotrope for a total of 10 hours. A Soxhlet extractor containing a drying bed of anhydrous Na2SO4 is placed on the reactor, and the toluene is refluxed through this drying bed to remove residual water. Toluene (260 ml) is removed by simple distillation, then the remaining mixture is cooled to 24° C. 1,2-Dibromotetrafluoroethane (276 g, 1.06 mole) is added slowly over 30 minutes, and the reaction mixture is stirred at 24° C. for 8 hours. After filtration and evaporation, the residue is flushed through a column of alumina using hexane as the eluent. Hexane is removed by evaporation, and the resulting residue weighs 109.4 g (0.19 mole) for an isolated yield of 42 percent.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([S:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:21].[CH3:22]O>>[ClH:21].[N:1]1[C:10]2[CH:9]([S:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:22])=[O:17])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccc(SC2CCCc3cccnc32)cc1
Agent: Cl
Product: COC(=O)c1ccc(SC2CCCc3cccnc32)cc1
Yield: 62 %

Procedure:
4.24 g (15 mmol) of 4-(5,6,7,8-tetrahydroquinoline-8-ylthio)-benzoic acid prepared by a method analogous to Example 1 were stirred in 30 ml of refluxing methanol saturated with hydrogen chloride for 2 hours and the solvent was then removed under reduced pressure. The residue was dissolved in iced water, made alkaline with sodium carbonate and extracted with ether. The residue obtained upon evaporation of the solvent was treated with ethereal hydrogen chloride to yield 2.9 g (62%) of methyl 4-(5,6,7,8-tetrahydroquinoline-8-ylthio)-benzoate hydrochloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])[CH2:3]1.[F:24][C:25]([F:35])([F:34])[C:26]1[N:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([NH:33][CH2:32][C:29]3[CH:30]=[N:31][C:26]([C:25]([F:35])([F:24])[F:34])=[CH:27][CH:28]=3)=[O:22])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:13]=2)=[O:7])[CH2:3]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)cc1
Reactant: NCc1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)cc(C(=O)N3CC(O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylic acid (80 mg, 0.26 mmol) in N,N-dimethylformamide (1.5 mL) were added C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (70 mg, 0.40 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.53 mmol), and N,N-diisopropylethylamine (200 pt, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[O:22]1[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]1>>[O:22]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:20][CH2:19][N:4]([C:5]3[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]4[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=4[C:15]=3[CH3:16])[CH2:3][CH2:2]2)=[N:23]1
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Reactant: Nc1ccon1
Product: Cc1c(C)c(N2CCN(c3ccon3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 8.8 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (165 mg, 0.50 mmol) synthesized in Reference Example 146 and isoxazol-3-amine (0.044 mL, 0.60 mmol), the reaction was carried out in the same manner as Example 117 to obtain 15 mg of the title compound as a colorless solid (yield 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:19]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (0.17 g, 0.6 mmol) (from Example 7b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 5 hours in a capped pressure tube. Mixture was then stirred at room temperature over night and then diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from ethyl acetate-hexanes to give rac-3-benzyl-6-chloro-3-(4-chloro-phenyl)-1,3-dihydro-indol-2-one as white plates. (Yield 0.16 g, 72.4%).