Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH:20]([CH:22]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH:23]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=O.C(O)(=O)C>O1CCCC1>[OH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:23]1[CH:22]([CH:20]=[CH:3][C:2](=[O:1])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:30][CH2:29][C:24]21[O:25][CH2:26][CH2:27][O:28]2
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(C=CC1CCC2(OCCO2)C1CCCCCCCO)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A solution of dimethyl 2-oxo-4-phenylbutylphosphonate [2.5g; prepared as described hereinafter in Example 9(iv)] in anhydrous tetrahydrofuran (50 ml.) was added to a stirred suspension of sodium hydride (0.24 g.) in tetrahydrofuran (20 ml.). The mixture was stirred at room temperature in an atmosphere of nitrogen for 24 hours, then treated dropwise with a solution of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane [2.7 g; prepared as described hereinbefore in Example 1(iv)] in tetrahydrofuran (30 ml.) and stirred for a further 2 hours in an atmosphere of nitrogen. The mixture was acidified to pH 4 by the addition of glacial acetic acid, the solvents were removed in vacuo and the residue was extracted with diethyl ether. The ethereal solution was washed with aqueous sodium bicarbonate solution (10% w/v) and then with water and dried over anhydrous magnesium sulphate. Evaporation of the solution gave 6-(7-hydroxyheptyl)-7-(3-oxo-5-phenylpent-1-enyl)-1,4-dioxaspiro[4,4] nonane (3.9 g.), in the form of a yellow oil (νmax 955 cm-1, 990 cm-1, 1625 cm-1, 1665 cm-1, 1690 cm-1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:16].[CH3:17][CH:18](O)[CH:19]=[CH2:20].O>COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:17]([CH:6]1[C:5](=[O:16])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[C:7]21[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:18]=[CH:19][CH3:20]
Reactant: Cc1ccc2c(c1)C(=O)CC21CCCCC1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(C)ccc2C12CCCCC2
Yield: 587.7 %

Procedure:
A solution of 2.50 g of 5'-methyl-2',3'-dihydro-spiro[cyclo-hexane-1,1'-[1H]indene]-3'-one, 24.1 ml (280 mol) of 3-buten-2-ol and 250 mg of p-toluenesulfonic acid in 250 ml of 2,2-dimethoxy-propane was boiled under reflux for 88 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 6:1). In addition to 8.4 g of educt, there were obtained 18.4 g (59%) of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one as a yellow oil.
Reaction SMILES: C([N:3]([CH:18](OC)[C:19](C)(C)C)[C:4](=[O:17])[C:5]1[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8](Br)=[CH:7][C:6]=1[Cl:16])C.[C:25](=O)=[O:26].CC(C)=O.[Li]CCCC.CN(C=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:16][C:6]1[CH:7]=[C:8]([CH:25]=[O:26])[CH:9]=[C:10]([Si:11]([CH3:12])([CH3:13])[CH3:14])[C:5]=1[C:4]([NH:3][CH2:18][CH3:19])=[O:17]
Reactant: CCN(C(=O)c1c(Cl)cc(Br)cc1[Si](C)(C)C)C(OC)C(C)(C)C
Reactant: O=C=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)c1c(Cl)cc(C=O)cc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-chloro-4-bromo-6-(trimethylsilyl)benzamide (820 mg, 1.89 mmol) in THF (2 mL) was added dropwise to a dry-ice/acetone cooled solution of 2.5M n-BuLi in hexanes (1 mL, 2.5 mmol) in THF (2 mL). The resulting red solution was stirred at -78° C. for 15 min, then DMF (500 mL, 6.5 mmol) was added in a single portion. After 5 min, the reaction was poured into sat aq NaHCO3 and extracted with ether (2×). The combined organic extracts were dried (MgSO4) and concentrated, then a solution of this protected amide in acetone (5 mL) was charged with 6N HCl and stirred overnight at RT. The resulting mixture was poured into sat aq NaHCO3 and extracted with ether (2×), then the combined organic extracts were dried (MgSO4), concentrated, and purified by RC with 3:7 EtOAc/hexanes to give 220 mg of the title compound as a white solid, a 40% yield. m.p. 95-97° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2.[CH3:15]OS(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[C:9](=[O:14])[CH2:8]2
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CC(=O)N2C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A dry round-bottom flask was charged with NaH (60% wt) (64 mg, 1.61 mmol) and toluene (2.0 mL). The suspension was heated to 100° C. and then 5-methoxyindolin-2-one (250 mg, 1.53 mmol) was added. After 30 min at 100° C., Me2SO4 (0.16 mL, 1.68 mmol) was added and the temperature maintained at 100° C. for 2.5 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 3:1 to 2:1) to give the product as a beige solid (144 mg, 53%); MS ESI 164.1 [M+H]+, calcd for [C9H9NO2+1-1]+ 164.07.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)c1cccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of 4-tert-butyl-N-(3-dimethylamino-phenyl)-benzene-sulfonamide with tert-butyl bromoacetate
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=[C:48]3C(CN([C@@H](C(C)C)C(OC)=O)[C:47]3=[O:50])=CC=2)=CC=1.C[O:60][C:61]1C=C(C=C(OC)[CH:69]=1)C(Cl)=O>>[CH2:47]([O:50][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:60][CH2:61][CH3:69])[CH:5]=1)[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8])[CH3:48]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCOc1cc(OCC)cc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)c1
Yield: 77 %

Procedure:
The compound of example 145 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,5-dimethoxy benzoyl chloride.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.8 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 3-methyl-4-[(4-phenylphenyl)methyl]piperazine-1-carboxylate (600 mg, 1.64 mmol, 1.00 equiv), dichloromethane (25 mL). Trifluoroacetic acid (1 mL) was added dropwise. The resulting solution was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure to yield 532 mg (crude) of 2-methyl-1-[(4-phenylphenyl)methyl]piperazine as brown oil. LCMS (ESI, m/z): 267 [M+H]+.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]#[CH:18]>CN(C)C=O.CCOC(C)=O.O>[Br:9][C:6]1[CH:7]=[CH:8][N:3]2[N:2]=[CH:18][C:17]([C:16]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]2[CH:5]=1
Reactant: N[n+]1ccc(Br)cc1
Reactant: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
Into a 250-mL three neck round-bottom flask, was placed a solution of 1-amino-4-bromopyridin-1-ium iodide (compound 64.2, 15 g, ˜50% purity, 24.9 mmol) in N,N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (11.7 mL, 115 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as the eluent to yield the title compound as a brown solid (300 mg, 6%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCN1CCOCC1
Reactant: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 6-methyl-5-nitropyridine-2-carboxylic acid (0.500 g, 3.0 mmol) in DCM (7 mL) were added 2-morpholin-4-ylethanamine (1.0 mL, 7.7 mmol), TBTU (0.992 g, 3.1 mmol), and DIEA (1.34 mL, 7.7 mmol). The reaction mixture was allowed to stir at rt overnight and then quenched with water. The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was purified by column chromatography to give 6-methyl-N-(2-morpholin-4-ylethyl)-5-nitropyridine-2-carboxamide (0.27 g, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[C:19](O)=[O:20])=[O:5])[CH3:2].O>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Temperature: 0 °C
Yield: 73.2 %

Procedure:
To a cold (ice bath) solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclopentane-1,2-dicarboxylic acid monoethyl ester (epimeric mixture, 0.7 g) in tetrahydrofuran (3.5 mL) was slowly added a borane complex with tetrahydrofuran (1M, 2.7 mL). The resulting solution was stirred for 3 h in the ice bath then slowly poured into water. The mixture was extracted with diethylether. The combined organic layers were washed with brine and dried over sodium sulfate then concentrated in vacuo. The residue was purified by flash chromatography on silica gel with cyclohexane/ethylacetate (6:1 v/v) as eluant to afford the title compound (0.49 g, 73%) as light yellow oil. MS (EI): 303.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3F)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=1.[H-].[Na+].[ClH:33]>O1CCCC1.CO>[ClH:33].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:28][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2OCc2ccc(F)cc2)cc1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of 2-(morpholin-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.60 g, 2.07 mmol), and 4-fluorobenzyl alcohol (3.3 g, 26.2 mmol) in tetrahydrofuran (15 ml) was added sodium hydride (1.03 g, 2.58 mmol) at 0° C. After stirring at 60° C. for 5 hours, the resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish colorless oil. The methanol (10 ml) solution of resulting oil was treated with 4N hydrochloric acid (5 ml). The residue obtained by evaporation was washed by ethyl acetate to furnish 6-(3-(4-fluorobenzyloxy)pyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one hydrochloride (0.23 g, 0.53 mmol, 31%) as white crystals.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].Cl.CN(C)CCCN=C=NCC.OS1C2C=CC=CC=2N=C1.C(N(CC)CC)C>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1)=[O:12]
Reactant: CC(C)(C)n1cc(C(=O)O)cn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O[SH]1C=Nc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnn(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 5.00 g (29.7 mmol) 1-tert-butyl-1H-pyrazole-4-carboxylic acid and 5.80 g (59.5 mmol) N,O-dimethylhydroxylamine hydrochloride in 60 ml dichloromethane are added 12.5 g (65.4 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 4.42 g (32.7 mmol) 1-hydroxybenzothiazol and 16.5 ml (119 mmol) triethylamine. The reaction mixture is stirred for 18 hours at room temperature. It is quenched with saturated sodium hydrogen carbonate solution and the mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-tert-butyl-1H-pyrazole-4-carboxylic acid methoxy-methyl-amide as colorless crystals; HPLC/MS 1.91 min (B), [M+H] 212.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[N:9]([CH3:33])[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2)=[O:7])(=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(Cl)(Cl)(Cl)Cl>C(#N)C>[CH3:33][N:9]1[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:17]1[CH2:18][CH2:19][CH:20]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][C:24]2=[O:32])[CH2:21][CH2:22]1
Reactant: CC(=O)NNC(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N′-acetyl-9-methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carbohydrazide (85 mg, 0.19 mmol, 1 equiv) and triphenylphosphine (90 mg, 0.34 mmol, 1.8 equiv) were weighed out into a 2 dram vial and suspended in acetonitrile (1 mL). Diisopropylethylamine (165 mL, 0.95 mmol, 5 equiv) and carbontetrachloride (36 μL, 0.38 mmol, 2 equiv) were added and the reaction stirred at room temperature overnight during which time a precipitate formed. Analysis by LCMS indicated about a 40% conversion to the desired product. Neither heating to 80° C. for several hours, nor the addition of additional carbontetrachloride, DIPEA, or TPP furthered the cyclization. The precipitate was collected, dissolved in DMF (3.5 mL) and purified by preparative reverse-phase HPLC (acetonitrile/water with 1% formic acid). Fraction containing pure 1-{1-[9-methyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-9H-purin-6-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one were combined. The desired material precipitated upon concentration of the fractions, was collected by filtration, washed with water, and dried under vacuum, which resulted in the isolation of 16 mg of material. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.33 (s, 1H), 7.16-7.10 (m, 1H), 6.93-6.82 (m, 3H), 4.53 (t, 1H), 4.03 (s, 3H), 2.59 (s, 3H), 2.30 (d, 2H), 1.83 (d, 2H). MS (EI) for C21H21N9O2: 432 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][CH2:40][N:41]1[CH2:46][C@H:45]([CH3:47])[O:44][C@H:43]([CH3:48])[CH2:42]1.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>C(Cl)Cl>[CH3:47][C@H:45]1[O:44][C@@H:43]([CH3:48])[CH2:42][N:41]([CH2:40][CH2:39][NH:38][C:34]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:37])[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:17]2)=[O:36])[CH2:46]1
Reactant: C[C@@H]1CN(CCN)C[C@H](C)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2F)C[C@H](C)O1
Yield: 94.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.20 g, 0.36 mmol) was reacted with 4-(2-aminoethyl)-cis-2,6-dimethylmorpholine (Oakwood) (0.20 g, 1.2 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.60 g, 4.6 mmol) in CH2Cl2 (20 mL) at room temperature for 20 hrs to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(cis-2,6-dimethyl-morpholin-4-yl)-ethyl]-amide as a white solid (0.20 g, 94%). HRMS (ES+) m/z Calcd for C31H39Cl2FN4O2+H [(M+H)+]: 589.2507. found: 589.2507.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:55]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][CH2:53][CH2:54]6)=[O:49])=[CH:44][C:43]=5[CH3:55])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)N2CCCC2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and (4-bromo-3-methyl-phenyl)-pyrrolidin-1-yl-methanone (38 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-pyrrolidin-1-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-267) as a pale yellow powder (7 mg, 16%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH2:31]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:32]>>[CH2:31]([C:33]1[CH:39]=[CH:38][C:36]([N:37]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:35][CH:34]=1)[CH3:32]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 483.15 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-ethylaniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH2:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:49][C:50]1[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[C:51]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH:5][C:52]([C:51]1[C:55]([CH3:59])=[CH:56][CH:57]=[CH:58][C:50]=1[Cl:49])=[O:53]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
To a suspension of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.125 mmol, 46 mg), HBTU (0.125 mmol, 47.5 mg) and 2-chloro-6-methylbenzoic acid (0.137 mmol, 25 mg) in DMF (2 mL) was added diisopropylethylamine (0.312 mmol, 44 uL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 72 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 42 mg (70% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a oily residue. ES-HRMS m/e calcd for C25H26ClN3O5 (M+Na) 506.1454, found 506.1459.