Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[O:26][CH2:25]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C.CO>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:31]3[CH:32]=[CH:33][C:27]4[O:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=4[CH:30]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)NC(=O)CO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 19.2 %

Procedure:
To 3.0 mL of a methanol solution containing 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 0.12 g of 3-oxo-3,4-dihydro-2H-1,4-benzooxazine-6-carbaldehyde, 38 μL of acetic acid and 83 mg of sodium cyanoborohydride were added at room temperature and stirred at the same temperature for 6.5 hours. To the reaction mixture, chloroform and aqueous saturated sodium hydrogen carbonate solution were added to be adjusted to pH 10.2, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=5:1], diethyl ether was added to the foam thus obtained, and the resulting solid was filtered to afford a yellow solid. To this solid, ethyl acetate and chloroform were added, the mixture was cooled to the room temperature after heating, and the resulting solid was filtered to give 59 mg of 6-(((1-(2-(7-methoxy-2-oxoquinoxaline-1-(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-1,4-benzooxazine-3(4H)-one a pale yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl.[I:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O.C(O)C>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([I:18])[CH:5]=1
Reactant: CCOC(=O)CNc1ccc(CCBr)cc1
Reactant: O=C1CCC(=O)N1I
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(CCBr)cc1I
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a stirred solution of ethyl N-[4-(2-bromoethyl)-phenyl]aminoacetate (580 mg) in acetonitrile (4.05 ml) were added concentrated hydrochloric acid (169 μl) and N-iodosuccinimide (912 mg) under ice-cooling, and the mixture was stirred for 1 hour. Ethanol (4.0 ml) was added to the reaction mixture, and the mixture was stirred for 45 minutes under ice-cooling. A solution of sodium thiosulfate (640 mg) in water (20 ml) was added to the reaction mixture, and the mixture was stirred for 1 hour under ice-cooling. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=9/1) gave ethyl N-[4-(2-bromoethyl) -2-iodophenyl]aminoacetate (449 mg).
Reaction SMILES: C[C:2]1([CH2:10][CH2:11][CH3:12])[NH:6][S:5](=[O:8])(=[O:7])[NH:4][C:3]1=[O:9].[C:13]1([CH2:19]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:13]1([CH2:19][N:4]2[C:3](=[O:9])[CH:2]([CH2:10][CH2:11][CH3:12])[NH:6][S:5]2(=[O:7])=[O:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC1(C)NS(=O)(=O)NC1=O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a mixture of 4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8.25 g, 42.92 mmol) in 80 ml of dry DMF was added phenylmethyl bromide (8.08 g, 47.21 mmol) and tetrabutylammonium bromide (2.08 g, 6.64 mmol) in one portion. The resulting mixture was heated at 120° C. for 8 hours and then stirred at room temperature overnight. The mixture was cooled, poured over ice-water (400 ml), and the mixture was extracted with ethyl acetate (2×250 ml). The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The brown residual oil was purified by flash chromatography (silica gel; 25% ethyl acetate in hexane) to afford 9.34 g (77.1%) of 2-phenylmethyl-4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IX: R1 =propyl; R2 =CH3) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Clc1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(-c2cnccn2)cc1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
A mixture of 2-chloropyrazine (0.230 ml, 2.62 mmol), 4-(hydroxymethyl)phenylboronic acid (517 mg, 3.41 mmol), tetrakis(triphenylphosphine)palladium (0) (303 mg, 0.262 mmol) and 2 M potassium phosphate aqueous solution (2.62 ml, 5.24 mmol) in dioxane (10 mL) was heated at 80° C. overnight under nitrogen. The mixture was cooled down, poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound (350 mg) as an off-white solid. LCMS m/z=187.0 [M+H]+. NMR (400 MHz, CDCl3) δ 4.79 (s, 2H), 7.52 (d, J=8.1 Hz, 2H), 8.02 (d, J=8.1 Hz, 2H), 8.51 (d, J=2.5 Hz, 1H), 8.63 (dd, J=2.4 and 1.6 Hz, 1H), 9.03 (d, J=1.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:33])=[CH:12][N:11]=1>>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([O:32][C:23]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[N:11][C:10]([NH2:9])=[N:15][CH:14]=3)=[C:17]([F:33])[CH:18]=2)[CH:3]=1
Reactant: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Reactant: Nc1cc(Cl)ncn1
Product: Nc1cc(Oc2cc(C(F)(F)F)ccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)ncn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 555 using 6-chloropyrimidin-4-amine and 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.60-8.54 (d, J=1.3, 2H), 8.11-8.07 (d, J=0.9, 1H), 7.82-7.69 (m, 2H), 7.60 (s, 1H), 7.59-7.52 (m, 1H), 7.47-7.36 (m, 2H), 5.95-5.88 (d, J=0.9, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][CH:19]([CH3:24])[CH2:20][C:21](Cl)=[O:22]>>[CH3:18][CH:19]([CH3:24])[CH2:20][C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CC(C)CC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(C)CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 57.8 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.048 mMol 3-methylbutanoyl chloride, 0.008 gm (60%) of the title compound were prepared essentially by the procedure described in Example 7.
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(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C1C=CC=CC=1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 13.5 parts of 1-(2-aminophenyl)ethanone, 12.1 parts of N,N-diethylethanamine and 72 parts of benzene are stirred and cooled at 5°-10° C. Then there is added dropwise a solution of 18.2 parts of trichloroacetyl chloride in 36 parts of benzene while still cooling at 1°-10° C. Upon completion, stirring at that temperature is continued for 30 minutes. The reaction mixture is filtered, the filter-cake is washed with benzene and the filtrate is evaporated. The solid residue is boiled in methanol. After cooling, the product is filtered off and dried, yielding 19 parts (68%) of N-(2-acetylphenyl)-2,2,2-trichloroacetamide; mp. 112.7° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[C:4]([O:28][CH3:29])=[CH:3][C:2]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 64.6 %

Procedure:
A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 80.29 mg, 0.178 mmol), (3-fluorophenyl)boronic acid (49.8 mg, 0.356 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.828 mg, 4.45 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (6.74 mg, 8.90 μmol), and potassium phosphate (113 mg, 0.534 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (809 μl) and water (81 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (3×). The aq. layer was acidified with 0.5N aq. HCl, then extracted with EtOAc (2×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM) to give 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (58.84 mg, 0.115 mmol, 64.7% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.79 (s, 1H), 8.71 (d, J=5.8 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.4 Hz, 1H), 7.94-7.88 (m, 1H), 7.85-7.78 (m, 1H), 7.64-7.53 (m, 3H), 7.42-7.27 (m, 3H), 3.72 (s, 3H). m/z (ESI) 511.2 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C(OC)(OC)OC.[CH3:12][O:13][N:14]=[C:15]([C:19](=O)[CH3:20])[C:16](=[O:18])[CH3:17]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][O:13]/[N:14]=[C:15](/[C:19]1([CH3:20])[O:4][CH2:1][CH2:2][O:3]1)\[C:16](=[O:18])[CH3:17]
Reactant: OCCO
Reactant: CON=C(C(C)=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: CO/N=C(\C(C)=O)C1(C)OCCO1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
2400 g (39 mol) of ethylene glycol, 430 g (3.62 mol) of trimethyl orthoformate, 550 g (3.9 mol) of pentane-2,3,4-trione 3-(O-methyloxime) and 9 g of p-toluene sulfonic acid (46 mmol) were heated with stirring to 85° C. over a period of 15 min. After 30 min at 85° C., the mixture was cooled to room temperature. During the reaction, volatile components were distilled off via a column head. For work-up, the mixture was washed with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether, and the combined organic phases were washed twice with water and finally dried over magnesium sulfate. Distillative removal of the solvent gave 580 g of a red-brown oil (phys. data see Tab. 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([Br:22])=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)cs2)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)c(Br)s2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester (13.0 g, 42.2 mmol) in N,N-dimethylformamide (250 mL) was added N-bromosuccinimide (8.25 g, 46. mmol) and the mixture was stirred under argon at ambient temperature for 30 minutes. Analysis by thin layer chromatography (silica stationary phase eluted with 25% v/v ethyl acetate in hexanes) indicated clean conversion of [(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester in to a slightly less polar compound. The reaction mixture was poured into water (1 L) and extracted with ethyl acetate (3×250 mL), the combined organic extracts were washed with brine (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give an off-white solid. The crude product was triturated with 1:1 v/v diethyl ether/petroleum ether (300 mL total volume). [(R)-1-(5-Bromo-4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester was obtained as a colorless solid by filtration, washing with 1:2 v/v diethyl ether/petroleum ether and drying by passage of air (14.33 g, 88%). An additional amount of [(R)-1-(5-bromo-4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester was obtained by purification of the residue obtained from concentration of the mother liquors by chromatography using a silica gel column gradient eluted from 5% up to 40% v/v ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to obtain additional [(R)-1-(5-bromo-4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester as a colorless solid (1.18 g, 7%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:30]([N-:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]([CH3:33])[CH3:32].CSC.C(S)CS.N1C2C(=CC=CC=2)C=C1.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C@@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:30]([N-:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)C[N-]CC(C)C
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: SCCS
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 78.5 %

Procedure:
Under N2 atmosphere, the Boc-DTrp-DPro-diisobutylamide was dissolved in 25 ml of CH2Cl2, 1 ml of methylsulfide and 0.5 ml of 1,2-ethanedithiol was added as scavenger in suppressing the indole alkylation of tryptophane. 10 ml of trifluoracetic acid was added dropwise while being stirred. The reaction mixture was stirred for 30 min. Volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH2Cl2 and washed with 10 ml saturated NaHCO3 aqueous solution. The organic layer was dried over anhydrous sodium sulfate and filtered and the solvents were removed in vacuum. The residue was further purified by column chromatography (SiO2, CHCl2/MeOH, 85:15) to afford 0.55 mmol (78.5%) of compound (2) which was characterized by TLC and mass spectra, M+=411.5.
Reaction SMILES: [OH:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]#[N:16])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)([CH3:5])[CH2:3][OH:4].[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>CN(C=O)C>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([O:4][CH2:3][C:2]([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:15]#[N:16])=[C:10]([C:17]([F:20])([F:18])[F:19])[CH:9]=3)([OH:1])[CH3:5])=[CH:25][CH:26]=1)#[N:29]
Reactant: CC(O)(CO)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)(COc1ccc(C#N)cc1)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1,2-dihydroxy-1-methyl-ethyl)-6-trifluoromethyl-1-H-indole-5-carbonitrile (209.6 mg, 0.7374 mmol) in dry DMF (4 ml) was added NaH (60 mg, 1.4749 mmol, 60% in mineral oil). After the reaction mixture was stirred at room temperature for 30 min., 4-fluorobenzonitrile (98.15 mg, 0.8115 mmol) was added, and the reaction mixture stirred at room temperature. After HPLC indicated the consumption of starting material, the reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was washed with 10% LiCl, brine and dried over MgSO4. Column chromatography (EtOAc/Hexanes 50%-100%) yielded the title product as a light yellow powder.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.Cl>C(O)(=O)C>[CH3:25][O:24][C:11]1[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2C)c1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(Oc2ccccc2C)cccc1C(C)C(=O)O
Yield: 56.4 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]propionate (6.1 g), conc. hydrochloric acid (20 ml) and acetic acid (40 ml) was refluxed under heating for 48 hours. The reaction mixture was treated in a similar manner to that of Example 10-(6) to give oily 2-[2-methoxy-3-(o-tolyloxy)phenyl]propionic acid (2.9 g).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1)(O)=O.CC(C)N=C=NC(C)C>CN(C=O)C>[C:7]1([NH:10][C:11]([NH2:13])=[S:12])[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=S)Nc1ccc(C(=O)O)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: NC(=S)Nc1ccccc1
Reaction time: 3 h

Procedure:
4-carboxyphenylthiourea (Lancaster, 13047) was dissolved to 0.2M in DMF. The resultant mixture was activated by adding a half equivalent of DIC for 15 min at room temperature. Aminopropylsilylated glass surfaces purified with compressed air (2.5×7.5 cm; Sigma, Silane-Prep™, S4651) were coated with the activated solution thus obtained and incubated for three hours at room temperature. The glass surfaces thus treated were then washed five times using respectively 30 mL of DMF for 3 minutes each at room temperature. After washing three times for three minutes each using respectively 30 mL of DCM at room temperature, the glass surfaces were dried and stored at 4° C. until further use.
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]2)=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CCCC1(C(=O)O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccc(Cl)cc2)CCCC1

Procedure:
To a solution of methyl 1-(4-chlorophenyl)cyclopentanecarboxylic acid (5.0 g, 22.25 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL0, dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1>CN(C=O)C>[CH2:22]([N:1]([CH2:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1)[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-aminobenzonitrile (1.0 g, 8.47 mmol, 1 eq), K2CO3 (5.85 g, 42.4 mmol, 5.0 eq) and KI (422 mg, 2.54 mmol, 0.3 eq) in dry DMF (10 mL) was added dropwise BnBr (4.0 mL, 33.9 mmol, 4.0 eq) under Ar(g). The reaction mixture was stirred at rt overnight, and was then partitioned with H2O (30 mL), and subsequently extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (9:1-4:1) to furnish the product, 2, as a pale yellow solid (970 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:17]([F:31])[CH:16]=2)[N:3]=1.CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C.N1CCCCC1>CN(C=O)C>[F:31][C:17]1[CH:16]=[C:15]([NH:14][C:4]2[CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[N:46]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12
Reactant: Nc1nc(CCCC(=O)O)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCNCC1
Product: Nc1nc(CCCC(=O)N2CCCCC2)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
70 mg (0.17 mmol) of 4-(2-amino-6-{[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amino}pyrimidin-4-yl)butyric acid (from example 130) are dissolved in 2.0 ml of DMF, 60 mg (0.16 mmol) of HATU, 23 mg (0.17 mmol) of 1-hydroxy-1H-azobenzotriazole hydrate, 43 mg (0.33 mmol) of diisopropylamine and 28 mg (0.33 mmol) of piperidine are added and the mixture is stirred at RT for 20 hours. Volatile components are removed under reduced pressure and the product is purified by preparative HPLC. The resulting product is purified further by thick-layer chromatography (1 mm silica gel coating, mobile phase: DCM:methanol=9:1).