Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-:20])=[O:19])=[C:9]([NH:11][CH:12](C)[CH2:13][C:14](O)=O)[CH:10]=1.C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38].CO>C1(C)C=CC=CC=1.O.CCOCC>[CH3:40][O:39][C:37](=[O:38])[CH2:14][CH2:13][CH2:12][NH:11][C:9]1[CH:10]=[C:5]([O:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:24][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)Cl
Reactant: CC(CC(=O)O)Nc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a suspension of 3-[5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitrophenylamino]butyric acid (2.50 gm, 5.97 mmol) in 50 ml toluene cooled to 0° C. was added triethylamine (0.83 ml, 5.97 mmol). Methyl chloroformate (0.51 ml, 6.57 mmol) was added. After 1 hour the reaction was warmed to room temperature, an excess of methanol was added and the mixture was allowed to stir overnight. The reaction mixture was diluted with water, ether extracted, shaken with brine and dried (MgSO4) filtered and concentrated under vacuum. The resulting viscous oil was purified by column chromatography, silica gel, 40% ether/hexane to afford 2 gm of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2].[H-].[Na+].[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].O>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][N:10]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
To 4-ethoxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (12, 2.70 g, 9.34 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodium hydride (411.0 mg, 10.27 mmol) is added. The reaction is stirred at room temperature for 20 minutes, then triisopropylsilyl chloride (3, 2.177 mL, 10.27 mmol) is added. The reaction is stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 5-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (13, 3.90 g).
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:45]=3[N:46]=2)=[CH:38][CH:37]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:51].[ClH:1].[Cl:51][C:48]1[CH:49]=[CH:50][C:44]2[O:43][C:42]([C:39]3[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:28]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=4[CH2:26][CH2:25][NH:9][CH:10]4[CH2:19][CH2:18][CH2:17][C:16]5[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]4=5)=[CH:41][CH:40]=3)=[N:46][C:45]=2[CH:47]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11 ml of a 4 N solution of hydrogen chloride in dioxane were added to 1025 mg (1.46 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 109A), and the mixture was stirred at room temperature for 2 h. The precipitated solid was filtered off, washed repeatedly with diethyl ether and then dried under high vacuum at 40° C. overnight. This gave 980 mg (1.46 mmol, about 99% of theory) of the target product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=S)[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C([O+](CC)CC)C.[N:39]#[C:40][NH2:41].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=[N:41][C:40]#[N:39])[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=S)NC2CCCCC2)C1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=NC#N)NC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 34 (200 mg, 0.48 mmol) in dichloromethane (15 mL) was added triethyloxonium tetrafluoroborate (0.96 mL, 0.96 mmol, 1 Min dichloromethane) and the mixture was stirred at room temperature for overnight. The reaction mixture was then heated to 50° C. for 3 more days with continued stirring. The reaction mixture was cooled, concentrated and triturated in ether. The obtained product was dissolved in ethanol (2 mL) and cyanamide (61 mg, 1.4 mmol) and triethylamine (0.2 mL, 1.4 mmol) were added. After stirring, at 80° C. for 16 hours, the reaction mixture was cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash 280™ (SiO2, 0-100% of ethyl acetate in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.34 (m, 5H), 1.44-1.91 (m, 9H), 2.60 (s, 3H), 2.60-2.70 (m, 1H), 2.83-2.98 (m, 1H), 3.08 (t, J=11.4 Hz, 1H), 3.64 (t, 3H), 7.47 (t, J=8.3 Hz, 1H), 7.80 (dd, J=8.1, 1.0 Hz, 1H), 7.83-7.89 (m, 1H), 8.31 (d, J=7.5 Hz, 1H); MS (ESI+) m/z 423 (M+H)+. Anal. Calculated for C20H27ClN4O2S: C, 56.79; H, 6.43; N, 13.29. Found: C, 56.42; H, 6.41; N, 12.98.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[C:24]1([CH:30]([OH:33])[C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:32]#[C:31][CH:30]([OH:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: C#CC(O)c1ccccc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CC(O)c3ccccc3)oc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 79, 0.593 g) was suspended in a mixture of triethylamine (15 mL) and DMF (3 mL). CuI (0.029 g), Pd(PPh3)2Cl2 (0.105 g), and then 1-phenyl-2-propyn-1-ol (0.36 mL) were added. The reaction mixture was stirred at room temperature for 30 min and then was partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was separated and then extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with a sat. aq. ammonium chloride solution (100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from methanol to yield 0.260 g of the title compound as a yellow solid. Physical characteristics. M.p. 209-211° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.48, 8.60, 7.53-7.51, 7.43-7.32, 6.43, 5.73, 4.55, 3.91; MS (ESI+) m/z 447 (M+H)+.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>CCOCC>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[N:7]=2)[N:13]=1
Reactant: C/C=C/C#N
Reactant: NNc1cccc(Cl)n1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CC1CC(N)=NN1c1cccc(Cl)n1

Procedure:
A 0.23 g. amount of sodium metal is dissolved in 75 ml. of absolute ethanol, then 7.2 g of 2-chloro-6-hydrazinopyridine is added followed by 3.4 g. of distilled crotononitrile. The reaction mixture is refluxed for 18 hours and the procedure of Example 5 is followed through the anhydrous magnesium silicate filtration step. The filtrate is evaporated to give a dark orange gum which crystallizes on standing. The residue is dissolved in ether, treated with activated charcoal and filtered through diatomaceous earth. The filtrate is concentrated while adding hexane at reflux to yield an oil. The oil is seeded and cooled. Ether is added and continued cooling provides light yellow crystals. The mixture is filtered to give 5.2 g. of the desired product as pale yellow crystals, m.p. 105°-107° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[Se](=O)=[O:16]>>[CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:16])=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2ccc(N(C)C)cc2n1
Product: CN(C)c1ccc2ccc(C=O)nc2c1
Temperature: 90 °C
Yield: 41.7 %

Procedure:
Referring to FIG. 21, compound 13a (304.3 mg, 1.63 mmol) was dissolved in m-xylenes (2 mL) and stirred under a nitrogen atmosphere. Selenium dioxide (272.29 mg 2.45 mmol) was added and the yellow-orange mixture was heated to 90° C. for 4 h. The black reaction mixture was filtered through cotton, washing several times with chloroform. The filtrate was directly adsorbed onto silica gel and purified by column chromatography (EtOAc) to afford 14a (136.4 mg, 0.68 mmol, 42%) as a pale yellow oil: 1H NMR (CDCl3,) δ 10.11 (1H, s), 8.11 (1H, d, J=8.0 Hz), 7.74 (1H, d, J=8.4 Hz), 7.73 (1H, d, J=8.0 Hz), 7.31 (1H, dd, J=9.6, 2.8 Hz), 7.23 (1H, d, J=1.6 Hz), 3.15 (6H, s); 13C NMR (CDCl3,) δ 194.5, 153.0, 151.9, 150.2, 136.9, 128.6, 123.1, 119.1, 113.8, 107.0, 40.7; FTIR (neat) 2920, 1705, 1620, 1537, 1508, 1382, 1255, 1155, 1066, 835, 761 cm−1; MS (ESI) m/z calculated for (C12H12N2O+H)+ 201, found, 201; HRMS (ESI) m/z calculated for (C12H12N2O+H)+ 201.1028, found, 201.1055.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:17]2[CH:18]=[C:19]([CH2:21][O:22][C:23]3[CH:28]=[C:27]([C:29](OC)=[O:30])[CH:26]=[CH:25][N:24]=3)[N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:11][C:12]1[N:17]2[CH:18]=[C:19]([CH2:21][O:22][C:23]3[CH:28]=[C:27]([CH2:29][OH:30])[CH:26]=[CH:25][N:24]=3)[N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
Diisobutylaluminium hydride (1.0M tetrahydrofuran solution, 30 ml) was added to a solution of methyl 2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridinecarboxylate (3.97 g) in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 30 minutes. Sodium sulfate decahydrate (12.2 g) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The resulting colorless crystals were collected by filtration to obtain 2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethanol (3.12 g, yield 86%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 143–144° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:10][C:9]=1Br)(C)(C)C.[C:23]1(B(O)O)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:15][NH:16][C:17](=[O:20])[NH:18][CH2:19]2)=[CH:10][C:9]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1Br
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[2-Bromo-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (99 mg, 0.26 mmol, as prepared in the previous step) was dissolved in TFA (1 mL). The resulting mixture was stirred at RT for 30 min and concentrated in vacuo. The residue obtained was dried in vacuo for 1 h and dissolved in EtOH (0.5 mL) and toluene (1 mL). To this solution cyclohex-1-enyl boronic acid (20.5 mg, 0.16 mmol), 2M Na2CO3 (0.5 mL, 1 mmol) and Pd (PPh3)4 (30 mg, 0.025 mmol) were added. The resulting mixture was heated at 80° C. overnight. The reaction mixture was allowed to cool to RT and extracted with EtOAc (2×10 mL). The EtOAc layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was purified on silica (2% MeOH-EtOAc) to afford the title compound (31 mg) contaminated with Ph3PO, which was used in the next step without further purification: Mass spectrum (ESI, m/z): Calcd. for C16H21N3O, 272.1 (M+H). found 272.1.
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]#[C:17]Br>CCOCC>[CH2:9]([N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]1=[N:2][C:17]#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cccc[n+]1Cc1ccccc1
Reactant: N#CBr
Agent: [Br-]
Solvent: CCOCC
Product: N#CN=c1ccccn1Cc1ccccc1
Yield: 43.5 %

Procedure:
5.3 g (20 mmole) of 2-amino-1-benzylpyridinium bromide [prepared according to Chem. Ber. 88, 1103 (1955)] are suspended in 20 ml of ether, then 20 ml of aqueous sodium hydroxide solution of 0.5 mole/liter concentration are added while stirring. After the dissolution of the solid phase the phases are separated and the aqueous phase is extracted with 20 ml of ether. The combined organic phase is dried over anhydrous sodium sulfate and evaporated to its half volume under reduced pressure. Then, a solution containing 1.1 g (10 mmole) of cyanogen bromide in 5 ml of ether is dropped to the ethereal solution at room temperature under stirring. After stirring for 30 minutes the crystalline precipitate is filtered, washed with ether and then with a great volume of water, then the product is dried in air to yield 0.91 g (44%) of the named product, m.p.: 139°-140° C. (after recrystallization from ethanol the melting point raises to 147°-148° C.). On the basis of its melting point, infrared spectrum and thin layer chromatography (TLC) characteristics, this product proved to be indentical to the target compound of Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](I)[CH:24]=[CH2:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:25]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:24]=[CH2:23]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: C=CCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 100 °C
Yield: 29.8 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 989 mg, 3.25 mmol), tetrabutylammonium iodide (600 mg, 1.63 mmol) and allyl iodide (1.05 mL, 9.75 mmol) in dimethylformamide (5.7 mL) was heated in an oil-bath at 100° C. overnight. The solvent was evaporated and dichloromethane (400 mL) was added. The solution was washed with aqueous sodium thiosulfate (2×100 mL) and the combined aqueous washes were back-extracted with dichloromethane (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), filtered, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated successively with methanol, ether, and petroleum ether. The residue was triturated with hexane and the solid was dried under high vacuum at 70° C. overnight and then at 85° C. for 1 h to give (4R,7S)-1-allyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (334 mg, 30%) as an off-white solid. APCI(+)-MS (M+H) 345.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[CH:23]1([NH:29][C:30]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)NC4CCCCC4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 50.8 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and cyclohexylisocyanate (0.39 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×100 mL), dried (MgSO4) and concentrated. The crude product was purified by prep-HPLC (40/60 CH3CN/H2O). The product fractions were combined, concentrated and dried in vacuo to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.65 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.16 min (99.05%); mp: 208-210° C.; 1H NMR (DMSO-d6) δ 1.01-1.36 (m, 5H), 1.46-1.83 (m, 5H), 2.00-2.14 (m, 1H), 2.53-2.66 (m, 2H), 2.79-3.01 (m, 1H), 3.34-3.44 (m, 1H), 4.36 (d, J=6.0 Hz, 2H), 5.14 (dd, J=5.3, 12.8 Hz, 1H), 6.00 (d, J=7.9 Hz, 1H), 6.42 (t, J=5.9 Hz, 1H), 7.67-7.79 (m, 2H), 7.87 (d, J=7.6 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.01, 24.50, 25.27, 30.93, 33.23, 42.67, 47.97, 48.97, 121.54, 123.39, 129.50, 131.53, 133.07, 149.49, 157.28, 167.05, 167.22, 169.83, 172.73; LCMS: MH=413; Anal Calcd for C21H24N4O5+0.2H2O: C, 60.76; H, 5.90; N, 13.47. Found: C, 60.61; H, 5.74; N, 13.31.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:10][CH:9]2[C:11](O)=[O:12])=[CH:4][CH:3]=1.[NH2:17]C(N)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:10][CH:9]2[C:11](=[O:12])[NH:17][C:14]3=[O:16])=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: Cc1ccc(C2(C(=O)O)CC2C(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C23CC2C(=O)NC3=O)cc1

Procedure:
A mixture of purified 1-(4-methylphenyl)-1,2-cyclopropanedicarboxylic acid (58 kg), toluene (465 kg) and urea (23.8 kg) was heated to reflux and the mixture held at reflux until the reaction was complete. On completion of the reaction period, the solution was cooled to 80–90° C. and washed with water (69 L). The lower aqueous layer was discarded. In this way (±)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexan-2,4-dione was obtained as a solution in toluene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:12][CH:11]=1)OS(C)(=O)=O.CCN(CC)CC.[OH:43][C@H:44]1[CH2:48][CH2:47][NH:46][CH2:45]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:12][CH:11]=1)[N:46]1[CH2:47][CH2:48][C@H:44]([OH:43])[CH2:45]1
Reactant: O[C@H]1CCNC1
Reactant: COC(=O)C(OS(C)(=O)=O)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-methanesulfonyloxy-acetic acid methyl ester (1.26 g, 2.5 mmol) and Et3N (0.76 g, 7.5 mmol) in CH2Cl2 (15mL) was added (S)-3-hydroxypyrrolidine (0.27 g, 3 mmol). This mixture was stirred overnight at room temperature, then diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 solution, water and brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid which was directly used in the next reaction without further purification. MS: calc'd 496 (MH+), exp 496 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[N:54][C:53]([Br:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:56][C:53]1[N:54]=[CH:55][C:50]([NH:49][C:40](=[O:42])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[N:51][CH:52]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
A stirred solution of triphenylphosphine (8.57 g, 32.6 mmol) in anhydrous methylene chloride (110 mL) under nitrogen at 0° C. was treated with N-bromosuccinimide (5.80 g, 32.6 mmol). After 15 min, 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 9.00 g, 27.2 mmol) was added to the reaction. The mixture was allowed to warm to 25° C. After stirring at 25° C. for 10 min, the reaction was treated with 2-amino-5-bromopyrazine (7.92 g, 45.6 mmol) followed by pyridine (8.79 mL, 108.8 mmol). The mixture was allowed to stir at 25° C. for 1.5 h. At this time, the reaction was diluted with methylene chloride and then was washed with a 1N aqueous hydrochloric acid solution (200 mL) followed by a 10% aqueous potassium carbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 3/7 ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (10.02 g, 76%) as a white foam: mp 77–82° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H21BrClN3O3S (M+H)+ 486.0249, found 486.0255.