Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[NH:20][C:21](=[O:51])[CH2:22][N:23]1[C:28](=[O:29])[C:27]3([CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30]3)[N:26](C(OC(C)(C)C)=O)[CH2:25][C@H:24]1[C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[NH:20][C:21](=[O:51])[CH2:22][N:23]1[C:28](=[O:29])[C:27]3([CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30]3)[NH:26][CH2:25][C@H:24]1[C:43]1[CH:44]=[C:45]([F:50])[CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2cc3c(cc2Cl)CC2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Agent: Cl
Product: O=C(CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1)Nc1cc2c(cc1Cl)CC1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
40 mg (0.06 mmol) (3R)-tert-butyl 4-(2-(5-chloro-2′-oxo-1,1′,2′,3-tetrahydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-6-ylamino)-2-oxoethyl)-3-(3,5-difluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate were combined with 30 ml of a 1N methanolic hydrochloric acid solution and stirred for 1 h at 50° C. The reaction mixture was concentrated by rotary evaporation. The residue was taken up in water and adjusted to pH=8 with saturated NaHCO3 solution. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1(C)C=CC=CC=1.CCO.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>[CH3:12][C:9]1[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc(C)ccc1I
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)c1cc(C)ccc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
Pd(PPh3)4 (523 mg, 0.45 mmol) was added to a rt solution of methyl 2-iodo-5-methylbenzoate in toluene (23 mL). After the solution was stirred for 10 min, a solution of phenylboronic acid (1.24 g, 9.96 mmol) in EtOH (10 mL) was added, followed by 2M aq. Na2CO3 (21 mL). The mixture was vigorously stirred and heated to reflux for 24 h. The rxn mixture was allowed to reach rt, then Et2O was added and the org. layer was separated and concentrated in vacuo. Purification by FC (Biotage SP1: EtOAc/hept eluting with a gradient of 0-10% EtOAc) was performed to give methyl 4-methyl-[1,1′-biphenyl]-2-carboxylate as a colorless oil. LC-MS A: tR=0.94 min; [M+H]+=227.16.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:16][C:17]#[CH:18])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 96 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 26 mg of 2-propyn-1-ol, to which 19 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 42 mg of 4-(2,3-difluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (82)).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:6][C:5]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:24][C@H:21]([CH2:22][CH3:23])[C:19]([NH:18][C:15]1[CH:16]=[N:17][C:12]([O:11][C:7]2[C:5]3[CH2:6][C:2]([CH3:1])([CH3:32])[O:3][C:4]=3[CH:10]=[CH:9][CH:8]=2)=[CH:13][CH:14]=1)=[O:20]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2CC(C)(C)O3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2CC(C)(C)O3)nc1
Reaction time: 4 h
Yield: 91.5 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[6-[(2,2-dimethyl-3H-benzofuran-4-yl)oxy]-3-pyridyl]carbamoyl]propyl]carbamate (Intermediate 208, 14 mg, 0.032 mmol) in dry dichloromethane (1 ml) at 0° C., TFA (98 μl, 1.268 mmol) was slowly added and the reaction mixture was stirred for 4 hours at the same temperature. Some more dichloromethane (4 ml) was added to the reaction mixture. An aqueous saturated aqueous solution of NaHCO3 was then added while the pH was allowed to reach ˜8. Two phases were separated and the aqueous one was further extracted with DCM (3×3 ml). Combined organic layers were dried over Na2SO4, filtrated and evaporated affording the title compound (10 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]1([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].O>CN1CCCC1=O.[Cu]>[C:4]1([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:1][CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCI
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN(c1ccccc1)c1cccc2ccccc12
Yield: 98 %

Procedure:
A mixture of ethyl iodide (0.1M), 1-phenylaminonaphthalene (0.05M), KOH (0.1M) and copper bronze (1 g) was stirred for 31/2 hours in N-methylpyrrolidone (20 cm3) at 120° C. under an atmosphere of nitrogen. The mixture was cooled, poured into water (2 liters) and extracted with CH2Cl2 (3×300 cm3). The combined extracts were washed with water, dried over MgSO4 and the CH2Cl2 solvent removed in vacuo to give 229 g (98% yield) of 1-(N-phenyl-N-ethylamino)naphthalene as a yellow liquid.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].C(O)(=[O:23])C.OO>C(Cl)Cl>[C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:23])=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(=O)O
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Agent: OO
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 51.6 g (0.178 mol) of 2-propionyl-3-hydroxy-5-(4-methylthiophenyl)cyclohex-2-en-1-one (prepared as in U.S. Pat. No. 4,555,263) in 150 mL of methylene chloride and 150 mL of glacial acetic acid was added 20.15 g (0.178 mol) of 30 percent hydrogen peroxide dropwise over 20 minutes. The reaction temperature rose 20° to 28° C. at which point, the reaction mixture was cooled in a cold water bath. After 20 minutes, an additional 6.75 g (0.0595 mol) of 30 percent hydrogen peroxide was added dropwise and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with 150 mL of methylene chloride, washed thrice with 250 mL portions of water and then with 200 mL of aqueous sodium bicarbonate. The organic layer was separated and dried over Na2SO4 and the solvent removed in vacuo leaving 51.6 g (94.8 percent of theoretical) of the above named product melting at 111°-117° C. Recrystallization of the residue from 2-propanol gave the pure product in a yield of 46.1 g (84.7 percent of theoretical). The product melted at 116°-117° C.; Rf -0.07 (silica gel, 50:50 ethyl acetatehexane and 1.0 percent acetic acid), 1H NMR (CDCl3): δ1.1 (t, 3H, --CH2CH3), 2.70 (s, 3H, CH3SO--), 2.7-3.7 (m, 7H, ring protons and --CH2CH3), 7.25-7.70 (m, 4H, ArH), 18.1 (s, 1H, OH).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]=[C:7]([N:19]([CH3:21])[CH3:20])[N:6]=1>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]2[N:8]=[C:7]([N:19]([CH3:21])[CH3:20])[N:6]=[C:5]([C:1]#[N:2])[N:10]=2)=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: CN(C)c1nc(Cl)nc(Nc2ccc(Cl)cc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(C#N)nc(Nc2ccc(Cl)cc2)n1
Temperature: 90 °C

Procedure:
Sodium cyanide (0.138 g) was added to a solution of the product from step (ii) (0.4 g) in N,N-dimethylformamide (20 ml) and heated at 90° C. for 16 h. The mixture was partitioned between ethyl acetate and water, a solid formed which was filtered off and purified by RPHPLC 15–85% acetonitrile in aqueous trifluoroacetic acid. Yield 0.05 g
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.[N+]([O-])(O)=O.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>CC(O)C>[F:19][C:20]([F:31])([F:32])[C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:30]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: FC(F)(F)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
150 mg (0.71 mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one are suspended in 1.5 ml of 2-propanol. 190 mg (0.712 mmol) of 3-trifluoromethylphenyl-guanidine nitrate and 31 mg (0.783 mmol) of sodium hydroxide are added and the reaction mixture is stirred for 18 h under RF. It is then cooled to RT and filtered, and the material retained on the filter is washed with 2-propanol and water and dried at 50° under HV to give N-(3-trifluoromethyl-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine;
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:47](=[O:48])[N:6]2[C:7]([C:41]([O:43]CC=C)=[O:42])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][O:20][C:21](=[O:40])[C@H:22]([CH:37]([CH3:39])[CH3:38])[NH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].CC1(C)CC(=O)CC(=O)C1.C(OCC)(=O)C.Cl>O1CCCC1.[Cl-].[Na+].O>[OH:1][C@@H:2]([C@H:4]1[C:47](=[O:48])[N:6]2[C:7]([C:41]([OH:43])=[O:42])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][O:20][C:21](=[O:40])[C@H:22]([CH:37]([CH3:39])[CH3:38])[NH:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C=CCOC(=O)C1=C(S/C=C\c2scnc2COC(=O)[C@@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C(C)C)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OCc1ncsc1/C=C\SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Allyl (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[[(Z)-2-(4-(N-4-nitrobenzyloxycarbonyl-L-valinyloxy-methyl)thiazol-5-yl)ethen-1-yl]thio]-1-carbapen-2-em-3-carboxylate (500 mg) and 250 mg of dimedone were dissolved in 10 ml of tetrahydrofuran. Tetrakistriphenylphosphine palladium (82 mg) was added to the solution, and the mixture was stirred under an argon atmosphere at room temperature for 30 min. The reaction mixture was poured into 50 ml of 20% brine and 50 ml of ethyl acetate, and the mixture was adjusted to pH 0.6 by the addition of a 1 N aqueous hydrochloric acid solution, followed by separation. The organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 317 mg of (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[[(Z)-2-(4-(N-4-nitrobenzyloxycarbonyl-L-valyloxymethyl)thiazol-5-yl)ethen-1-yl]thio]-1-carbapen-2-em-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(N(CC)CC)C.Cl.Cl[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>CCO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(N[C@@H](COCC1CCN(c2ccncc2)CC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Temperature: 120 °C

Procedure:
To a suspension of 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (1.0 g, 2.2 mmol) in 20 mL of EtOH was added triethylamine (1.56 mL, 11 mmol) and 4-chloropyridine hydrochloride (336 mg, 2.2 mmol). Heating the mixture at 120° C. in a sealed tube afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 185 mg (16%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH:17]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[O:15]C2=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(CC)CC.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].O[CH2:48][C:49]1[N:50](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:51]=[CH:52][N:53]=1.[H-].[Na+]>C(Cl)Cl.O.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:17][CH:16]([OH:15])[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][O:27][CH2:48][C:49]3[NH:50][CH:51]=[CH:52][N:53]=3)=[CH:24][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCn2cc(COc3ccc(CO)cc3)oc2=O)cc1OC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CCNCC(O)COc2ccc(COCc3ncc[nH]3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Compound XXXI (2.71 g, 0.007 mL) was dissolved in CH2Cl2 (25 mL), cooled and Et3N (0.78 g, 0.0077 mol) added. To the cooled solution, methanesulfonyl chloride (0.88 g, 0.0077 mol) in CH2Cl2 (2 mL) was added and stirred at room temperature. After 3 hours another portion of methanesulfonylchloride (0.09 g, 0.007 mol) was added. After 1 hour, the reaction was poured in H2O (25 mL) containing K2CO3 (1 g) and the organic extracted with CH2Cl2 (3X). The aqueous extracts were washed with H2O, 0.5N, HCl, H2O, dried, filtered and concentrated to dryness. The residue was dissolved in dry DMSO (20 mL) and added with stirring at room temperature to a solution of XXX (1.7 g, 0.005 mol) and NaH (60% oil dispersion, 0.22 g, 0.0055 mol) in DMSO (20 mL). After 2 hours, another portion of NaH (0.2 g) was added and stirred at room temperature for an additional 2 hours. The solution was then poured in H2O and the aqueous extracted with EtOAc (2X). The organic extracts were dried, filtered and concentrated to dryness. The residue was treated with CH3OH (25 mL) and 40% NaOH (6 mL) and the solution heated at reflux. After 2 hours, the solution was poured into H2O. The aqueous layer was extracted with CHCl3 (3X) and the organic extracts dried, filtered and concentrated to dryness. The residue was treated with CH3OH (50 mL) and HOAc (2.5 mL) and heated at reflux for 2 hours. The reaction was then concentrated to dryness, 0.1N HCl (75 mL) added, the aqueous extracted with CHCl3 (3X) and the organic extracts discarded. The aqueous solution was basified to pH 10 with saturated Na2CO3 and extracted with CHCl3 (2X). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel eluting with CHCl3 saturated with NH3 and CHCl3 --CH3OH--NH4OH (70:5:0.5 to 90:10:1) to yield XXXII; 13% yield.
Reaction SMILES: [OH:1][C:2]1([C:12]([F:21])([F:20])[C:13](O)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:6][CH:5]([C:8](OC)=[O:9])[CH2:4][CH2:3]1.O>C1(C)C=CC=CC=1>[OH:1][C:2]1([C:12]([F:20])([F:21])[CH:13]([OH:18])[C:14]([F:15])([F:16])[F:17])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CCC(O)(C(F)(F)C(O)(O)C(F)(F)F)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1CCC(O)(C(F)(F)C(O)C(F)(F)F)CC1
Reaction time: 18 h
Yield: 80.3 %

Procedure:
In 300 ml of toluene was dissolved 30.0 g of methyl 4-hydroxy-4-(2,2-dihydroxy-1,1,3,3,3-pentafluoropropyl)-cyclohexanecarboxylate obtained in <6-1>. The solution was stirred and heated under reflux while the water formed was continuously removed. Under nitrogen atmosphere and with stirring, this solution was added dropwise to a solution of 5.0 g lithium aluminum hydride in 100 ml tetrahydrofuran. The mixture was stirred at 5° C. for one hour and then at room temperature for 18 hours. The reaction mixture was combined with 500 ml of 10% hydrochloric acid and extracted with ethyl acetate. Through conventional work-up including washing, drying and concentration, a crude product was obtained. Recrystallization from n-hexane gave 20.8 g (yield 80%) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:13])[CH3:12])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccccc1N
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 4 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To 1-(2-amino-phenyl)-ethanone 2 (90.37 g, 0.67 moles) was added acetic anhydride (68.25 g, 0.67 moles) and stirred for 2 h at 4° C. The reaction mixture was poured into crushed ice and the precipitate was filtered, washed with ice water, and air-dried to afford N-(2-acetyl-phenyl)-acetamide 3 (104.70 g, 88% yield). 1HNMR (400 MHz, DMSO-d6) δ2.10 (s, 3H), 2.60 (s, 3H), 7.17-7.21 (m, 1H), 7.55-7.59 (m, 1H), 7.95 (d, 1H, J=8.0 Hz), 8.26 (d, 1H, J=8.0 Hz), 11.16 (s 1H); MS m/z 17 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].I[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:11]=[CH:10]2)=[O:4]
Reactant: CC(C)CI
Reactant: COC(=O)c1cc(Br)cc2cn[nH]c12
Product: COC(=O)c1cc(Br)cc2cnn(CC(C)C)c12
Yield: 70 %

Procedure:
Compound 10 was prepared following general method 1, using 5-bromo-1H-indazole-7-carboxylic acid methyl ester as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 70%.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+]>C(O)C.O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:18]/[OH:19])/[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: O/N=C1\CCOc2ccccc21
Temperature: 70 °C
Yield: 97.5 %

Procedure:
To a solution of 2,3-dihydro-4H-chromen-4-one (3.00 g) in ethanol (15 ml)/water (3 ml) was added sodium acetate (6.64 g) and hydroxylamine hydrochloride (5.52 g). The reaction mixture was heated at 70° C. for 1 h, poured into saturated sodium bicarbonate (50 ml), extracted methylene chloride (3×50 ml), dried MgSO4, filtered and concentrated to provide the title compound as a solid (3.22 g, 99%): 1H NMR (300 MHz, CDCl3) δ) 7.86, 7.28, 7.00–6.91, 4.27, 3.02; HRMS (FAB) calcd for C9H9NO2+H 164.0712, found 164.0703. Anal. Calcd for C9H9NO2: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.21; H, 5.58; N, 8.57.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=3[O:18][CH3:19])[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(O)CCC3)=NC=2)=C2C=C(C3C=NN(CCN4CCOCC4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1>>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([O:39][CH2:40][O:41][CH3:42])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=3[O:18][CH3:19])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(N)cc3OC)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cc1ccc(S(=O)(=O)n2c(-c3cnn(CCN4CCOCC4)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(N)cc5OC)cc34)s2)CCC1

Procedure:
The title compound was prepared as described in Example 1I, 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methoxyaniline (Example 68B) for 1-(5-(5-chloro-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 1H). MS ESI(+) m/z 471.0 [M+H]+.