Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])=[C:6]([N+:22]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH3:14])=[C:6]([NH2:22])[CH:5]=1
Reactant: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)c(N)c1
Yield: 90 %

Procedure:
3-Amino-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethylamino]-benzoic acid methyl ester (1.4 g) was prepared by following General Procedure B starting from 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethylamino]-3-nitro-benzoic acid methyl ester (1.7 g) and Pd—C (350 mg) in methanol:EtOAc (1:1, 20 mL).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:7]([NH:9][CH:10]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([OH:13])=O)=[O:8].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:37]([NH:40][CH2:41][CH2:42][CH3:43])[CH2:38][CH3:39]>ClCCl>[CH2:37]([N:40]([CH2:41][CH2:42][CH3:43])[C:11](=[O:13])[CH:10]([NH:9][C:7](=[O:8])[C:6](=[C:2]1[S:1][CH:5]=[CH:4][S:3]1)[C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:38][CH3:39]
Reactant: CCCNCCC
Reactant: COC(=O)CCC(NC(=O)C(C(=O)OC)=C1SC=CS1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)C(CCC(=O)OC)NC(=O)C(C(=O)OC)=C1SC=CS1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
2-((2-(1,3-Dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-methoxy-5-oxopentanoic acid (4) (239 g) was dissolved in dichloromethane (1.5 l), followed by the addition of 70.7 g of triethylamine. To the resulting solution, 71.8 g of ethyl chlorocarbonate were added dropwise at 5-10° C. under stirring over 30 minutes. Subsequent to further stirring at 15-20° C. for 3 hours, di-n-propylamine (70.7 g) was added dropwise at 5-10° C., followed by stirring at room temperature for 12 hours. The solvent was removed under reduced pressure, and ethyl acetate (2 l) was then added to the residue. The resulting precipitate was filtered off. After the ethyl acetate layer was washed with 0.5 N hydrochloric acid and then with water, the solvent was removed under reduced pressure. Diethyl ether (800 ml) was added to the residue and the resulting precipitate was collected by filtration, whereby methyl 5-(dipropylamino)-4-((2-(1,3-dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-oxopentanoate (5) (113 g, yield: 57%) was obtained as pale yellow crystals.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cncc(-c2ccc(Cl)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(-c2ccc(Cl)cc2)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 68.1 %

Procedure:
A solution of 900 mg (3.49 mmol) 5-(4-Chloro-phenyl)-nicotinic acid methyl ester in 30.0 ml Ethanol was treated at room temperature (r. t.) with 264 mg (69.9 mmol) of sodium borohydride. The mixture was stirred for two days at 50° C. Then it was poured on ice and extracted tree times with ethyl acetate. The combined organic phases were washed with water, dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/methanol 6:1) gave 522 mg (67%) of [5-(4-Chloro-phenyl)-pyridin-3-yl]-methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])(C)(C)C.[I:22]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>CCOCC>[I:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: COc1ccccc1NC(=O)OC(C)(C)C
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: COc1cccc(I)c1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To tert-butyl 2-methoxyphenylcarbamate (24.1 g, 108 mmol) in dry Et2O (100 mL) at −20° C. was added dropwise tert-butyllithium (140 ml, 237 mmol). The clear solution turned cloudy at the end of the addition. The reaction was stirred for 3 hours at −20° C., then cooled to −100° C. with a liquid N2/Et2O bath. Iodine (27.4 g, 108 mmol) in Et2O (250 mL) was added to the solution. Following addition of I2, the reaction was slowly warmed to ambient temperature over night. Na2S2O3 (saturated, 200 mL) was then added to the reaction mix and phases were separated. The aqueous was extracted with Et2O, and the combined organic layers were dried (MgSO4), filtered and concentrated. DCM (50 mL) was added, followed by hexanes (200 mL). The solution was concentrated to remove DCM. The product crashed out, and was collected by filtration and washed with hexanes (100 mL) to give the crude product (58%).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.C([O:42][C:43](=[O:51])[CH2:44][C@H:45]([NH2:50])[CH2:46][N:47]=[N+:48]=[N-:49])C1C=CC=CC=1.CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:50][C@@H:45]([CH2:46][N:47]=[N+:48]=[N-:49])[CH2:44][C:43]([OH:51])=[O:42])=[O:17])=[CH:9][CH:10]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: [N-]=[N+]=NC[C@@H](N)CC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: [N-]=[N+]=NC[C@@H](CC(=O)O)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h

Procedure:
4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (4.6 g, 18.5 mmol) was added to dry DMF (250 ml) followed by N-methylmorpholine (1.8 g, 18.5 mmol) and isobutyl chloroformate (2.8 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Benzyl-3-amino-4-azido-(3S)-butyrate hydrochloride (1 eq; from Step 1, Example 22) was added followed by dimethylaminopyridine. After 1 h the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (water/acetonitrile) to result in 3.0 g of a white solid. A portion (750 mg) of the benzyl ester was subjected to the saponification conditions as previously described and purified by reverse phase chromatography (water/acetonitrile) to result in 340 mg of a white solid: 1H NMR (d6 -DMSO) δ2.44 (m, 4H), 2.6 (m, 2H), 3.35 (bs, 2H), 4.18 (m, 1H), 7.78 (s, 4H), 8.1 (d, 1H,J=8 Hz), 8.27 (bs, 2H), 9.15 (bs, 2H), 10.40 (s, 1H); MS (FAB) m/z 362.1 (MH+).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[O:19]=[C:14]1[CH2:15][CH2:16][C:17](=[O:18])[N:13]1[O:10][C:1](=[O:11])[C@@H:2]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(ON1C(=O)CCC1=O)[C@@H](O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of (S)-(+)-mandelic acid (0.50 g, 3.3 mmol) and N-hydroxy succinimide (0.38 g, 3.3 mmol) in EtOAc (10 mL) was added 1,3-dicyclohexylcarbodiimide (0.67 g, 3.3 mmol) in EtOAC (5 mL) drop wise. The resulting solution was let stir for 4 h and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13](Br)=[CH:12][N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16].O1CCOC[CH2:18]1.CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:18])=[CH:12][N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16]
Reactant: COc1ccc(-c2nn(C)cc2Br)cc1C
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB(O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2nn(C)cc2C)cc1C

Procedure:
A mixture of 3-(4-methoxy-3-methyl-phenyl)-4-bromo-1-methyl-1H-pyrazole (described in Reference Preparation example 55) 3.9 g, 1,4-dioxane 80 ml, water 20 ml, methylboronic acid 3.3 g, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adducts 1.4 g and potassium phosphate 11.8 g was stirred with heating under reflux for six hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-1,4-dimethyl-1H-pyrazole 2.4 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][CH3:21])([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][CH3:21])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCC[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a stirred solution of methyl (1S,4S)-4-[(tert-butoxycarbonyl)amino]-1-(2-methoxyethyl)cyclopent-2-ene-1-carboxylate (0.78 g, 2.6 mmol) in tetrahydrofuran (1.5 mL), methanol (15 mL), and water (3.0 mL) was added lithium hydroxide monohydrate (0.55 g, 13 mmol) and the resulting orange mixture was stirred at 80° C. overnight. The solvents were evaporated and the mixture was acidified with 6 N HCl to a pH of about 4. The aqueous was then extracted with methylene chloride three times. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to give the desired product as an oil (0.47 g, 63.2%). LCMS calculated for C14H24NO5: (M+H) 286.2; found 286.2.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]([CH:17]([NH:23][C:24]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)[CH2:27]3)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO>[C:44]([O:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33][C:32]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24]([NH:23][CH:17]([C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:6]=4)[CH:12]=3)[CH2:18][C:19]([OH:21])=[O:20])=[O:25])[CH2:27]2)=[O:48])[CH2:40][CH2:39]1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(OCCF)c2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cncc(-c4cccc(OCCF)c4)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
95 mg (0.14 mmol) Tert-butyl 4-{3-[(3R)-3-{[1-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 17 ml methanol. 448 mg (1.42 mmol) barium hydroxide octahydrate were added. The mixture was stirred at room temperature for 20 hours and then concentrated to give 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[S:29]([CH3:28])(=[O:31])=[O:30])[CH2:18][CH2:19]1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(Nc3ccc(F)cc3)CC1)C2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1C2CCC1CC(N1CCC(N(c3ccc(F)cc3)S(C)(=O)=O)CC1)C2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-[4-(4-fluoro-phenylamino)-piperidin-1-yl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (25 mg; 0.07 mmol; 1 eq.) was dissolved in dry prydine (2 mL) and MsCl (19 mg; 2.5 eq.) was added. The reaction mixture was heated to 80° C. and stirred under N2 overnight. The solution was diluted with DCM (10 mL) and washed with saturated NaHCO3 (2×20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under high vacuum to provide the product as an oil. The crude residue was purified by reversed-phase HPLC (2-99% CH3CN/water gradient with 0.05% TFA). LC/MS M/Z 454.2, Retention time=1.88 minutes; 10-99% CH3CN/H2O gradient with 0.05% TFA.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:5][CH:4]=1)[CH3:2].[OH-].[K+].[BH4-].[Na+].[CH2:24]([OH:26])[CH3:25]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH2:15][C:16]([O:26][CH2:24][CH3:25])([CH3:18])[CH3:17])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCO
Reactant: CCc1ccc(SCC=C(C)CCC=C(C)C)cc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(C)(C)CCCC(C)=CCSc1ccc(CC)cc1
Reaction time: 2 h

Procedure:
To a solution of 2 g. of 1-(4'-ethylphenyl)thio-3,7-dimethylocta-2,6-diene in 20 ml. of ethanol, cooled to 0°, is added a suspension of 2.3 g. of mercuric acetate in 50 ml. of ethanol over 15 minutes. The reaction mixture is stirred for two hours and then, with cooling, 1.2 g. of potassium hydroxide in 20 ml. of ethanol is added. Then 0.14 g. of sodium borohydride is added in small portions and stirring continued for about 30 minutes. The solution is then decanted, concentrated to half volume, diluted with 100 ml. of water and extracted with ether. The ethereal phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 1-(4'-ethylphenyl)thio-7-ethoxy-3,7-dimethyloct-2-ene which is purified by chromatography. ##STR12##
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[C:17]([O:18][CH3:19])=[C:16]2[C:11]([CH2:12][CH2:13][NH:14][CH:15]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O>[Cl:1][CH2:2][C:3]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:17]([O:18][CH3:19])[C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:15]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:4]
Reactant: COc1ccc2c(c1OC)C(c1ccccc1)NCC2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1OC)C(c1ccccc1)N(C(=O)CCl)CC2
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A solution of chloroacetyl chloride (177 mg) in EtOAc (12 mL) was added dropwise to a mixture of 7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (350 mg), a saturated aqueous sodium hydrogen carbonate solution (50 mL), and EtOAc (50 mL) under stirring. After the dropwise addition was complete, the mixture was stirred for 2 hours and extracted with EtOAc. The extract was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-EtOH) to obtain 2-(chloroacetyl)-7,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (349 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][C:25]=1[C:34]([F:37])([F:36])[F:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])=[CH:26][C:25]=1[C:34]([F:35])([F:36])[F:37]
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)c(C(F)(F)F)c2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), [4-fluoro-3-(trifluoromethyl)phenyl]acetic acid (99 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), and DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. LCMS analysis indicated good conversion, so the resulting suspension was poured into water (10 mL) and stirred for 30 min, forming a precipitate. This precipitate was collected by filtration, dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-8% MeOH in EtOAc, 12-g column) to afford 5-(1-{[4-fluoro-3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (198 mg, 95% yield) as a white solid. LC-MS (ES) m/z=470 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 3.26 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 4.02 (s, 2H), 4.27 (t, J=8.34 Hz, 2H), 5.91-6.20 (m, 2H), 7.19-7.29 (m, 2H), 7.33 (s, 1H), 7.50 (t, J=9.73 Hz, 1H), 7.64-7.70 (m, 1H), 7.73 (d, J=6.57 Hz, 1H), 8.11 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[Na:14].[Na].[P:16]([C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1[NH2:22])([OH:19])([OH:18])=[O:17]>CS(C)=O>[Na:14].[Na:14].[P:16]([C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:8]=[C:7]([C:2]([F:13])([F:12])[F:1])[CH:6]=1)=[O:11])([OH:18])([OH:19])=[O:17]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Br)cc1P(=O)(O)O
Agent: [Na]
Solvent: CS(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Nc1ccc(Br)cc1P(=O)(O)O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a 30 mL vial containing a stirring bar DMSO-D6 (0.5 mL), pyridine-D5 (1 drop), 3-trifluoromethylphenylisocyanate (14 mg, 0.080 mol) and 2-Phosphono-4-bromoaniline disodium salt (10 mg, 0.036 mmol) were added. The resulting mixture was stirred at 65° C. for 3 hours, resulting in a DMSO solution of the desired urea.
Reaction SMILES: [Cl-].[Li+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>C1COCC1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])=[CH:16][CH:15]=1
Reactant: BrCCCCCCCCBr
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CCCCCCCCBr)cc1
Reaction time: 0.5 h

Procedure:
Lithium chloride (0.15 g, 3.5 mmol) and cupric chloride (0.3 g, 2.2 mmol) were added to THF (100 ml) and stirred for 1 hour 30 minutes. 1,8-Dibromooctane (37 g, 137 mmol) was then added. While keeping the temperature between 0° C. and 5° C., 4-methylphenyl magnesium bromide in THF (prepared from magnesium (2.3 g, 95 mmol) and 4-methylphenyl bromide (15.4 g, 90 mmol) in THF (150 ml)) was added over 1 hour, allowing the temperature to reach room temperature overnight. The reaction mixture was poured over concentrated hydrochloric acid/ice mixture and the product was extracted into ether. The ether was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to give an oil, which was distilled under vacuum to give 8-(4-methylphenyl)octylbromide as an oil, bp 128° at 0.2mm.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[S:14][C:13]([CH2:15][CH:16](O)[C:17]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][O:20][C:21]=2[CH3:22])=[N:12][C:11]=1[CH3:30])=[O:9]>C(=O)(O)[O-].[Na+]>[CH3:6][O:7][C:8]([C:10]1[S:14][C:13](/[CH:15]=[CH:16]/[C:17]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:19][O:20][C:21]=2[CH3:22])=[N:12][C:11]=1[CH3:30])=[O:9]
Reactant: COC(=O)c1sc(CC(O)c2c(-c3ccccc3)noc2C)nc1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Temperature: 90 °C
Yield: 83.9 %

Procedure:
Concentrated sulfuric acid (5 mL) was added to 2-[2-hydroxy-2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (200 mg, 0.56 mmol) then the mixture was heated at 90° C. for 10 min. The solution was carefully dropped into saturated sodium bicarbonate solution (100 mL) then extracted with ether. The combined organic extracts were dried, filtered and concentrated, to give the title compound (160 mg, 84%) as a yellow oil which solidified on standing to a yellow solid. This material was used directly without further purification. MS: m/e=341.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11].[CH3:12][N:13]=[C:14]=[S:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11])=[S:15]
Reactant: CN=C=S
Reactant: CC1CCCC(C)N1CCN
Product: CNC(=S)NCCN1C(C)CCCC1C

Procedure:
By the general method described in Example 1, 1-(2-aminoethyl)-2,6-dimethylpiperidine is reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: [Na].Cl.[CH2:3]([N:5]=[C:6]=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N#N.C1(C[CH2:33][CH2:34][C:35]2[N:36]=[C:37]([C:40]([NH:42][C@H:43]([C:45]([NH:47][CH:48]3[CH2:52][C:51](=[O:53])[O:50][CH:49]3[O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:46])C)=[O:41])NC=2)C=CC=CC=1.C(OC(NC1CC(=O)OC1OCC1C=CC=CC=1)=O)C=C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:33][C:34]1[C:6]2[N:5]=[CH:3][N:42]([CH2:43][C:45]([NH:47][CH:48]3[CH2:52][C:51](=[O:53])[O:50][CH:49]3[O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[O:46])[C:40](=[O:41])[C:37]=2[NH:36][CH:35]=1
Reactant: C[C@H](NC(=O)c1nc(CCCc2ccccc2)c[nH]1)C(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c[nH]c2c(=O)n(CC(=O)NC3CC(=O)OC3OCc3ccccc3)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A suspension of the sodium salt 41 (344 mg, 1.5 mmol) in dry DMF (15 ml) was treated with ethyl dimethylaminopropyl carbodiimide hydrochloride (373 mg, 1.95 mmol) and 1-hydroxybenzo-triazole (405 mg, 3.0 mmol). The mixture was kept at 25° C. for 1 h then (2R,S, 3S) N-allyloxycarbonyl-3-amino-2-benzyloxy-5-oxotetrahydrofuran (437 mg, 1.5 mmol; Chapman, Biorg. Med. Chem. Lett., 2, pp. 613-18 (1992)) and (Ph3P)2PdCl2 (25 mg) were added followed by the dropwise addition of n-tributyltin hydride (0.6 ml, 2.25 mmol). The resulting mixture was stirred at 25° C. for 1 h then water (20 ml) was added. The mixture was extracted with ethyl acetate (3×15 ml), and the combined organic extracts were washed with water (5 ml), dried (MgSO4), and concentrated to afford a mixture of diastereomers. Evaporation of the aqueous phase and purification of the residue by flash chromatography (5% methanol/chloroform) gave an additional quantity affording a total 182 mg of 42 (31%): m.p. 240-244° C.; IR (KBr) 3274, 1772, 1691, 1664, 1562; 1H NMR (d6 -DMSO) δ 11.81 (1H, s), 8.85 (0.6H, d, J=6.6), 8.72 (0.4H, d, J=7.4), 7.98 (0.6H, s), 7.95 (0.4H, s), 7.40-7.30 (5H, m), 7.20 (1H, d, J=2.2), 5.61 (0.4H, d, J=5.0), 5.46 (s), 4.85-4.60 (m), 4.28 (m), 3.20-2.35 (2H, m), 2.16 (3H, s).