Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[C:8]1([C:7](=[N:6][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:33])([CH3:34])[O:27]2)[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OB(CCCCBr)OC1(C)C
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N=C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 64.3 %

Procedure:
A solution of N-(diphenylmethylene)glycine ethyl ester (8.24 g, 30.8 mmol) and 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.92 g, 33.9 mmol) in freshly distilled THF (77 mL, 0.4 M) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (32.3 mL, 1.0 M in THF). Once the addition was complete, the reaction was warmed to 50° C. and heated for 8 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Rapid purification by MPLC (1-15% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave ethyl 2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (8.9 g, 64%). Rf 0.40 (30% ethyl acetate in heptane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[O:17][CH2:18][C:19](=[O:26])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>C(O)C>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29]([CH:36]=[C:18]2[O:17][C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=3)=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]2=[O:26])=[CH:28]1
Reactant: CCOC(=O)C1=C(Nc2ccc(NC(=O)OC(C)(C)C)cc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(NC(=O)OC(C)(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.32 g, 0.88 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.13 g, 0.88 mmol) in ethanol (5.0 mL), piperidine (0.18 mL, 1.8 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[(tert-butoxycarbonyl)amino]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.095 g, y. 21%).
Reaction SMILES: [CH:1]1([CH:7]([N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH2:8]OC2C=CC(C(O)=O)=CN=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=1>>[CH3:40][O:41][C:42](=[O:52])[C:43]1[CH:48]=[C:47]([CH3:49])[C:46]([O:50][CH2:8][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:19]2[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=[C:20]2[C:30]2[C:31]([O:38][CH3:39])=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)=[C:45]([CH3:51])[CH:44]=1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2ccc(C(=O)O)cn2)C2CCCCC2)c(OC)n1
Product: COC(=O)c1cc(C)c(OCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)c(C)c1
Yield: 27 %

Procedure:
The title compound was prepared according to Example 4, intermediate, from 2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethanol (Example 73, intermediate b), 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester (commercially available), tri-N-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The resulting powder was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:tert-butyl methyl ether (100:0 to 50:50) to give the desired compound as an off-white solid (27%). MS (Turbo Spray): m/z=580.3 [M+H].
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12]([C:14]1[N:15]=[N:16][C:17]([Cl:22])=[CH:18][C:19]=1[O:20][CH3:21])=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:22][C:17]1[N:16]=[N:15][C:14]([CH2:12][OH:11])=[C:19]([O:20][CH3:21])[CH:18]=1
Reactant: COC(=O)c1nnc(Cl)cc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Cl)nnc1CO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
DIBAL (1N solution in THF, 4 mL) is added to a stirred solution of 6-chloro-4-methoxy-pyridazine-3-carboxylic acid methyl ester (182 mg, 0.9 mmol) in CH2Cl2 (10 mL) cooled to 0° C. The solution is stirred at 0° C. for 3 hours. Excess (Na2SO4).10H2O is then added and the mixture is stirred at room temperature for 45 minutes. The solid is washed with EtOAc, filtered, and the filtrate evaporated in vacuo. The resulting alcohol is used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]Cl.[Na+].[CH3:21][OH:22]>C(O)(=O)C>[CH3:21][O:22][C:16]([CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)=[O:17]
Reactant: CO
Reactant: O=CC1CCC(COCc2ccccc2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: COC(=O)C1CCC(COCc2ccccc2)CC1
Yield: 65 %

Procedure:
4-Benzyloxymethyl-cyclohexanecarbaldehyde (1.70 g, 2.0 mmol) is dissolved in acetic acid (0.24 mL) and 2 mL of methanol. The reaction mixture is cooled to 0° C. to 5° C. and stirred while 10% NaOCl solution (2.5 mL, 4 mmol) is added dropwise over 20 minutes. The cooling bath is removed, and the mixture is allowed to come to room temperature. After addition of saturated aqueous NaHCO3, the mixture is extracted with EtOAc. The combined organic layer after dried over MgSO4 is concentrated to obtain 4-benzyloxymethyl-cyclohexanecarboxylic acid methyl ester as clear oil (343 mg, 65%) after purification.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:19][CH2:20]Br>CN(C)C=O.O>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:20][CH:19]=[C:18]([CH3:17])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCC(C)=CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
To a solution of p-nitrophenol (2 g.) in dimethylformamide (10 ml.) is added anhydrous potassium carbonate (2 g.) and 3,7-dimethylocta-2,6-dienyl bromide (3.1 g.). The reaction is kept at 50° for 12 hours, diluted with water and extracted with ether. The ethereal extract is washed with 5% aqueous sodium hydroxide and dried over sodium sulfate. The crude product is purified by distillation to yield 3,7-dimethylocta-2,6-dienyl p-nitrophenyl ether.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1csc(Cl)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc(C)cs2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-4-methylthiazole. ESI-MS (m/z): 411 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13](I)=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: CNCCO
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnc(I)s1
Solvent: CC(C)=O
Product: CN(CCO)c1ncc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
130 mg (0.219 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(2-iodo-1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were initially charged in 2.5 ml of acetone, 0.885 ml (10.963 mmol) of 2-(methylamino)ethanol was added and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated and the product was isolated by preparative HPLC. This gave 74 mg (63% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:19])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:25][CH2:26]O>>[CH2:25]([O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[Cl:19])[CH3:26]
Reactant: CCO
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-benzyloxy-2-chloro-phenyl)-acetic acid (1.5 g, 5.4 mmol) in EtOH (30 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was worked up to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[S:11]([NH:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])(=[O:13])(=[O:12])[NH2:14]
Reactant: NS(N)(=O)=O
Reactant: Cc1sc(N)c(C#N)c1C
Solvent: C1COCCO1
Product: Cc1sc(NS(N)(=O)=O)c(C#N)c1C
Temperature: 25 °C
Yield: 19.7 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (Example 4b) (1.0 g, 6.57 mmol) in 1,4-dioxane (50 mL) was added sulfamide (3.87 g, 40.30 mmol). The reaction mixture was heated to reflux for 24 hr, after cooled to room temperature, the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with EtOAc/Hexanes (2:3) to give 300 mg of product as a dark red oil. 1H NMR (400 MHz, DMSO-d6) δ 2.09 (3, 3H), 2.26 (s, 3H), 7.32 (s, 2H), 10.17 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([OH:16])=[O:15].[CH3:17]O>>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
After adding thionyl chloride (3.80 ml) to a solution of 2-benzofurancarboxylic acid (2.00 g) in MeOH (60 ml) at −40° C., the mixture was stirred for 19 hours while the temperature gradually increased to room temperature. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=6/1) to obtain methyl 2-benzofurancarboxylate.
Reaction SMILES: C([NH:9][C:10]([NH:20][CH2:21][CH2:22][C:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])=[N:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)(=O)C1C=CC=CC=1.[ClH:37]>>[ClH:37].[NH:18]1[CH:19]=[C:15]([CH2:14][CH2:13][CH2:12][NH:11][C:10]([NH2:9])=[N:20][CH2:21][CH2:22][C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[N:16]=[CH:17]1
Reactant: CC(CCNC(=NCCCc1c[nH]cn1)NC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(CCN=C(N)NCCCc1c[nH]cn1)(c1ccccc1)c1ccccc1

Procedure:
1.00 g (2.1 mmol) of N1 -benzoyl-N2 -[3-(1H-imidazol-4-yl) propyl]-N3 -(3,3-diphenylbutyl)-guanidine are boiled under reflux with 20 ml of conc. hydrochloric acid for 20 hours. After the reaction mixture has been highly concentrated by evaporation under vacuum, the residue is diluted with 30 ml of water. The solution is extracted 5 times with 20 ml portions of diethylether. The aqueous phase is then filtered and concentrated by evaporation under vacuum at temperatures of up to 50° C. and the residue is concentrated twice by evaporation with 10 ml portions of absolute ethanol. The crude product obtained is chromatographed on silica gel with dichloromethane/methanol (80:20) as solvent. After concentration by evaporation under vacuum, the main fraction yields 0.53 g (61%) of a colourless, amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30](O)=[O:31]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:31]
Reactant: C1CCNCC1
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
Piperidine (0.358 g, 4.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g, 6.30 mmol) were added to a methylene chloride solution (50 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.95 g, 2.10 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the titled compound (1.02 g, 2.09 mmol, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([OH:15])=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:30][C@H:31]1[C@@H:34]([CH2:35][N:36]2[C:40]([CH3:41])=[N:39][CH:38]=[N:37]2)[NH:33][C:32]1=[O:42].CCN=C=NCCCN(C)C.N1C=CC=CC=1>CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:29])/[C:13]([NH:30][C@@H:31]2[C:32](=[O:42])[NH:33][C@@H:34]2[CH2:35][N:36]2[C:40]([CH3:41])=[N:39][CH:38]=[N:37]2)=[O:15])[N:17]=1)=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: Cc1ncnn1C[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ncnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (310 mg, 0.72 mmol), (3S,4R)-3-amino-4-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)azetidin-2-one (130 mg, 0.72 mmol) and EDCI (150 mg, 0.79 mmol) in DMF (5 mL) at 0° C. was added pyridine (64 μL, 0.79 mmol). After stirring at rt for 24 h it was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 10%), affording the title compound (190 mg, 45%) as a white solid. LCMS: m/z=593.0 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:27][CH2:26][C@H:25]3[C@@H:20]([CH2:21][CH2:22][CH2:23][NH:24]3)[C:19]=2[CH:28]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@H:20]([C:19]5[CH:28]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc2c(c1)[C@@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1ccc2c(c1)[C@@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 77 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-9-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 77% of theory; LC (method 1): tR=2.61 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C@@H:10]([OH:20])[CH2:11][C@@H:12]([CH3:19])[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])=[O:7])(C)(C)C.[C:28]([O:32][C:33]([NH:35][C@H:36](C(O)=O)[CH2:37][C:38]1[N:39]=[CH:40][S:41][CH:42]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:6]([NH:8][C@@H:9]([CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C@@H:10]([OH:20])[CH2:11][C@@H:12]([CH3:19])[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14])=[O:7])[CH2:37][C:38]1[N:39]=[CH:40][S:41][CH:42]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Product: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Yield: 78 %

Procedure:
The procedure described in Example 5(a) was repeated, but using 280 mg (0.728 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2-methyl-N-propylhexanamide (prepared as described in Preparation 18) and 204 mg (0.75 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine, to afford 306 mg of the title compound as colorless crystals, melting at 182°-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:6][CH:7]=1
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)c1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)COc1ncc(Br)cn1
Yield: 74 %

Procedure:
A mechanically stirred slurry of 5-bromo-2-(methanesulfonyl)pyrimidine (24 g, 0.10 mol), trifluoroethanol (15 g, 0.15 mol), and potassium carbonate (28 g, 0.20 mol) in acetonitrile (250 mL) was heated at 70° C. for 12 hours. HPLC analysis indicated complete conversion. The solids were removed by filtration, and rinsed well with acetonitrile. The solvent was removed in vacuo and the residue partitioned between ether (50 mL) and water (25 mL). The aqueous phase was extracted with ether (2×25 mL), the organic layers combined, and washed with brine. Dried (Na2SO4), filtered, and solvent removed in vacuo, affording product as a pale yellow liquid, 19 g, 74 percent yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C@@H:29]1[C@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:32][C:31](=[O:40])[NH:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[C@H:29]([CH3:28])[C@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:32][C:31]3=[O:40])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)O[C@@H](c5ccccc5)[C@H]4C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 12.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (4R,5S)-(+)-4-methyl-5-phenyloxazolidin-2-one (354 mg), the title compound (134 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41](Br)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])[CH:25]=1.CN(C=O)C>CCOCC.[Cu]I.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>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[CH:36]=2)=[O:34])[CH3:31])[CH:25]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1cccnc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)c1cccnc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
6-Chloro-3-tributylstannyl-1H-indazole (584 mg, 1.32 mmol), copper(I) iodide (14 mg, 0.074 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide (350 mg, 0.74 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with nitrogen for 10 min then tetrakis(triphenylphosphine)palladium (0) (42 mg, 0.037 mmol) was added and the reaction was stirred under nitrogen at 90° C. for 15 h. The reaction mixture was cooled, diluted with ether (60 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% methanol in dichloromethane with 0.5% ammonium hydroxide) to afford 203 mg (48%) of 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=549.