Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([O-])([O-])=O.[K+].[K+].OC1C=CC(C=O)=CC=1.[Br:37][CH2:38][CH2:39]CCCCCCCC(Br)CC>>[Br:37][CH2:38][CH2:39][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[O:18])=[CH:20][CH:21]=1
Reactant: CCC(Br)CCCCCCCCCBr
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc(O)cc1
Agent: [K+]
Product: O=Cc1ccc(OCCCCCCCCCCCCBr)cc1

Procedure:
Synthesized as described above for compound 1. Quantities: K2CO3 (4.6 g, 33 mmol), p-hydroxybenzaldehye (3.27 g, 27 mmol), 1,10-dibromododecane (11.56 g, 35 mmol). Yield 7.0 g (70%). 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.52 (16 H, m, CH2), 1.84 (4 H, m, O—CH2—CH2/Br—CH2—CH2), 3.40 (2 H, t, 3J=6.9 Hz, Br—CH2), 4.06 (2 H, t, 3J=6.5 Hz, O—CH2), 6.98 (2 H, d, 3J=8.7 Hz, Ar—H), 7.82 (2 H, d, 3J=8.8 Hz, Ar—H), 9.88 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 26.3, 28.6, 29.1, 29.4, 29.7, 29.8, 29.9, 33.2, 34.4, 68.8, 115.1, 130.1, 132.3, 164.6, 191.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl.C(OCC)C>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([C:8]3[N:9]=[CH:10][CH:11]=[CH:12][N+:13]=3[O-:29])[C:5]=2[CH:14]=1)#[N:19]
Reactant: CC1(C)CC(c2ncccn2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CC(c2nccc[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 8 h
Yield: 9.7 %

Procedure:
242 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 5 ml of dichloromethane at room temperature and 450 mg of m-chloroperbenzoic acid were added. After stirring overnight the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/ethanol/formic acid (40:4:1) for the elution. The product was obtained in the form of an oil which was dissolved in diethyl ether and washed with sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was crystallized from t-butyl methyl ether to give 25 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyrimidine 1-oxide of melting point 98°-100° C.
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2([O:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[CH3:30][O:29][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[C:14]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:15]=2[CH2:16][CH2:17]1
Reactant: COC1(c2ccccc2)CCc2c(Br)cccc21
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC1(c2ccccc2)CCc2c(Nc3ccccc3)cccc21

Procedure:
Under an argon atmosphere, to a solution of 4.56 ml (4.66 g, 50.0 mmol) of PhNH2 in 200 ml of toluene, 20.0 ml of 2.5 M nBuLi (50.0 mmol) in hexanes was added dropwise at ambient temperature. Then, hexanes were distilled off under vacuum. To the obtained suspension, 12.1 g (39.7 mmol) of 4-bromo-1-methoxy-1-phenylindane, 434 mg (0.76 mmol) of Pd(dba)2, and 503 mg (1.47 mmol) of N-{2′-[di(tert-butyl)phosphino][1,1′-biphenyl]-2-yl}-N,N-dimethylamine were added. This mixture was refluxed for 1 hour, then, 300 ml of water was added. The organic layer was separated; the aqueous layer was extracted with 3×75 ml of ether. The combined extract was dried over Na2SO4 and, then, evaporated to dryness. The analytically pure 1-methoxy-N,1-diphenyl-4-indanamine was obtained by flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, 1300 mm, eluant: CH2Cl2). Yield, 12.5 g (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C@H:8]2[OH:11])=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O[C@@H]1C[C@H](c2ccccc2)c2ccc(Cl)cc21
Solvent: CO
Product: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21

Procedure:
Racemic cis-6-chloro-3-phenylindan-1-ol (V) (492 grams) is resolved by preparative chromatography, using a CHIRALPAK® AD column, 10 cm ID×50 cm L, 10 μm at 40° C. Methanol is used as mobile phase at a flow rate of 190 ml/min, detection is performed using a UV detector at 287 nm. The racemic alcohol (V) is injected as a 50,000 ppm solution in methanol; 90 ml is injected with intervals of 28 min. All the fractions, which contain the title compound with more than 98% enantiomeric excess, are combined and evaporated to dryness using a rotary evaporator, followed by drying “in vacuo” at 40° C. Yield 220 grams as a solid. Elemental analysis and NMR conform to the structure, the enantiomeric excess is higher than 98% according to chiral HPLC, [α]D20+44.5° (c=1.0, methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.[C:13]([NH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)(=[O:15])[CH3:14].N1CCCCC1>C(OCC)(=O)C>[C:13]([NH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:8]2[CH2:7][CH2:6][C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=3[C:9]2=[O:12])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: Cc1cnc2c(c1)C(=O)CCC2
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C=C2CCc3ncc(C)cc3C2=O)cc1
Temperature: 110 °C
Yield: 73.7 %

Procedure:
7,8-Dihydro-3-methylquinoline-5[6H]one (8 g) was mixed with 4-acetamidobenzaldehyde (9 g) and piperidine (0.5 ml) and heated at 110° C. for 3 hours. Ethyl acetate (30 ml) was added to the hot reaction mixture and the mixture allowed to cool. Crystals formed and were isolated by filtration, then washed with diethyl ether to give the title compound (11.2 g). A portion was recrystallised from ethyl acetate to give an analytical sample, mp 226°-228° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH3:10])=[O:8])[C@H:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:3]1.[CH2:15]([BH-](CC)CC)C.[Li+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:15][O:1][CH:2]1[N:6]([C:7]([O:9][CH3:10])=[O:8])[C@H:5]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC
Reactant: CC[BH-](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1CCC(OC)N1C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold solution (−78° C.) of dimethyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (5.80 g, 28.8 mmol) in tetrahydrofuran (100 mL) was added a solution of lithium triethylborohydride (1 M in THF, 35 mL, 35 mmol) dropwise via syringe over 10 minutes. The resulting solution was stirred at −78° C. for 30 minutes, quenched by the careful addition of saturated sodium bicarbonate solution (50 mL), allowed to warm to 0° C. and 30% hydrogen peroxide (6 mL) was carefully added dropwise. The mixture was stirred for 30 minutes at room temperature, reduced in volume under reduced pressure, and diluted with ethyl acetate (300 mL) and brine (200 mL). The milky aqueous layer was separated and further extracted with ethyl acetate (2×300 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to a light yellow oil. The yellow oil was taken up in methanol (50 mL) containing para-toluenesulfonic acid hydrate (487 mg, 2.6 mmol) and stirred at room temperature for 16 hours. The reaction was diluted with aqueous sodium bicarbonate solution (40 mL), the volatile solvents were removed under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and brine (200 mL). The aqueous layer was further extracted with ethyl acetate (200 mL), the combined organic layers were dried (sodium sulfate), filtered, and concentrated to an oil which was chromatographed on a Biotage 40M with 60% hexane/40% ethyl acetate to provide the titled compound as a mixture of diastereomers. (mixture of amide bond rotomers) 1H NMR (300 MHz, CDCl3): δ ppm 5.37 (d, 1H), 5.33 (dd, 1H), 5.24 (d, 1H), 5.18 (dd, 1H), 4.44-4.31 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.42 (s, 3H), 3.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[CH3:31][O:32][CH2:33][C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(NC(=O)COC)cc3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
In an ice-bath, to a solution (4 mL) of the crude compound (0.84 mmol) obtained in Example 36b in tetrahydrofuran were added triethylamine (0.15 mL, 1.1 mmol) and methoxyacetylchloride (110 mg, 1.0 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (250 mg, 74% in 2 steps) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1.ClC(Cl)(Cl)C(Cl)=O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)([C:25]([OH:27])=[O:26])O>C(OCC)C>[F:11][C:2]([F:1])([F:10])[CH2:3][CH2:4][C:5]1[NH:6][C:7]([C:25]([OH:27])=[O:26])=[CH:8][CH:9]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: FC(F)(F)CCc1ccc[nH]1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)c1ccc(CCC(F)(F)F)[nH]1
Temperature: 25 °C
Yield: 68 %

Procedure:
2-(3,3,3-Trifluoro-propyl)-1H-pyrrole (8.15 mmol, 1.33 g) was added to a solution of trichloroacetyl chloride (8.15 mmol, 0.91 ml) in diethyl ether (10 ml). The resulting solution was held at room temperature for 1h, then concentrated under reduced pressure. The resulting solid was dissolved in 1:1 dioxane-water (20 ml), treated with lithium hydroxide (24.5 mmol, 0.59 g), and heated to reflux for 30 minutes. After cooling to room temperature, the solution was acidified with saturated aqueous citric acid (20 ml), then extracted with ethyl acetate (2×50 ml). The combined organics were concentrated under reduced pressure. Purification of the resulting solid by silica gel chromatography provided 1.15 g (68%) of 5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid. 1H NMR (CDCl3) δ9.33 (1H, br s), 6.99 (1H, dd, J=3.7, 2.5), 6.07 (1H, t, J=3.3), 2.96-2.89 (2H, m), 2.55-2.39 (2H, m).
Reaction SMILES: [CH:1]1([C:7]2[C:11](=C)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][Li]>C1COCC1.CCOCC.O>[CH3:13][C:1]1([C:7]2[CH2:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [Li]C
Reactant: C=C1C=CC=C1C1CCCCC1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C2=CC=CC2)CCCCC1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of 6.50 g (44.5 mmol) of cyclohexylfulvene in 60 ml of THF, 44.8 ml (51.1 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.72 g (16.76 mmol) of a colorless transparent liquid (yield: 38%) The analyzed values are given below.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([S:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:21])=O)[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([S:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][NH2:21])[CH:17]=3)[N:12]([CH3:22])[CH:11]=2)[CH2:5][CH2:4]1
Reactant: CON1CCC(Sc2cn(C)c3ccc(C(N)=O)cc23)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CON1CCC(Sc2cn(C)c3ccc(CN)cc23)CC1
Reaction time: 10 h
Yield: 58.8 %

Procedure:
A solution of 3-[(1-methoxypiperidin-4-yl)thio]-1-methyl-1H-indole-5-carboxamide (3.2 g, prepared in Example 73) in dry THF (40 ml) is added dropwise at 0° C. to a suspension of lithium aluminum hydride (LiAlH4, 1.2 g) in anhydrous THF (200 ml). After 10 hours at room temperature, the reaction mixture is hydrolyzed at 0° C. by the addition of a saturated solution of sodium sulfate. After filtration on Celite, the solution is concentrated, taken up with ether and extracted with a dilute solution of hydrochloric acid. The aqueous phase is rendered basic with sodium hydroxide and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated. After chromatography on silica gel (eluent: AcOEt), 3-[(1-methoxypiperidin-4-yl)thio]-1-methyl-1H-indole-5-methanamine (1.8 g) is obtained in the form of a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([CH3:35])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11](=[O:30])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)[C:7]([OH:9])=O.[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([CH3:35])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:28]3[CH:27]=[CH:26][CH:25]=[CH:22][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)=[O:30])[C:7]([N:45]1[CH2:44][CH2:43][N:42]([CH:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH2:47][CH2:46]1)=[O:9]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1O
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1O

Procedure:
Prepared analogously to Example 7i from 100 mg (0.20 mmol) (S)-2-(3-chloro-4-hydroxy-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 37.5 mg (0.22 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[N:14]=[C:13]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[N:19]=3)=[CH:17][C:12]2=[C:11]2[N:30]([CH3:33])[CH:31]=[N:32][C:10]=12)C)(C)(C)C.FC(F)(F)C(O)=O.CN1C(=O)CCC1>C(Cl)Cl>[CH3:33][N:30]1[C:11]2=[C:12]3[CH:17]=[C:16]([C:18]4[N:19]=[C:20]([CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH:21]=[CH:22][CH:23]=4)[NH:15][C:13]3=[N:14][C:9]([NH:7][CH3:6])=[C:10]2[N:32]=[CH:31]1
Reactant: CC(=O)NCCc1cccc(-c2cc3c(nc(N(C)C(=O)OC(C)(C)C)c4ncn(C)c43)[nH]2)n1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc2[nH]c(-c3cccc(CCNC(C)=O)n3)cc2c2c1ncn2C
Reaction time: 0.25 h

Procedure:
A450.4 (147 mg, 0.30 mmol), was dissolved in DMA (5 mL) and the solution heated to 77° C. One equivalent of 1.0M potassium t-butoxide in THF (0.3 ml, 0.30 mmol) was quickly added and the reaction heated at 70° C. for thirty minutes. A second equivalent of 1.0M potassium t-butoxide in THF (0.3 ml, 0.30 mmol) was quickly added and the reaction mixture stirred an additional thirty minutes. The reaction mixture was concentrated in vacuo. The crude product residue was purified by Silica Gel (230-400 Mesh) chromatography eluting with 2-5% MeOH/CH2Cl2 to give the Boc-protected intermediate, tert-butyl-7-(6-(2-acetamidoethyl)pyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamate as an off-white solid. (76 mg, 52% yield). The solid was dissolved in methylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL) was added and the reaction mixture stirred for 0.25 h. The solvent was evaporated under reduced pressure to provide A450 (37 mg, 63%). M+H+=364.26. 1H NMP (400 MHz) MEOD δ 8.14 (s, 1H), 7.84 (m, 2H), 7.52 (s, 1H), 7.30 (m, 1H), 4.18 (s, 3H), 3.77 (m, 2H), 3.29 (s, 3H), 3.11 (m, 2H), 1.94 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/C.[F:18][C:19]([Si](C)(C)C)([F:21])[F:20]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[C:19]([F:21])([F:20])[F:18]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C/C(=N\[S@@](=O)C(C)(C)C)c1ccc(F)cc1Br
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@H](c1ccc(F)cc1Br)C(F)(F)F
Temperature: -60 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Add tetrabutylammonium triphenyldifluorosilicate (29.8 g, 55.19 mmol) to a stirring mixture of (S,E)-N-(1-(2-bromo-4-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (13 g, 42.46 mmol) in THF. Cool the mixture to about −60° C. and add the (trifluoromethyl)trimethylsilane over about 10 min. Warm up to −55° C. and stir for 2 h. Continue to warm up to 0° C. Cool the mixture back to −30° C., and quench with saturated NH4Cl (150 mL). Extract product into ethyl acetate (2×200 mL). Combine extracts, wash with aqueous saturated sodium chloride, dry over Na2SO4, filter, and concentrate. Purify the material on 700 g silica eluting with 8:2 to 1:1 hexanes:ethyl acetate to a crude material. Crystallize the material to give long needles (9.7 g, 91%). MS (ES) m/z 377 [M+1]+.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:50]([O:52][C:53]([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:76])[C@@H:62]([NH2:75])[CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:57][CH2:56]1)=[O:54])[CH3:51]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:52][C:53]([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:76])[C@@H:62]([NH:75][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[O:29])[CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:57][CH2:56]1)=[O:54])[CH3:51]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 448 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 10 ml DMF were added 216 mg HOBt, 271 mg EDC and 0.45 ml DIPEA. After 5 minutes 410 mg (S)-4-(2-Amino-6-benzyloxy-hexanoyl)-piperazine-1-carboxylic acid ethyl ester were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product was obtained by evaporation of the solvent. An aliquot (70 mg) was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 31 mg MS (ES+): m/e=772.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CN(C)C=O.[Tl+].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:27](=[O:28])[N:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:25]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:23]1=[O:24]>CCOCC>[C:35]1([N:25]2[C:23]([O:24][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])=[C:22]([CH2:21][CH2:20][CH2:19][CH3:18])[C:27](=[O:28])[N:26]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Tl+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1c(OS(=O)(=O)c2ccc(C)cc2)n(-c2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 8 h
Yield: 33 %

Procedure:
Then, p-Toluenesulfonyl chloride (0.95 g, 5.0 mmole) was allowed to react with a dimethylformamide (20 ml) suspension of the Thallium (I) salt of phenylbutazone. Within a few minutes the solvent became pink and a yellow solid, instead of the white Thallium (I) salt of phenylbutazone, was observed suspended in the pink solution. The suspension was stirred overnight in a tightly sealed flask, then it was diluted with 100 ml of ether and filtered. The filtrate was concentrated in vacuo to remove the ether and the dimethylformamide was evaporated under a stream of nitrogen. The residue from the evaporation was suspended in dichloromethane and filtered. Analysis of the filtrate by TLC showed that it contained only one major component. The dichloromethane was evaporated in vacuo and the residue was crystallized from ether to give 0.76 g (mp 112°-121° C., 33% yield) of yellow crystals which contained only one component by TLC analysis. Recrystallization of the yellow crystals gave analytically pure crystals, mp 125°-127° C. with spectral properties identical to the crystals, mp 112°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]2[CH2:25][CH:26]=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:30][N:31]([CH3:33])[NH2:32].C(OCC)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH2:14][C@H:13]2[CH2:25][CH2:26][NH:32][N:31]([CH3:33])[CH3:30])=[O:11])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CN(C)N
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)NCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-formylmethyl-4-t-butyldimethylsilyloxypyrrolidine (423 mg) was dissolved in 2 ml of ethanol, and 65 mg of N,N-dimethylhydrazine was added thereto, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added ethyl acetate, and the mixture was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-dimethylhydrazinoethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [CH2:1]1[C:3]2([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:4]([NH:6][C:7](=O)[CH:2]12)=O.[CH2:16]([Mg]Br)[CH3:17].O>CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]23[CH2:1][CH:2]2[CH:7]([CH2:16][CH3:17])[NH:6][CH2:4]3)=[CH:10][CH:11]=1
Reactant: CC[Mg]Br
Reactant: O=C1NC(=O)C2(c3ccc(Cl)cc3)CC12
Solvent: O
Solvent: CCOCC
Product: CCC1NCC2(c3ccc(Cl)cc3)CC12
Reaction time: 18 h

Procedure:
To 4.43 g of 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 ml of ether is added 16.4 ml of 2M ethylmagnesium bromide. The mixture is allowed to stand at room temperature for 18 hours and then is combined with water. The ether solution is dried over sodium sulfate and evaporated to give 4.05 g of a pink semisolid. Crystallization from ether hexane gives 1-(p-chloropehnyl)-4-ethyl-4-hydroxy-3-azabicyclo[3.1.0]hexan-2-one as colorless crystals, m.p. 154°-157° C.