Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:14])[NH:8]OC(C)(C)C.C1(C)C=C(C)C=C(C)C=1S([N:46]1C=NC([N+]([O-])=O)=N1)(=O)=O.CN1C=CN=C1>C(Cl)Cl>[NH2:1][C@H:2]([C:15]([NH2:46])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:14])[NH2:8]
Reactant: CC(C)(C)ONC(=N)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1cc(C)c(S(=O)(=O)n2cnc([N+](=O)[O-])n2)c(C)c1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: N=C(N)NCCC[C@H](N)C(N)=O
Reaction time: 0.08 h

Procedure:
Fmoc-Arg(OtBu)-OH, 1-mesitylenesulfonyl-3-nitro-1,2,4-triazole (MSNT) and N-methylimidazole were dissolved in CH2Cl2, and the solution was stirred for 5 minutes and thereafter placed into the solid-phase synthesis column containing the resin, followed by stirring at room temperature for 3 hours. The resin was thereafter washed with methylene chloride, isopropanol and DMF and dried. The unreacted hydroxyl group on the solid phase was thereafter acetylated using a 20% DMF solution of acetic anhydride for 20 minutes for capping. The resin was washed with DMF and stirred along with a 20% piperidine/DMF solution for 20 minutes to remove the protective Fmoc group, whereby resin-Arg-NH2 was obtained. The product was washed with DMF and dried.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:10](=[O:27])[C:11]([CH2:19][CH2:20][CH2:21][C:22](OCC)=[O:23])=[C:12]([CH3:18])[C:13](=[O:17])[C:14]=1[O:15][CH3:16].Cl>C(OCC)C>[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([OH:17])[C:12]([CH3:18])=[C:11]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:10]=1[OH:27]
Reactant: CCOC(=O)CCCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1c(O)c(C)c(CCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of lithium aluminum hydride (0.5 part) in diethyl ether (5 volume parts) was added a solution of 2,3-dimethoxy-5-methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=2, in the form of ethyl ester) (0.78 part) in diethyl ether (10 volume parts) under cooling in ice-bath. After stirring at room temperature for 1 hour, the mixture was acidified with dilute hydrochloric acid. The diethyl ether layer was separated and the aqueous layer was extracted with diethyl ether. The combined diethyl ether and extract were washed with water, dried over anhydrous sodium sulfate. The diethyl ether was removed in vacuo to give 2,3-dimethoxy-5-methyl-6-(4'-hydroxybutyl)-hydroquinone (formula III-2 wherein R=H3CO, n=2, in the free form). A solution of the above product in diethyl ether was shaken with 16% aqueous ferric chloride (10 volume parts). The diethyl ether layer was separated, washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted with chloroform to give 2,3-dimethoxy-5-methyl-6-(4'-hydroxybutyl)-1,4-benzoquinone (formula IV-2 wherein R=H3Co, n=2, in the free form) (0.52 part) as an orange oil.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CN(C)C=O.Cl>O>[C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C(=Cc1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
A mixture of 24.0 parts of the compound of formula ##STR18## 25.8 parts of p-phenylbenzaldehyde-anile and 50.0 parts of potassium hydroxide powder in 600.0 parts by volume of dimethyl formamide is raised to 60° in 30 minutes with stirring and in the absence of air. It is maintained at this temperature for a further 30 minutes, after which it is cooled to about 10°. At a temperature between 10° and 20° 20 parts of water and then 500.0 parts by volume of 10% hydrochloric acid are added. The precipitated product is filtered off with suction, washed with water until neutral and dried. The 4-(5"-methoxybenzoxazolyl-2")-4'-phenylstilbene of formula (10) is obtained in very good yield. It can be purified as described above.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1Br)[CH2:6][CH3:7])[CH3:2].[CH3:29][N:30](C)C=O>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])[CH:12]=[CH:11][C:10]=1[C:29]#[N:30])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reactant: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reaction time: 4 h

Procedure:
A 10 g of ethyl-α-[2-bromo-5-(2-chloro-4-trifluoromethyl phenoxy) phenoxy]butyrate was dissolved in 20 ml of dimethylformamide. A 2.5 g of cuprous cyanide was added to the solution and the reaction was conducted at 145° to 150° C for 4 hours with stirring the mixture. The reaction mixture was poured into suitable amount of an aqueous solution of ferric chloride. The product was extracted with chloroform. The extract was washed with water and was dried. The chloroform was evaporated off and the product was distilled at reduced pressure to obtain 6 g of the object compound having a boiling point of 200° to 205° C/1 mmHg.
Reaction SMILES: [CH:1]([CH:4]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[C:27]1([C:33]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Br)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC.O.C1COCC1>[CH:1]([CH:4]([CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([O:7][CH2:38][C:37]1[CH:40]=[CH:41][CH:42]=[C:35]([C:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:34])[CH:36]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: CC(C)C(C=Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C=Cc1ccccc1)C(=O)OCc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-isopropyl-4-phenyl-3-butenoic acid (0.22 g, 1.07 mmol), 2 ml DMF, 3 ml THF and potassium carbonate (0.23 g, 1.66 mmol) is added m-phenylcarbonylbenzyl bromide (0.33 g, 1.2 mmol). The reaction mixture is stirred overnight at RT and then ether/water is added. The ether phase is washed with 5% NaOH, water and brine, dried over sodium sulfate and concentrated under vacuum. The crude product is plated on silica gel plates eluting with 10% ether/hexane to yield m-phenylcarbonylbenzyl 2-isopropyl-4-phenyl-3-butenoate, MS m/e 398.3 (M+).
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[OH:11].[CH:12]([O:14][CH2:15][CH3:16])=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13]
Reactant: C=COCC
Reactant: O[C@@H]1c2ccccc2C[C@H]1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: CCOC(C)O[C@@H]1c2ccccc2C[C@H]1Cl

Procedure:
A stirrer, thermometer and reflux condenser were mounted to a 100-ml three-necked flask which was filled with 10.0 g (0.059 mol) of trans-2-chloroindan-1-ol, 13 ml of monochlorobenzene and 4.72 g (0.066 mol) of ethyl vinyl ether. While the mixture was stirred, 5.6 g (0.03 mol) of p-toluenesulfonic acid was added and stirred for 3 hours at 25° C. to form trans-2-chloro-1-(1-ethoxyethoxy)indane in the reaction system. Moreover, to the reaction liquid was added 123.4 g (0.77 mol) of a 25% aqueous solution of NaOH and 1.44 g (0.0035 mol) of tetrabutylammonium bromide and the mixture was stirred for 30 hours at 103° C. to form 1-(1-ethoxyethoxy)indene in the reaction system. The reaction liquid was separated into a monochlorobenzene layer and a water layer. To the monochlorobenzene layer were added 20 ml of water and 0.65 g (0.0065 mol) of 98% sulfuric acid and the mixture was stirred for 1 hour at 78° C. After the reaction, the reaction liquid was separated into a monochlorobenzene layer and a water layer, and the monochlorobenzene layer was rinsed twice with 100 ml of water. The monochlorobenzene layer was dried with anhydrous sodium sulfate and then vacuum-concentrated to obtain 6.93 g of a black oil of 1-indanone (giving a yield of 88.4%). The purity of this oil according to gas chromatography (GC) was 63.9% (surface area percentage). The IR spectrum of this oil matches the IR spectrum of commercial 1-indanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]=O)[CH:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.CCN(CC)CC.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][NH:24][CH:21]2[CH2:23][CH2:22]2)[CH:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CCN(Cc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(Cc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-ethyl-carbamic acid tert-butyl ester (240 mg, 0.806 mmol), cyclopropylamine (0.085 mL, 1.2 mmol) and Et3N (0.169 mL, 1.21 mmol) in MeOH (2.7 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (76.2 mg, 2.01 mmol) was added. The mixture was stirred for 1 h at rt, and aq. sat. NaHCO3 was added. The mixture was extracted several times with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 1:49) yielded the title compound (125 mg, 46%). LC-MS: tR=0.78 min; ES+: 380.20.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]12([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH:25]=O)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>ClCCl>[C:12]12([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH:25]=[N:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Product: COC(=O)c1ccc(N=Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
3 g of basic alumina and 1.94 g (12.9 mmoles) of methyl 4-aminobenzoate are mixed in a mortar, then introduced into a round bottom flask. 3 g (11.1 mmoles) of 3-(1-adamantyl)-4-methoxybenzaldehyde in 50 ml of anhydrous dichloromethane are added with stirring. After heating at reflux for 24 hours, the reaction medium is extracted with dichloromethane and evaporated to dryness. The crude product is recrystallized in a mixture of ethyl acetate and acetone. After filtration, 3.4 g (75%) of the expected product whose melting point is 180°-182° C. are obtained.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Br[CH2:7][C:8]([O:10]CC)=[O:9].C(OCCC(O)=O)CC#C>>[CH2:1]([O:5][CH2:7][C:8]([OH:10])=[O:9])[CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: CCOC(=O)CBr
Agent: C#CCCOCCC(=O)O
Product: C#CCCOCC(=O)O

Procedure:
2-(But-3-ynyloxy)acetic acid was prepared from but-3-yn-1-ol and ethyl bromoacetate using methodology analogous to that describing the synthesis of 3-(but-3-ynyloxy)propionic acid (Example XIX).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[N:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C.O>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]2[O:18][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[N:8][C:9]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: Cc1ccsc1C=Nc1cc([N+](=O)[O-])ccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccsc1-c1nc2cc([N+](=O)[O-])ccc2o1
Yield: 41.5 %

Procedure:
2-[[(3-Methyl-2-thienyl)methylene]amino]-4-nitrophenol (13.1 g, 0.05 mole) is heated to reflux in 500 ml of glacial acetic acid and lead tetraacetate (22.2 g, 0.05 mole) is added to the hot mixture. After heating for 10 minutes, the mixture is diluted with 1 liter of water and the precipitated product collected. The crude material is dissolved in chloroform (350 ml) and treated with activated charcoal. The chloroform is evaporated yielding 5.4 g of product, melting point 174°-176° C.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1.B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]([N:10]3[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12][CH2:11]3)[N:6]([CH3:9])[C:7](=[O:8])[C:2]=2[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[CH:25][CH:26]=1)#[N:31]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)cc2)c(Cl)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(-c3ccc(C#N)cc3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(C)c2=O)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
A mixture of tert-butyl 1-(5-chloro-4-(4-cyanophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-ylcarbamate (200 mg, 0.45 mmol), p-tolylboronic acid (123 mg, 0.90 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (28 mg, 0.045 mol) and K2CO3 (124 mg, 0.90 mmol) in DMF (10 mL) was flushed with nitrogen and stirred at 85° C. for 2 h. Water was added, and the mixture was extracted with EA (3×). The organics were combined, washed with water, washed with brine, dried and concentrated in vacuo. The residue was purified by silica chromatography (1:1, EA:PE) to give 50 mg (22%) of the title compound. [M+H] Calc'd for C29H33N5O3, 500. Found, 500.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:31]([CH3:41])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@@H:29]4[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:31]([CH3:41])[CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](C)N(C(=O)OC(C)(C)C)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and commercially available tert-butyl(2S,4S)-4-amino-2-methylpyrrolidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH:1]1[C:10]([OH:11])=[C:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][C:2]=1C.[C:12](OCC)(=O)C1C(=CC=CC=1)C(OCC)=O>>[CH3:12][C@:6]12[C:10](=[O:11])[CH2:1][C@@H:2]([C:7]1([CH3:8])[CH3:9])[CH2:4][CH2:5]2
Reactant: CCOC(=O)c1ccccc1C(=O)OCC
Reactant: Cc1ccc(C(C)C)c(O)c1
Product: CC1(C)[C@H]2CC[C@@]1(C)C(=O)C2

Procedure:
Thymol--10% in Diethyl Phthalate: 2%
Reaction SMILES: C([O:8][C:9]([C:11]1([N:19]([CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)C.O>[CH2:42]([O:41][C:39]([CH2:38][CH2:37][N:19]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:11]1([C:9]([OH:10])=[O:8])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:40])[CH3:43]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN(C1(C(=O)O)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 48 h

Procedure:
A solution of (4.4 mmol) of the product of step D in 25 mL of ethanol is treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi olF hydrogen for 48 hours. The catalyst is removed by filtration and washed with ethanol (4×25mL). The filtrate and washings are combined and concentrated under vacuum to crude product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10](=O)[O:11]C.CC(C)([O-])C.[K+]>>[CH3:8][O:9][C:10]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)=[O:11]
Reactant: O=C1CCOCC1
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C1COCCC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 26.5 %

Procedure:
To a solution of tetrahydro-pyran-4-one (1.3 kg, 12.98 mol) and carbonic acid dimethyl ester (11.69 kg, 129.8 mol) was added solid potassium tert-butoxide (1.89 kg, 16.08 mol) in portions at −10° C. over 2 h under nitrogen protection. The suspension was stirred at room temperature 10 h after the addition. LCMS (215 nm) indicated that tetrahydro-pyran-4-one had been completely consumed. The reaction was acidified by HCl (2 N) to pH 6˜7 and then the phases were separated. The organic phase was washed with water (3 L×2) and the combined aqueous phases were extracted with MTBE (2.5 L×2). The combined organic phase was concentrated under reduced pressure at 25° C. to remove most of MTBE. The residue was distilled out by oil pump (˜200 Pa) at 74° C. to give the title compound as colorless oil (545 g, 26.3%). CHN analysis: calculated (results). C, 53.16 (53.10), H, 6.37 (6.245), N, 0.00 (0.00).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]([CH3:18])([C:14]([OH:16])=[O:15])[CH3:17])[CH:7]=1
Reactant: CC(C)(N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O

Procedure:
A mixture of 32.62 g of 2,4-difluoronitrobenzene, 24.2 g of 2-aminoisobutyric acid, 15.2 g of potassium carbonate, 100 ml of acetonitrile, and 100 ml of water is heated at 80° for 2 days (until TLC shows little or no starting material). The reaction is then cooled and acetonitrile is removed under reduced pressure. The pH is adjusted to 5 with 4N hydrochloric acid and the mixture is extracted with chloroform (3×300 ml). The organic layers are dried over sodium sulfate and concentrated. The material is used in the next step without further purification.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:31]3[CH2:30][CH2:29][C:28]([C:25]4[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=4)([OH:34])[CH2:33][CH2:32]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Yield: 24 %

Procedure:
A mixture of 6.7 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 4.2 parts of 4-(4-chlorophenyl)-4-piperidinol, 3.2 parts of sodium carbonate and 32 parts of 4-methyl-2-pentanone is stirred and heated at 50°-60° C. for 1.50 hours. The reaction mixture is poured onto ice-water. The precipitated product is filtered off and dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in a small amount of trichloromethane. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 2 parts (24%) of 5-chloro-1-{3-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 190.8° C.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:2]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.FC(F)(F)C(O)=O>>[NH:1]([C:17]([O:19][CH2:20][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[C@H:2]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:3][C:4](=[O:5])[OH:10]
Reactant: C=CCOC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
FmocAsp(OtBu)Oallyl (40 g, 88.7 mmol) was treated with 25 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 30 min. The solvent was stripped off on a rotary evaporator. The residue was dried in vacuo. FmocAsp(OH)Oallyl was obtained as a yellow oil (33.9 g, 97%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:29])[C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:12]1([NH:11][C:4]2[C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:29])[C:24]([CH:26]4[CH2:27][CH2:28]4)=[O:25])=[CH:21][CH:22]=3)[N:3]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Clc1nc(NC2CCC2)c2cc[nH]c2n1
Reactant: CN(C(=O)C1CC1)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN(C(=O)C1CC1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Temperature: 115 °C
Yield: 6.2 %

Procedure:
To a suspension of 2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (67 mg, 0.3 mmol) in nBuOH (0.8 mL) was added N-(4-aminophenyl)-N-methylcyclopropanecarboxamide (85 mg, 0.45 mmol) and TMSCl (0.02 mL, 0.15 mmol). After heating at 115° C. for 2 h, the mixture was cooled and purified by preparative HPLC to give N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylcyclopropanecarboxamide (7 mg). MS found for C21H24N6O as (M+H)+377.2. λ=208.7, 272.4, 304.5.