Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[NH:17][C:16](=[O:18])[C:15]([C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:14][N:13]=2)C[CH2:2]1.[O:24]=[C:25]1NC(C2C=C(OC)C=CC=2OCCC)=NC=C1C#N>>[CH3:25][O:24][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:1][CH3:2])=[C:7]([C:12]2[NH:17][C:16](=[O:18])[C:15]([C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:14][N:13]=2)[CH:8]=1
Reactant: O=c1[nH]c(-c2ccccc2OCC2CC2)ncc1-c1nnn[nH]1
Reactant: CCCOc1ccc(OC)cc1-c1ncc(C#N)c(=O)[nH]1
Product: CCCOc1ccc(OC)cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1

Procedure:
In a manner similar to that described for the preparation of 2-(2-cyclopropylmethoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one in Example 9, the title compound was prepared from 1,6-dihydro-6-oxo-2-(5-methoxy-2-n-propoxyphenyl)pyrimidine-5-carbonitrile. The crude product was recrystallized from 2-methoxyethanol to give analytical material (65%), m.p. 257°-260°.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:12]2[C@H:8]([O:9][CH2:10][CH2:11]2)[O:7][CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl>[O:7]1[C@H:8]2[O:9][CH2:10][CH2:11][C@H:12]2[C@@H:5]([OH:4])[CH2:6]1
Reactant: CC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 30 °C
Reaction time: 7 h
Yield: 99.2 %

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate (II, 14.0 g) was dissolved in methanol (42 mL). Potassium carbonate (0.34 g) was added and stirred at 25-35° C. for 6-8 hours. Methanol Was distilled out completely under vacuum, to the distillate methylenedichloride (28 mL) was added, stirred the mass for 30 minutes and again distilled the solvent to get residue. Dissolved the residue in dichloromethane (56 mL), the resultant solution was treated with carbon and the solvent was completely distilled out get title compound I (yield 10.5 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>CC(C)=O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25]([NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[O:26]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCC(C(=O)O)c1ccc(CCN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(C(=O)O)c1ccc(CCNC(=O)c2cc(Cl)ccc2OC)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6.2 g 2-[4-(2-Aminoethyl)-phenyl]-butyric acid hydrochloride are suspended in 100 ml acetone. After the addition of 50 ml 2 N aqueous sodium hydroxide solution, a solution of 4.8 g 5-chloro-2-methoxybenzoyl chloride in 50 ml acetone is added dropwise thereto at ambient temperature and the reaction mixture then stirred for 2 hours at 50° C. After cooling, the reaction mixture is evaporated in a vacuum and the aqueous solution acidified with dilute hydrochloric acid. The 2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-butyric acid obtained solidifies upon triturating with diisopropyl ether and is recrystallized from diisopropyl ether. The yield is 3.2 g (42.5% of theory); m.p. 120°-122° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CC[N:21]([CH:25]([CH3:27])C)[CH:22](C)C.N1CCC1.[NH4+].[Cl-]>C(Cl)Cl.CCOC(C)=O>[N:21]1([S:2]([C:5]2[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3])[CH2:22][CH2:27][CH2:25]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (0.3 g, 991 μmol; Buttpark Ltd.) in CH2Cl2 (1 mL) were added DIPEA (192 mg, 260 μL, 1.49 mmol) and azetidine (62.3 mg, 73.5 μL, 1.09 mmol). The clear, light yellow solution was stirred at room temperature for 4 hours and then poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, and evaporated. Light brown solid (0.316 g; 98%). MS (EI): m/z=323 [M].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].[CH2:33]([O:40][P:41]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[C:45]=1[C:52]([CH3:58])([CH3:57])[CH2:53][C:54](O)=[O:55])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:60]([O:59][P:41]([O:40][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[C:45]=1[C:52]([CH3:58])([CH3:57])[CH2:53][C:54]([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)=[O:55])=[O:42])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: Cc1cc(C)c(C(C)(C)CC(=O)O)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(C(C)(C)CC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
Tolvaptan (0.63 g), 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyric acid (0.70 g), and 4-dimethylaminopyridine (DMAP) (24 mg, 0.22 mmol) were suspended in dichloromethane (10 ml). N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (WSC) (383 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=70:30→35:65). The purified product was concentrated under reduced pressure to obtain 0.92 g of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate as white amorphous solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[Na+].Cl>C1COCC1.O>[CH3:11][Si:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:4]=[C:3]([Si:2]([CH3:16])([CH3:1])[CH3:17])[CH:8]=1
Reactant: CC(=O)c1cc([Si](C)(C)C)cc([Si](C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1cc(C(=O)C=Cc2ccc(C(=O)O)cc2)cc([Si](C)(C)C)c1
Yield: 65.7 %

Procedure:
Under ice-cooling, to a solution of 114 mg (0.43 mmol) of 3',5'-bis(trimethylsilyl)acetophenone and 70 mg (0.43 mmol) of methyl 4-formylbenzoate in 3 ml of THF was added a solution of 40 mg (1.00 mmol) of NaOH in 2 ml of H2O with stirring, and the mixture was stirred in an atmosphere of prepurified argon overnight. The reaction mixture was further added to 39 mg of NaOH, stirred for 2 days, and then the solution was adjusted with 2N-HCl to pH≤7 and extracted with ethyl acetate. The extract was dried and evaporated. The residue was purified by column chromatography using methylene chloride-methanol (10:1) as an eluant to give 112 mg of the desired compound (yield 66%), which was recrystallized from a mixture of ethyl acetate and n-hexane to give 98 mg of pale yellow prisms, m.p. 194°-195.5° C. (yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[N+:20](=[CH:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])=[N-:21]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[C:22]([C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:20][NH:21][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C#CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(C(=O)c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Yield: 74.3 %

Procedure:
A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-oxo-2-butynoate (prepared as described in Example 48(a)) (1.2 g, 4.11 mmol) and diazoacetophenone (1.2 g, 8.22 mmol, prepared as described in Org. Syn. Coll. Vol. VI, pp. 386-388) in tetrahydrofuran (THF) (21.6 mL) was stirred at room temperature for 16 hours. The reaction was concentrated by rotary evaporation and purified by flash chromatography eluting with hexanes:ethyl acetate (90:10, 80:20, 70:30) to give the title compound (1.3 g, 74.3%); Rf 0.38 (1:1 ethyl acetate:hexanes).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][N:60]1[C:64]([CH3:65])=[CH:63][C:62]([CH2:66]O)=[N:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:62]2[CH:63]=[C:64]([CH3:65])[N:60]([CH3:59])[N:61]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(CO)nn1C
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cc(C)n(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (1,5-dimethyl-1H-pyrazol-3-yl)methanol (0.53 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.80 g, 61%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([OH:33])=[O:32]>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([O:33][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:32]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: CN1CCC(=NO)CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CN1CCC(N=O)(OC(=O)c2cc(F)cc(F)c2)CC1

Procedure:
1-Methyl-4-nitrosopiperidin-4-yl 3,5-difluorobenzoate is prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and 3,5-difluorobenzoic acid using conditions of General Method 3.
Reaction SMILES: [CH2:1](Cl)[O:2][CH3:3].[I:5][C:6]1[CH:11]=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[N:9]=[C:8]([O:16][CH3:17])[C:7]=1[CH2:18][OH:19].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[I:5][C:6]1[CH:11]=[C:10]([Si:12]([CH3:14])([CH3:13])[CH3:15])[N:9]=[C:8]([O:16][CH3:17])[C:7]=1[CH2:18][O:19][CH2:1][O:2][CH3:3]
Reactant: COCCl
Reactant: COc1nc([Si](C)(C)C)cc(I)c1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1c(I)cc([Si](C)(C)C)nc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
MOMCl (2.0 mL, 26.7 mmol) was added dropwise to a 0° C. solution of 2a (3 g, 8.9 mmol) and iPr2EtN (4.6 mL, 26.7 mmol) in dry CH2Cl2 (35 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 5% aq. NaHCO3 solution and the product was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 3.0 g (88% yield) of the crude product 3a as an orange oil. The crude product was sufficiently pure for the subsequent reaction. 1H NMR (300 MHz, CDCl3) δ0.27 (s, 9H), 3.46 (s, 3H), 3.98 (s, 3H), 4.71 (s, 2H), 4.75 (s, 2H), 7.51 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−2.08, 53.79, 55.53, 67.85, 96.39, 113.84, 122.6, 132.98, 161.43, 166.37; IR (film, NaCl, cm−1) 2946, 1528, 1340, 1042, 840; LRMS (70 eV, EI) m/z (rel int %) 381 (M+), 366, 336, 320, 306, 169, 128, 84 (100), 73. HRMS m/z calcd for C12H20NO3SiI (M+) 381.0257, found 381.0241.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[N:5][N:6]=1.[Li]CCCC.[CH2:12]([O:14][CH2:15][C:16](OCC)=[O:17])[CH3:13]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:16]([CH2:15][O:14][CH2:12][CH3:13])=[O:17])=[N:5][N:6]=1
Reactant: CCOCC(=O)OCC
Reactant: Cc1nnco1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOCC(=O)c1nnc(C)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 2-methyl-1,3,4-oxadiazole (5.0 g, 59.5 mmol) in THF (100 mL) was added dropwise n-BuLi (23.79 mL, 59.5 mmol) in toluene under N2 at −78° C. After 1 h, ethyl ethoxyacetate (10.22 g, 77 mmol) was added. The reaction mixture was then allowed to warm to −40° C. and stirred for 2 h. The reaction mixture was then quenched with 65 mL of LON HCl and extracted with EtOAc. The organic layer was washed with water and then brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified on a flash chromatography column (Biotage™-40M) using a gradient of 0-100% of n-hexane/Et2O to give the desired product. 1H NMR (500 MHz, CD3OD): δ 1.27 (t, 3H), 2.64 (s, 3H), 3.69 (q, 2H), 4.88 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[N:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1.CN(C1C=CC=CN=1)C>[C:37]([O:36][C:34]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[N:10]=1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: COC(=O)c1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(CO)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 56.5 %

Procedure:
Methyl 2,6-di(bis(tert-butoxycarbonyl)amino)pyrimidine-4-carboxylate Crude methyl 2,6-diaminopyrimidine-4-carboxylate (2.52 g, 15 mmol) was suspended in dry tetrahydrofuran (200 ml) then treated sequentially with di-tert-butyl dicarbonate (19.6 g, 90 mmol), triethylamine (16.7 ml, 120 mmol), and 4 dimethylaminopyridine (0.092 g, 0.75 mmol). This mixture was refluxed gently for 16 h, evaporated, dissolved in diethyl ether, washed with water and brine, dried and evaporated to give a dark red gum. This residue was purified by flash chromatography, eluting with 0-18% ethyl acetate in petroleum ether, to give the title compound as an off-white foam (4.58 g, 54%); m/z (APCI+) 569 [MH]+100%.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].O.[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[CH2:14]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.6 %

Procedure:
To a solution of 2-mercaptobenzimidazole (4.95 g, 33 mmol) in methanol (150 mL) and 2N NaOH/H2O (50 mmol) was added octyl bromide (7.16 g, 33 mmol). The solution was stirred at ambient temperature for 72 hours, during which a suspension formed which was filtered and the solid residue dissolved in CH2Cl2, washed with saturated NaHCO3, and dried over Na2SO4. Evaporation of the solvent gave the title compound as a white solid (6.2 g, 72%). m.p. 110°-113° C. NMR CDCl3)δ7.4(m, 4H), 3.22(t, J=8 Hz, 2H), 1.20(br, 15H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[C:5]=1[F:23].[N-:25]=[N+:26]=[N-:27].[Na+].[Si](Cl)(Cl)(Cl)Cl>C(#N)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[N:27][N:26]=[N:25]2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[C:5]=1[F:23]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cn2)c1F
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-n2nnnc2C(C)C)cc(-c2ccc(C)cn2)c1F
Temperature: 25 °C
Yield: 90822.2 %

Procedure:
2-Fluoro-5-isobutyrylamino-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (690 mg, 1.89 mmol), NaN3 (1.1 g, 17 mmol) and SiCl4 (964 mg, 5.67 mmol) were added 20 mL acetonitrile, and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCO3, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 610 g (83%) of 2-fluoro-5-(5-isopropyl-tetrazol-1-yl)-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3CO2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[C:37]([N:40]1C2C(=CC=C(NS(C3C=CC(F)=CC=3Br)(=O)=O)C=2C(OC)=O)[C@H]2CCO[C@H]2[CH2:41]1)(=[O:39])[CH3:38]>>[C:37]([N:40]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([NH:17][S:14]([C:8]3[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=3/[CH:6]=[CH:5]\[CH2:4][N:3]([CH2:1][CH3:2])[CH2:35][CH3:36])(=[O:15])=[O:16])[C:27]=2[C:28]([O:30][CH3:31])=[O:29])[C@H:22]2[CH2:34][CH2:33][O:32][C@H:23]2[CH2:41]1)(=[O:39])[CH3:38]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)N(C(C)=O)C[C@@H]1OCC[C@H]21
Temperature: 80 °C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl cis-(3aRS,9bRS)-5-acetyl-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 28) and heating at 80° C. for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[NH:9][CH2:10][CH2:11][N:12]2[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:6].N1C=CC=CC=1.[Br:36][CH2:37][C:38](Br)=[O:39]>C(Cl)Cl>[Br:36][CH2:37][C:38]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:5](=[O:6])[C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[CH:3]=2)[N:12]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10]1)=[O:39]
Reactant: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2C(=O)OCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1)c1cccc2c1N(C(=O)CBr)CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of benzyl 5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1D (50 g, 123 mmol) in DCM (500 mL) at 0° C. was added pyridine (14.91 ml, 184 mmol). Bromoacetyl bromide (26.7 ml, 307 mmol) in DCM (1.0 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with H2O, saturated NaHCO3, and brine, dried over Na2SO4, filtered, concentrated to afford benzyl 4-(2-bromoacetyl)-5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1E (55 g, 104 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.0 (1H, bs), 7.85 (1H, s), 7.75 (1H, m), 7.6 (2H, m) 7.4 (7H, m), 7.10 (1H, m), 5.3 (2H, s), 4.15 (2H, m), 4.0 (2H, m), 3.8 (2H, m).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:36])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]#[CH:27])[N:24]=3)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[N:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)=[N+:38]=[N-:39].CC(O)(C)C>S([O-])([O-])(=O)=O.[Cu+2].[Cu].O>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:36])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[N:39]=[N:38][N:37]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH:27]=4)[N:24]=3)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: [N-]=[N+]=NC1CCCC1
Reactant: C#Cc1cnc2c(n1)c(C(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1)cn2COCC[Si](C)(C)C
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-c3cn(C4CCCC4)nn3)cnc21
Temperature: 125 °C
Yield: 68.8 %

Procedure:
A microwave vial was charged with 2-ethynyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol), azidocyclopentane (32.9 mg, 0.3 mmol), t-BuOH (0.6 mL), and H2O (0.6 mL). To this sticky mixture was added 1.0 M aqueous copper (II) sulfate (39.5 μL, 0.04 mmol) and copper powder (10.0 mg, 0.16 mmol). The vial was sealed and the heterogeneous reaction mixture was heated in a microwave reactor at 125° C. for 5 min. The reaction mixture was cooled to room temperature and filtered, rinsing with EtOAc. The filtrate was washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes) to afford 85 mg (70%) of 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as an off-white foamy solid.