Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].BrBr>ClC(Cl)=C(Cl)Cl>[CH2:1]([C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=C1CCCC1=O
Agent: BrBr
Solvent: ClC(Cl)=C(Cl)Cl
Product: CCCCCCCC1=CCCC1=O
Yield: 84 %

Procedure:
In a 100 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-heptylidenecyclopentanone (20 g) synthesized in Reference Example 6, bromine (0.05 g) and tetrachloroethylene (10 ml), followed by 4 hours of the reaction under refluxing. The reaction mixture was washed with water and the layers were separated from each other. Further, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover tetrachloroethylene, whereby a crude product (19 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 16.8 g of 2-heptyl-2-cyclopentenone (boiling point: 111° C./900 Pa; GC purity: 97.3%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:3].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH2:13]([O:20][C:21]([N:5]1[C:6](=[O:11])[CH2:7][C:8]([CH3:9])([CH3:10])[NH:3][C:2]([CH3:1])([CH3:12])[CH2:4]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)CC(=O)NCC(C)(C)N
Solvent: c1ccccc1
Product: CC1(C)CC(=O)N(C(=O)OCc2ccccc2)CC(C)(C)N1

Procedure:
A mixture of 17 parts of 2,2,7,7-tetramethyl-1,4-diazaheptan-5-one, 19 parts of benzylchloroformate and 250 parts of dry benzene was heated at reflux for 16 hours. The solvent was then evaporated in vacuo to yield an almost colourless oil. Addition of 20 parts of petroleum ether (of boiling range 40° to 60°C) produced 4-benzyloxycarbonyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a colourless solid of melting point 86° -88°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][CH2:5][N:6]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)(=[O:24])=[O:23])[C@@H:7]([C:12]([O:14]CC1C=CC=CC=1)=O)[C:8]([CH3:11])([CH3:10])[CH3:9].O1CCCCC1[O:40][NH2:41].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.O.O.O.O.O.O.O.O.O.O.C(=O)(O)[O-].[Na+].Cl>CO.[Pd].CN(C=O)C>[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][CH2:5][N:6]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)(=[O:24])=[O:23])[C@@H:7]([C:12]([NH:41][OH:40])=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1cccc(S(=O)(=O)N(CCCN(C)C)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Reactant: NOC1CCCCO1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1cccc(S(=O)(=O)N(CCCN(C)C)[C@@H](C(=O)NO)C(C)(C)C)c1
Reaction time: 78 h
Yield: 89.2 %

Procedure:
To a de-gassed solution of benzyl N[3-(dimethylamino)propyl]-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate (500 mg, 0.634 mmol) in methanol (10 mL), catalytic palladium on carbon (10% on activated carbon, 7 mg, 0.063 mmol) is added and the reaction mixture is stirred vigorously under hydrogen for 78 h. The reaction mixture is diluted with anhydrous DMF (5 mL), concentrated in vacuo to remove methanol. To the DMF solution of the acid intermediate, O-(tetrahydro-2H-pyranyl)hydroxylamine (149 mg, 1.27 mmol), EDC·HCl (249 mg, 1.27 mmol), and HOAt (173 mg, 1.27 mmol) are added at rt. The reaction was allowed to stir at rt for 18 h and was complete by LC/MS. To the reaction mixture, sodium bicarbonate decahydrate (779 mg, 2.64 mmol) is added and is stirred vigorously for 30 min. The decahydrate crystals are filtered, and the filterate is concentrated in vacuo, and purified by silica gel chromatography eluting with 15-100% EtOAc/heptanes to obtain 250 mg of the THP-protected hydroxamide intermediate. (81% yield over 2 steps). To the solution of the intermediate in methanol (1 mL), concentrated hydrochloric acid solution (37% in water, 840 mL, 0.70 mmol) is added dropwise. The reaction mixture is stirred for 15 min, resulting in the precipitation of slightly pink white solid. The precipitate is washed with methanol and ether, then dried in vacuo to give the desired product as a white solid (227 mg, 100% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm 10.82 (s, 1H), 9.86 (br s, 1H), 8.91 (s, 1H), 7.52-7.90 (m, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 3.98 (m, 1H), 3.97 (s, 1H), 3.85 (s, 3H), 3.07 (ddd, J=12, 4, 4Hz, 1H), 2.97 (m, 2H), 2.73 (br s, 6H), 2.13 (m, 1H), 1.94 (m, 1H), 1.01 (s, 9H). Mass spectrum (402.20; M+1).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.O.[CH3:34][N:35]1[CH2:42][CH2:41][CH2:40][C@@H:36]1[C:37](O)=[O:38].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:37]([C@H:36]4[CH2:40][CH2:41][CH2:42][N:35]4[CH3:34])=[O:38])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: CN1CCC[C@@H]1C(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@@H]1C(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
The mixture of compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (50 mg, 0.11 mmol), N-methyl-D-proline monohydrate (33 mg, 0.22 mmol), DIEA (180 μL, 1.1 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (210 mg, 0.55 mmol). The mixture was stirred for overnight, quenched with TFA, and subjected to reverse phase preparative HPLC to isolate the title compound (32 mg). MS found for C30H34F2N6O2 as (M+H)+ 549.5. UV: =259 nm. 1H NMR (a pair of rotomers): (CD3OD) δ 8.18 (1H, s), 7.32 (with 7.33, 2H, d, J=8.4 Hz), 7.25 (1H, m), 7.17 (1H, m), 7.13-7.07 (3H, m), 5.77 (with 5.79, 1H, s), 4.68 (2H, m), 4.57 (1H, m), 4.54 (2H, s), 3.90 (1H, m), 3.74 (1H, m), 3.27 (1H, m), 2.93 (with 2.97, 3H, s), 2.90 (2H, m), 2.68 (1H, m), 2.25 (1H, m), 2.11-1.95 (4H, m), 1.82-1.63 (2H, m) ppm.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:27][C:28]1[CH:32]=[C:31](Br)[N:30]([S:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:29]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.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>[CH3:26][N:25]([CH2:27][C:28]1[CH:32]=[C:31]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[N:30]([S:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:29]=1)[C:24](=[O:43])[O:23][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2cccs2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of crude tributyl(2-thienyl)stannane (1.1 g) and tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg) in toluene was added tetrakis(triphenylphosphine)palladium (116 mg), and the mixture was stirred under a nitrogen atmosphere at 120° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a pale-yellow oil (yield 315 mg, 73%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.CCCCCC.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[CH3:39][N:40](C=O)C>[C-]#N.[C-]#N.[Zn+2].[Zn].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([C:39]#[N:40])[CH:10]=3)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccc(Br)cc3[nH]2)cc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCC
Product: N#Cc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an oven dried 250 mL flask, 2.77 g of 2A (1 eq), 1.85 g Zn(CN)2 (1.8 eq), 68 mg of Zn powder and 160 mg (0.02 eq) of Pd2 dba3 were added followed by 75 mL of dry DMF. Under magnetic stirring, 1.07 mL of 10% hexane solution (0.04 eq) of PtBu3 was added and the mixture was stirred at room temperature for a period of 30 min followed by heating at 100° C. for another 35 min. The mixture was cooled to room temperature and poured into ice water. The solid was collected, washed with water and dried. The product was dissolved in THF, filtered and concentrated to dryness to produce crude 3 that was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[C:23]([C:29]#[N:30])=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:21]=1>>[F:28][C:25]1[CH:24]=[C:23]([C:29]#[N:30])[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:31])=[CH:27][CH:26]=1
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Reactant: N#Cc1cc(F)ccc1-c1cc(Br)ccc1F
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 44.6 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (221 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 4,2′-difluoro-5′-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)-biphenyl-2-carbonitrile (93 mg, 45%) as an off-white solid: δH (360 MHz, CDCl3) 7.00 (1H, dd, J 7 and 6), 7.40-7.47 (2H, m), 7.55 (1H, dd, J 8 and 3), 7.57-7.65 (3H, m), 7.86 (1H, s), 8.34 (1H, d, J 7); m/z (ES+) 418 (100%, [MH]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH3:17].CC([O-])=O.[K+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][N:12]1[C:16]([C:2]2[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:15][N:14]=[C:13]1[CH3:17]
Reactant: COc1cc(Br)cnc1N
Reactant: Cc1nccn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2cnc(C)n2C)cnc1N
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A suspension of 5-bromo-3-methoxypyridin-2-amine (55.5 mg, 0.273 mmol), 1,2-dimethyl-1H-imidazole (52.6 mg, 0.547 mmol), Pd(OAc)2 (2.5 mg, 0.011 mmol), KOAc (53.7 mg, 0.55 mmol) in DMA (3 mL) was stirred at 150° C. under microwave irradiation for 8 hours. The reaction mixture was filtered, diluted with NaCl solution and extracted with EtOAc. The organic layer was purified by eluting through an SCX-2 column using 2M NH3/MeOH followed by Biotage silica gel column chromatography eluting with 0-12% MeOH/EtOAc to give the title compound as yellow waxy solid (9 mg, 15%).
Reaction SMILES: CS([C:4]1(SC)[CH2:7][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1)=O.Cl(O)(=O)(=O)=[O:19].C([O-])(O)=O.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC>[CH2:9]([O:8][CH:6]1[CH2:7][C:4](=[O:19])[CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CSC1(S(C)=O)CC(OCc2ccccc2)C1
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: O=C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
([3-(methylsulfinyl)-3-(methylthio)cyclobutyl]oxymethyl)benzene (2.4 g, 0.0089 mol) was dissolved in Et2O (40 mL) and 35% perchloric acid (1.8 mL) was added. The resulting mixture was stirred at rt overnight. To the reaction mixture was added solid NaHCO3 and MgSO4 and stirred for a while. The insoluble solid was filtered off. The filtrate was concentrated and purified with combiflash (silica gel, 100% dichloromethane) to give the desired product (0.7 g) as light yellow oil. LCMS calculated for C11H13O2(M+H)+: 177.1. Found: 177.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.Cl.[NH2:15]O.O.O.O.C([O-])(=O)C.[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(O)C.O.C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:15][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)CCCCN2
Yield: 42.8 %

Procedure:
6-Methoxytetralone (6.86 g, 39 mmol), hydroxylamine hydrochloride (8.15 g, 117 mmol) and sodium acetate trihydrate (25 g, 184 mmol) were stirred at reflux in a mixture of ethanol (200 ml) and water (50 ml) for 45 min, concentrated in vacuo, and diluted with water (200 ml). The white solid (6-methoxytetralone oxide, 7.44 g) was collected and dried. A portion of this (6.31 g, 33 mmol) was stirred in dry THF (150 ml) under argon as lithium aluminium hydride (1.80 g, 47 mmol) was added portionwise. This mixture was stirred at reflux for 3 h, cooled, and treated successively with water (1.5 ml), 10% NaOH (1.5 ml) and water (4.5 ml). The solids were filtered off, and the filtrate was evaporated to give an amber oil. This was chromatographed on silica, eluting with ethyl acetate, giving the title compound (2.96 g, 50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]([CH3:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2]
Reactant: CI
Reactant: N#Cc1ccc2c(c1)CCC(NC(=O)c1ccc(-c3ccc(F)cc3)cc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(-c2ccc(F)cc2)cc1)C1CCc2cc(C#N)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-Fluoro-biphenyl-4-carboxylic acid (6-cyano-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, 3, (0.200 g, 0.541 mmol) in anhydrous DMF (4 mL) is added 60% NaH dispersed in mineral oil (32 mg, 1.5 eq.) and the resulting solution is stirred at room temperature for 30 min. Methyl iodide (0.101 mL, 3 eq.) is added to the solution and the reaction solution is stirred for another 30 min. A minimal amount of water is added to quench the reaction and the mixture is dried over anhydrous MgSO4 then concentrated in vacuo to afford 0.201 g of the desired product which is used without further purification. LRMS: 385.22 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Br[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: BrCC1CCCO1
Product: Cc1cc(OCC2CCCO2)cc(C)c1Br

Procedure:
The title compound is prepared from 4-bromo-3,5-dimethylphenol and 2-(bromomethyl)tetrahydrofuran following a procedure analogous to that described in Step 3 of Intermediate 2. LC (method 1): tR=1.37 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[C@H:47]([CH3:48])[CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:49])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[C@H:47]([CH3:48])[CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:49])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:60]([CH3:59])(=[O:62])=[O:61])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 130a (175 mg, 0.26 mmol) in DCM (2.5 mL) was added DIPEA (184 μL, 1.0 mmol) followed by methanesulfonyl chloride (41 μL, 0.52 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.72 min, m/z 741 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]([OH:28])=O)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:47]([NH:50][NH2:51])(=[O:49])[CH3:48]>C1COCC1>[C:47]([NH:50][NH:51][C:26](=[O:28])[CH2:25][C:21]1[C:22](=[O:24])[N:23]=[C:18]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:29]([F:30])([F:32])[F:31])[CH:4]=3)=[CH:10][CH:11]=2)[NH:19][CH:20]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)NN
Reactant: O=C(O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(=O)NNC(=O)Cc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
To a solution of (2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-4-oxo-1,4-dihydro-5-pyrimidinyl)acetic acid (91 mg, 0.194 mmol) in THF (2 mL) was added EDC (149 mg, 0.776 mmol) and HOBT (89 mg, 0.582 mmol). The mixture was stirred at room temperature for 15 min and acetohydrazide (21.57 mg, 0.291 mmol) was added. The mixture was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (28 mg, 0.053 mmol, 27.5% yield). LCMS: rt=3.04 min, [M+H+]=525
Reaction SMILES: C[N:2]1C(=O)CCC1.N.Br[C:10]1[CH:18]=[C:17]([Cl:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][CH3:21])[N:15]=2)[CH:11]=1>C(OCC)(=O)C.[Cu](I)I>[Cl:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][CH3:21])[N:15]=2)[CH:11]=[C:10]([NH2:2])[CH:18]=1
Reactant: CCn1cc2cc(Br)cc(Cl)c2n1
Reactant: CN1CCCC1=O
Agent: I[Cu]I
Agent: N
Solvent: CCOC(C)=O
Product: CCn1cc2cc(N)cc(Cl)c2n1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Copper oxide (I) (200 mg), NMP (7 mL), and concentrated aqueous ammonia (7 mL) were added to 5-bromo-7-chloro-2-ethyl-2H-indazole obtained in the above-described Step 1 (1.43 g), and the reaction solution was stirred in a microwave reactor at 80° C. for 10 hours. The reaction solution was cooled to room temperature, and diluted with ethyl acetate. Thereafter, the reaction solution was washed successively with water four times and then with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 7-chloro-2-ethyl-2H-indazol-5-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)N1CCNCC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution containing 12.1 g of 2,5-dibromopyridine (51.1 mmol), 8.8 ml of 1-isopropyl-piperazine (61.5 mmol) and 9.2 ml of DBU (61.5 mmol) is stirred overnight at 100° C. The reaction mixture is returned to ambient temperature and the solution is diluted with water and extracted with ethyl acetate. The organic phases are collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue is chromatographed on an SiO2 column, eluting with a mixture of CH2Cl2/MeOH 98/2 and then 96/4, to yield the title product.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)[C:50]1=[O:64]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)[C:50]1=[O:64])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: COc1cccc(N2CCCC[C@H](N)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4cccc(OC)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-methoxyphenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (24 mg, 0.042 mmol) and Intermediate 65 (19 mg, 0.055 mmol) to give a white solid (21 mg, 62% yield). Anal. Calcd. for C44H54N4O7S m/z 782.7. found: 783.7 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.02 (m, 11H), 6.83 (dd, J=8.2, 2.1 Hz, 1H), 6.69 (dt, J=4.2, 1.6 Hz, 2H), 6.42 (s, 2H), 5.32 (t, J=4.6 Hz, 1H), 5.17-5.07 (m, 1H), 5.04-4.91 (m, 1H), 4.76 (dd, J=9.7, 6.9 Hz, 1H), 3.98 and 3.78 (2s, 3H), 3.93 (dd, J=15.4, 11.6 Hz, 1H), 3.68 (s, 3H), 3.63-3.54 (m, 1H), 3.16-3.06 (m, 1H), 2.90-2.67 (m, 5H), 2.53-2.32 (m, 3H), 2.07-1.79 (m, 5H), 1.79-1.43 (m, 11H), 1.40-1.23 (m, 1H).