Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:12][CH2:11][C@@H:10]1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]1=[O:36])=O)(C)(C)C.[CH3:37]S(O)(=O)=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(O)C.C(O)(=O)C.C(N(CC)CC)C>[C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([N:15]([CH:17]([CH3:18])[CH3:19])[CH3:16])[CH2:12][CH2:11][C@@H:10]1[N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:21]1=[O:36])(=[O:5])[CH3:37]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 60 °C

Procedure:
Example 1, Alternative Preparation, Step 5: The tert-Butyl carbamate 9 (50 g) was dissolved in Toluene (500 mL) and i-PrOH (150 mL). The resulting solution was then heated to 60° C. Methanesulfonic acid (19.6 mL) was added below 65° C. Upon reaction completion (HPLC), the mixture was cooled to RT and triethylamine (69.4 mL) added slowly below 25° C. Acetic anhydride was then added below 25° C. After 1 h acetic acid (250 mL) was added below 25° C. The toluene phase was discarded and 2-methyl-THF (500 mL) was added to the aqueous phase. The mixture was stirred vigorously and basified with NaOH (25% aqueous solution) to pH 12. The aqueous phase was discarded and the organic layer was washed with brine (250 mL). The organic layer was concentrated under reduced pressure and continuously replaced with i-PrOH. The solution was cooled and filtered to provide benzyl {(S)-1-[(1S,2R,4R)-2-acetylamino-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamate 10 in i-PrOH solution which was used directly in the hydrogenation.
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[C:4](=[O:14])[N:5]([CH2:10][CH2:11][CH2:12][OH:13])[N:6]=[CH:7][C:8]=1Cl.[OH-].[K+]>C(O)C>[Cl:2][C:3]1[C:4](=[O:14])[N:5]([CH2:10][CH2:11][CH2:12][OH:13])[N:6]=[CH:7][C:8]=1[OH:1]
Reactant: O=c1c(Cl)c(Cl)cnn1CCCO
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=c1c(Cl)c(O)cnn1CCCO

Procedure:
To a mixed solvent of 150 ml of water and 150 ml of ethanol was added 22.3 g of 4,5-dichloro-2-(3'-hydroxypropyl)-3(2H)-pyridazinone (0.1 mol) and 19.6 g of potassium hydroxide (0.35 mol) and then heated under reflux for about 10 hours. After reaction, ethanol was removed under reduced pressure and added with water to filter off the insoluble matters. The filtrate was converted into acidity by diluted hydrochloric acid and the crystals produced were filtered off. The crystals thus obtained were washed with water and dried to give 14.5 g of 4-chloro-5-hydroxy-2-(3'-hydroxypropyl)-3(2H)-pyridazinone.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:14]([N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (2.7 g) and ethyl-(2-methoxy-ethyl)-amine (2.18 g) are dissolved in toluene (20 ml), and thereto is added potassium carbonate (5.83 g) and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated brine and the mixture is separated, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzaldehyde (3.75 g). MS (m/z): 276 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH:8]=[N:9][OH:10])=[O:5].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.[CH3:37][OH:38].Cl.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]([CH:37]=[O:38])[OH:10])=[O:5]
Reactant: CO
Reactant: O=C(NCC=NO)c1cc(Cl)ccc1Cl
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Product: O=CN(O)CCNC(=O)c1cc(Cl)ccc1Cl
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 2,5-dichloro-N-(2-hydroxyimino-ethyl)-benzamide (0.72 g, 2.9 mmol) in MeOH (20 mL) under an argon atmosphere at 0° C. was added methyl orange (trace) followed by a saturated solution of MeOH/HCl until a persistent red color was observed. Sodium cyanoborohydride (0.22 g, 3.5 mmol) was dissolved in MeOH (5 mL) and was added sequentially with saturated MeOH/HCl over 0.5 h. The reaction mixture was stirred an additional 1 h and the MeOH was removed in vacuo. The residue was basidified with saturated Na2CO3 and extracted (7×25 mL) with dichloromethane/MeOH (9:1). The combined organic extracts were washed with brine, were dried (Na2SO4) and were concentrated. The residue was purified by flash chromatography (2%-5% MeOH/dichloromethane) to provide the title compound (0.29 g, 40%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.53 (s, 1H); 7.44 (s, 2H); 3.56 (t, j=6.2 Hz, 2H); 3.06 (t, j=6.2 Hz, 2H). ESMS: M+H=249.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2NN=[N:27][N:26]=2)=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[N:26][N:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccc(F)cc2)o1
Yield: 74.2 %

Procedure:
The title compound (1.34 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.22 g), 5-(4-fluorophenyl)tetrazole (0.82 g) and dicyclohexylcarbodiimide (1.05 g) according to the method of description 1.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].[Mg]>O1CCCC1>[CH2:1]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCI
Reactant: COc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1ccccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
To a refluxing solution of about 35.3 g of hexadecyl iodide in tetrahydrofuran was added a solution of about 37.4 g of bromoanisole and about 4.86 g of magnesium in tetrahydrofuran which had been refluxed for about 2 hours. An about 10 ml portion of about 0.1M lithium cupric chloride was added, the mixture was refluxed about 2 hours and stirred at room temperature for about 16 hours giving about 34 g of the desired reagent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16].Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:26][N:27]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH2:14][CH2:15][CH3:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NOCc1ccccc1
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Yield: 29.1 %

Procedure:
A solution of N-(4-chloroquinolin-3-yl)butyramide (3.3 g, 13 mmol, 1.0 eq) and O-benzylhydroxylamine hydrochloride (4.23 g, 26.5 mmol, 2.0 eq) in ethanol (150 mL) was heated at reflux for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 3% methanol in dichloromethane) to provide 1.20 g of 1-benzyloxy-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[N:10]([O-])=O.[Na+]>Cl>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][NH2:10]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: NNc1c(Cl)cccc1Cl
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 227.7 %

Procedure:
To a cold solution of 2,6-dichloroaniline (10.0 g, 61.72 mmol) in conc. HCl was added aqueous solution of sodium nitrite (5.11 g, 74.00 mmol) at −15° C. The reaction mass was stirred at 0-10° C. for 15 minutes. The reaction mass was filtered off to remove insolubles and stannous chloride in conc. HCl (34.7 g, 150 mmol) was added to the filtrate. The reaction mass was further stirred at −15° C. for 30 min and filtered to afford 15.00 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.18-7.28 (m, 1H), 7.39-7.52 (m, 2H), 10.30 (br s, 3H); MS (m/z): 176.90 (M)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1cccc(O)c1)nn2C1CCCCO1
Yield: 85.1 %

Procedure:
To a stirred solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (1.47 g, 4.82 mmol) in dimethoxyethane (24.0 mL) was added 3-hydroxyphenylboronic acid (1.60 g, 7.27 mmol), dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (0.396 g, 0.485 mmol), and potassium phosphate (5.12 g, 24.1 mmol) and the mixture was heated at reflux for 48 h. The mixture was diluted with dichloromethane. The organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by column chromatography with 20–50% ethyl acetate/hexanes furnished the product (1.31 g, 85% yield). ES-MS (m/z) 320 [M+1]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:18][N:17]=1)([O-])=O>N1C=CC=CC=1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:18][N:17]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCCNc1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCNc3ccccn3)[nH]c2=O)cn1
Yield: 69.7 %

Procedure:
2-(3-Aminopropylamino)pyridine (1.74 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (2.0 g) were heated together under reflux in pyridine (8 ml) for 22 hr. The mixture was stripped, the residue triturated with ether and then water (the pH of which was adjusted to 6.5 with dilute acetic acid) to give a white solid. Recrystallisation from isopropanol gave 2-[3-(pyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone, (1.87 g; 70%), m.p. 163°-165° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=O)=[CH:18][CH:17]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:23]([CH2:22][C:19]4[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NNC(=O)c1ccc2occc2c1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(Cc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 58 %

Procedure:
In the same manner as in Example 14 and using 1-benzofuran-5-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and (4-methoxyphenyl)acetic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 58%) was obtained as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[N:15]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:17]3[C:22]=2[CH2:21][CH:20]=[CH:19][CH2:18]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:23]1([C:16]2[N:15]([CH2:29][C:30]([OH:32])=[O:31])[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:22]3[C:17]=2[CH2:18][CH:19]=[CH:20][CH2:21]3)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)Cn1c(-c2ccccc2)c2c(c1-c1ccccc1)CC=CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(-c2ccccc2)c2c(c1-c1ccccc1)CC=CC2

Procedure:
5 ml of trifluoroacetic acid are added at 0° C. to a solution of 5 g of the compound of Step A in 50 ml of anhydrous dichloromethane. After reaction for 12 hours at ambient temperature, the reaction mixture is concentrated in vacuo and the residue obtained is rinsed with ether to allow isolation of the expected product.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:3].[OH2:22].[CH2:23]([OH:25])[CH3:24]>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:1].[CH3:24][C:23]([OH:22])=[O:25]
Reactant: O
Reactant: CCO
Agent: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(CN)CCC[C@]21C
Product: CC(=O)O

Procedure:
The acetate salt of dehydroabietylamine was available in the form of technical-grade compositions. One was a tan colored paste containing 70% solids and 30% water. The other was an aqueus alcoholic solution of the salt which held 50% of solids. Each water soluble amine acetate was used as obtained to prepare 5% alcoholic solutions and then diluted with ethanol for 2.5% and 1.25% solutions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Cl:11])=[N:6][CH:5]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH3:15])[C:7]([Cl:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cnc(Cl)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-chloro-5-hydroxynicotinic acid methyl ester (1.8 g, 9.6 mmol), methyl iodide (2 M solution in Et2O, 5.8 mL, 11.6 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in acetone (190 mL) was refluxed for 6 h. The reaction was then concentrated via rotavap and H2O was added (100 mL). The resulting white precipitate was filtered and rinsed with additional H2O to furnish the product 6-chloro-5-methoxynicotinic acid methyl ester as a white solid (1.33 g, 68%); mp=83-85° C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (d, 1H), 7.77 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H): GC-MS: Exact mass calcd for C8H8ClNO3 [M]+, 201. Found 201.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH2:15][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)([CH2:11]2)[C:9]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C(O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]23[CH2:11][CH:12]([CH2:15]2)[C:13](=[O:14])[N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]3=[O:25])=[CH:21][CH:20]=1
Reactant: CCCCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 2.1 g of 3-n-heptyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 100 ml of ethanol are hydrogenated in the presence of 0.1 g of palladium-on-carbon and worked up. After purification by column chromatography on silica gel with the system hexane/ethyl acetate 1:1, the title compound is obtained in the form of wax-like crystals. Melting point 69°-71°, Rf (hexane/ethyl acetate 1:1)=0.25.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9](B4OC(C)(C)C(C)(C)O4)[CH:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.Br[C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[CH2:33][C@@H:32]([CH3:34])[O:31][C:30]2=[O:35])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:24]4[CH:37]=[CH:36][C:27]([CH2:28][N:29]5[CH2:33][C@@H:32]([CH3:34])[O:31][C:30]5=[O:35])=[CH:26][CH:25]=4)[CH:10]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2)C(=O)O1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2)C(=O)O1
Yield: 35.9 %

Procedure:
2-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.204 mmol, 60.9 mg) was mixed with (R)-3-(4-bromobenzyl)-5-methyloxazolidin-2-one (5F3) (0.185 mmol, 50 mg), tricyclohexylphosphine (0.022 mmol, 8.5 mg), tris(dibenzylidineacetone) dipalladium (0.009 mmol, 8.5 mg) and potassium phosphate (0.315 mmol, 66.7 mg) in dioxane (1mI) and water (0.5 ml). The mixture was heated to 130° C. for 10 minutes in the microwave before addition of DCM (3 ml) and water (2 ml). The phases were mixed and the organic phase collected using a hydrophobic fritted tube and concentrated under reduced pressure. Purification was achieved using basic HPLC to afford (R)-3-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-5-methyloxazolid in-2-one (Example 5a) 24.1 mg (36%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H) 7.66 (d, 1H) 7.59 (m, 3H) 7.38 (d, 2H) 4.64 (m, 1H) 4.51-4.41 (m, 2H) 4.37 (s, 2H) 3.54 (m, 1H) 3.03 (m, 1H) 2.97 (m, 1H) 1.43 (d, 3H) 0.95-0.89 (m, 4H) m/z (M+H) 363.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:36]=1[C:37]([OH:39])=[O:38]>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([NH:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:36]=1[C:37]([OH:39])=[O:38])=[O:18])[CH:13]([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cccc(N)c1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)[C@H](NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Reaction time: 0.5 h
Yield: 33 %

Procedure:
After a tetrahydrofuran solution (40 ml) of N-benzyloxycarbonyl-D-valine (5.08 g) was cooled to -15° C., N-methylmorpholine (2.23 ml) and isobutyl chloroformate (2.61 ml) were added to the solution, and the mixture was stirred for 0.5 hour. An N,N-dimethylformamide solution (25 ml) containing 2-amino-6-methylbenzoic acid (2.04 g) and N-methylmorpholine (1.79 ml) was added dropwise to the above reaction mixture, and the resultant mixture was stirred at -15° C. for 0.5 hour and then at room temperature for two hours. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 2-(N-benzyloxycarbonyl-D-valyl)amino-6-methylbenzoic acid (1.71 g).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[N:17][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15]2)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[N:17][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15]2
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2nn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2nn1
Reaction time: 24 h

Procedure:
Palladium on charcoal catalyst (30% w/w; 100 mg.) was added to a solution of ethyl 6-(benzyloxycarbonylamino)-cinnolin-3-yl carboxylate (1 g.) in dry ethanol (25 ml.). The solution was shaken in an atmosphere of hydrogen at room temperature and atmospheric pressure for 24 hours. The mixture was filtered and the filtrate evaporated in vacuo to give, as solid residue, ethyl 6-aminocinnolin-3-yl carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:49])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:49])=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@@H](C)N3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@@H](C)N3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 2-({2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (278 mg, 0.397 mmol) in dioxane (10 mL) and a 2M aqueous NaOH solution (2 mL) was heated at 80° C. for 6 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a pink solid (172 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=5.68 Hz, 3H), 2.27 (s, 6H), 2.59 (d, J=15.57 Hz, 1H), 2.80 (d, J=4.58 Hz, 3H), 3.07 (d, J=14.28 Hz, 1H), 3.24-3.46 (m, 2H), 3.80 (s, 3H), 4.71-4.85 (m, 1H), 6.29 (dd, J=3.02, 1.74 Hz, 1H), 6.85-7.07 (m, 3H), 7.26-7.43 (m, 1H), 7.54 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 8.55 (dd, J=4.40, 1.65 Hz, 1H), 8.64 (s, 1H), 10.15 (s, 1H), 11.30 (s, 1H). ESIMS (M+H)+=547.43; Optical rotation +11.0 (1 mg/mL MeOH, rt).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26]O.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCCc1cccs1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCc1cccs1)c1cc(F)ccc1F
Yield: 66.1 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5 and 2-(2-thienyl)ethanol (144 mg, 1.32 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (159 mg, 0.660 mmol). The resulting mixture was heated under reflux for 15 hours under a nitrogen atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=12:1 eluate was concentrated, whereby the title compound (90.0 mg, 0.218 mmol, 53%) was obtained as a colorless oil.