Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[F:53])(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[F:53])(=[O:43])=[O:44])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3c(F)cccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3c(F)cccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 96 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (white-yellow solid) in 96% yield.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[C:10]([N+:20]([O-:22])=[O:21])[CH:9]=2)=[N:6][NH:5][C:4](=[O:23])[CH2:3]1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:25][CH2:26][CH2:27][N:28]4[C:32](=[O:33])[C:31]5=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]5[C:29]4=[O:38])[CH2:16][CH2:15]3)=[C:10]([N+:20]([O-:22])=[O:21])[CH:9]=2)=[N:6][NH:5][C:4](=[O:23])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(CCCN3C(=O)c4ccccc4C3=O)CC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 3.16 g (10 mmol) of 5-methyl-6-[3-nitro-4-(1-piperazinyl)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 2.68 g (10 mmol) of N-(3-bromopropyl)-phthalimide, 1.38 g (10 mmol) of potassium carbonate and 50 ml of dimethyl formamide is stirred at 100° C. for 24 hours.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:4]=[CH:5][N:6]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[ClH:18].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: NCCON
Reactant: Cc1nccn1CCCC(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nccn1CCCC(=NOCCN)c1ccccc1
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A mixture of 4-(2-methyl-1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.35 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for four hrs. The solvent was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 3.1 g (66%) of product, mp 153°-155° C.
Reaction SMILES: C(O)(=O)C.[C:5]1(=[O:15])[O:10][C:8](=O)[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>O.C1CCCCC1>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([N:21]2[C:5](=[O:15])[C:6]3=[CH:14][CH:13]=[CH:12][CH:11]=[C:7]3[C:8]2=[O:10])[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
800 ml of glacial acetic acid are initially introduced into a three-necked flask provided with a thermometer, stirrer and water separator, and are warmed to 55° C. A mixture of 44.4 g (0.3 mol) of phthalic anhydride and 68.7 g (0.3 mol) of distilled 3,5-bis-trifluoromethylaniline is then added and the components are stirred vigorously. On warming to 108° C., a clear solution is obtained. This is kept under reflux at 117° C. for 21/2 hours and is then cooled. 100 ml of cyclohexane are added to the reaction mixture and the mixture is kept under reflux at 93° C. for 5 hours, during which the water of reaction can be removed in the water separator.
Reaction SMILES: O1CCOCC1.O.[CH:8]1(B(O)O)[CH2:10][CH2:9]1.Br[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N+:24]([O-:26])=[O:25])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>[CH:8]1([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[N+:24]([O-:26])=[O:25])[N:17]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)[N:16]=2)[CH2:10][CH2:9]1
Reactant: OB(O)C1CC1
Reactant: Cc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
A 250 mL round bottom flask was charged with 1,4-dioxane/H2O (150 mL/30 mL). The flask was cooled to 0° C. and vacuum was applied for 20 minutes. A 500 mL round bottom flask was charged with cyclopropylboronic acid (Preparation C, 15.90 g, 185.1 mmol), 3-bromo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (Preparation C, 25.71 g, 74.06 mmol), K2CO3 (40.94 g, 296.2 mmol), palladium acetate (0.4988 g, 2.222 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (2.278 g, 4.443 mmol). The flask was evacuated and back filled with nitrogen three times. The cold degassed dioxane/H2O mixture was added to the 500 mL flask, which was evacuated and back filled with argon 5 times. The reaction mixture was heated at reflux for 5 hours under argon. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite, and the filter pad was washed with H2O (100 mL) and EtOAc (300 mL). The aqueous layer with extracted with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The resulting solid was dissolved in DCM and washed with saturated NaHCO3 aqueous solution. The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give a dark colored residue, which was dissolved in DCM (30 mL) and silica gel (50 g) was added. The DCM was removed under reduced pressure. The crude product absorbed by silica gel was loaded onto a column of silica gel and the column was eluted with EtOAc/hexanes (1:1). The fractions containing product were concentrated under reduced pressure to provide the product (22.1 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].B(Br)(Br)Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 4 (416 mg, 1.23 mmol) in 15 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 6.13 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 60 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography through silica gel (3-10% MeOH/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C13H16N3O5S (M+H+). 326.0805. Found 326.0808.
Reaction SMILES: [CH2:1]1[C@@H:3]([NH2:4])[C@@H:2]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]([CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([O:17]CC)=O)=[C:12]=[O:13]>ClCCl>[CH2:20]([CH:14]1[NH:11][C:12](=[O:13])[N:4]([CH2:3][C:2]2([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:1][CH2:5][CH2:2][CH2:1][CH2:3]2)[C:15]1=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOC(=O)C(Cc1ccccc1)N=C=O
Solvent: ClCCl
Product: O=C1NC(Cc2ccccc2)C(=O)N1CC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A solution of compound 1 (0.255 g; 1.35 mmol) in anhydrous dichloromethane (8 mL) was treated with ethyl 2-isocyanato-3-phenylpropionate (0.325 g; 0.38 mmol) and stirred at room temperature overnight. The solvent was removed by evaporation, the residue was dissolved in ethanol (1 mL), 6N hydrochloric acid (0.5 mL) and water (0.5 mL) and the reaction mixture was heated to 50° C. After 3 h at 50° C., additional 6N hydrochloric acid (1 mL) was added and the reaction mixture was heated at 65° C. overnight. The reaction mixture was concentrated and the crude product was purified directly by column chromatography on silica gel using 1:1 ethyl acetate:hexane as the eluent to give 0.053 g of 5-Benzyl-3-(1-phenyl-cyclohexylmethyl)-imidazolidine-2,4-dione as a white solid. Mass Spec [M+H]+=363.
Reaction SMILES: FC(F)(F)CCC([N:7]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][C:8]21[CH2:10][CH2:9]2)=O.[CH2:26]([N:33]=[C:34]=[S:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([NH:33][C:34]([N:7]1[CH:8]2[CH2:9][CH2:10][CH:14]1[CH2:13][N:12]([C:15]1[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=1)[CH2:11]2)=[S:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: S=C=NCc1ccccc1
Reactant: O=C(CCC(F)(F)F)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: C1CCOC1
Product: S=C(NCc1ccccc1)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in THF (1 mL), and benzyl isothiocyanate (0.06 mmol) was added. The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:22])([CH3:23])[C:19]([O:1][CH2:2][C:3]2[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc(CO)s1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(COC(=O)C(C)(C)Oc2ccc(Cl)cc2)s1

Procedure:
Using the procedure of Example 3, methyl 2-hydroxymethyl-thiazole-5-carboxylate and p-chlorophenoxy-isobutyric acid chloride were reacted in toluene and triethylamine to obtain methyl 2-[α-(p-chlorophenoxy)-α,α-dimethylacetoxymethyl]-thiazole-5-carboxylate melting at 80° C.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3][NH:2]1)[CH2:9]2.[Cl:12][CH2:13][C:14](Cl)=[O:15]>ClCCl.O>[Cl:12][CH2:13][C:14]([N:2]1[CH2:3][CH:4]2[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][CH:1]1[CH2:9]3)[CH2:5]2)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: C1NC2CC3CC1CC(C3)C2
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N1CC2CC3CC(C2)CC1C3
Yield: 73.1 %

Procedure:
To a solution of 2-azatricyclo[4.3.1.14,8 ]undecane (0.30 g) in dichloromethane (4 ml) and water (0.4 ml) was added dropwise a solution of chloroacetyl chloride (0.26 g) in dichloromethane (2 ml) under stirring at cooling in an ice-bath. The mixture was stirred 2 hours under the same condition and then at ambient temperature overnight. The reaction mixture was washed with IN hydrochloric acid aqueous solution and saturated sodium bicarbonate aqueous solution, and dried over sodium sulfate. Removal of the solvent gave N-chloromethylcarbonyl-2-azatricyclo-[4.3.1.14,8 ]undecane (0.33 g), which was used in a following reaction step without further purification.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Br:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Br:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (150 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) were added to pyridine (3 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, a mixed liquid of ethanol and diethyl ether was added to the residue, and solids were collected by filtration to obtain the title compound (40 mg) as a light brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:13][CH:12]2[C:14]#[N:15])(O)[CH3:9])=[CH:4][CH:3]=1.[CH3:16][S:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[CH:24]2.[Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:13][CH:12]2[C:14]#[N:15])([C:24]2[C:23]3[C:27](=[C:19]([CH2:18][S:17][CH3:16])[CH:20]=[CH:21][CH:22]=3)[NH:26][CH:25]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
150 mg (0.68 mmol) of the compound from Example 75A and 120 mg (0.68 mmol) of the compound from Example 8A were introduced into 4 ml of dichloromethane at 0° C., 157 mg (0.71 mmol) of indium(III) chloride were added, and the mixture was stirred at RT for 1 h and under reflux for 0.5 h. After cooling, 0.05 ml (0.68 mmol) of trifluoroacetic acid was added, and the mixture was stirred under reflux for 5 min. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 117 mg (45% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[CH:40]1([C:27]2([CH2:26][NH:25][C:22](=[O:24])[C:3]3[C:2]([F:1])=[C:7]([S:8][C:9]4[S:13][C:12]([NH:14][C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[N:11][CH:10]=4)[CH:6]=[CH:5][N:4]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(C5CCCCC5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-cyclohexylpiperidine-1-carboxylate (amine intermediate “R”) were reacted to give the title compound. LC/MS (M+H)+: 641. Ret. time: 2.18 min. (Condition L); analytical HPLC Ret. time: 12.41 min (Condition O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH2:16])[CH:13]([CH3:15])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Yield: 26.3 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and isobutylamine (0.39 mL, 3.90 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-isobutylbenzenesulfonamide (0.12 g, 28%) was provided after purification. MS (ESI) m/z 292.HPLC purity 100.0% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1>Cl.O1CCOCC1>[ClH:25].[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reaction time: 2 h
Yield: 192.7 %

Procedure:
4-amino-5-chloro-N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-2-methoxybenzamide (18.9 g) was dissolved in 4N hydrochloric acid-dioxane solution (150 ml). The mixture was stood at room temperature for 2 hr and the precipitated crystals were collected by filtration to give 15.3 g of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)-benzamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]([NH:1][C:2]1([C:12]([OH:14])=[O:13])[CH:9]2[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]1[CH2:11]3)[CH2:10]2)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)C2CC3CC(C2)CC1C3)OCc1ccccc1
Temperature: 50 °C

Procedure:
1.015 g of 2-amino-2-adamantanecarboxylic acid and 6 ml of bis(trimethylsilyl)acetamide in 10 ml of DCM is heated to reflux for one and a half hours. 0.75 ml of benzyloxycarbonyl chloride is added and the mixture is heated at 50° C. for 15 minutes. The reaction medium is cooled to -70° C., decomposition is then effected by adding ice and the mixture is extracted with AcOEt. The organic phase is washed with water (twice) and with brine, dried over MgSO4 and evaporated under vacuum. The product crystallizes in hexane; 1.164 g are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[Cl:15])=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH3:3][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:10][C:9]=1[Cl:15])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(Cl)c1
Reaction time: 6 h

Procedure:
To a 50 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-chlorophenol (0.831 g, 3.41 mmol) and DMF (16 mL). This mixture was cooled in an ice bath then Cs2CO3 (0.552 g, 1.69 mmol) and ethyl bromoacetate (0.37 mL, 3.34 mmol) were added. The resulting mixture was stirred for 6 h, during which time the cooling bath was allowed to expire. The mixture was filtered through a frit and the DMF was removed in vacuo. The residue was dissolved in EtOAc and washed with water (12×) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil which was purified by silica gel chromatography (EtOAc-hexane) to give ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-chlorophenoxyacetate (34-4) as an oil. 1H NMR (CDCl3): δ 1.30 (m, 3H), 1.53 (s, 9H), 4.27 (m, 2H), 4.57 (s, 2H), 6.78 (br s, 1H), 6.83 (dd, J=2.8, 8.8 Hz, 1H), 6.96 (d, J=2.8 Hz, 1H), 8.02 (br d, J=8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([CH2:39][CH2:40][OH:41])[C:20]3[C:21]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([CH2:39][CH2:40][OH:41])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CCO)[C@@H]4CCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCC[C@@H](N(CCO)c2ncnc3[nH]ccc23)C1
Yield: 46.6 %

Procedure:
A solution of (R)-2-(3,5-dichlorophenylamino)-1-(3-((2-hydroxyethyl)(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethanone (400 mg, 0.649 mmol) and K2CO3 (341 mg, 2.46 mmol) in MeOH (16 mL) was heated at 70° C. for 2 h. The solvent was concentrated in vacuo to give a solid, which was purified by column chromatography (silica gel, gradient 0-4% methanol in chloroform) to afford the titled compound (0.14 g, 46%). 1H NMR (400 MHz, DMSO-d6): 11.73 and 11.68 (2s, 1H), 8.12 (d, J=6.4 Hz, 1H), 7.35 (s, 1H), 7.20 and 7.15 (2s, 1H), 6.76 (s, 1H), 6.69 and 6.56 (2s, 1H), 6.62 and 6.49 (2s, 1H), 6.37-6.34 (m, 1H), 5.10-5.00 (m, 1H), 4.69-4.60 (m, 1H), 4.49-4.39 (m, 1H), 4.14-3.88 (m, 3H), 3.79-3.59 (m, 3H), 3.18 and 2.99 (2t, J=12.4 Hz, 1H), 2.84 and 2.70 (2t, J=12.4 Hz, 1H), 2.61-2.57 (m, 1H), 2.02-1.81 (m, 3H), 1.65-1.49 (m, 1H). LCMS [M+1]: 463.