Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:25](O)=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[O:26])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cc(Cl)cc(C(=O)O)c1O

Procedure:
A solution of 5-chloro-2-hydroxybenzoic acid (102 g) and hexamethylenetetramine (166 g) in trifluoroacetic acid is heated overnight. Dilute hydrochloric acid is added to the mixture and the mixture is heated. After cooling, the precipitates are collected by filtration, whereby 5-chloro-3-formyl-2-hydroxybenzoic acid (96.9 g) is obtained. m.p. 218° C.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:24])[C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH2:22][CH3:23])=O>C(O)(C(F)(F)F)=O>[CH3:8][O:9][C:10](=[O:24])[CH2:11][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH2:22][CH3:23]
Reactant: CCc1[nH]c2ncccc2c1C(=O)C(=O)OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1[nH]c2ncccc2c1CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of triethylsilane (818 μl, 5.12 mmol) in TFA (1.6 ml) at −10° C. is added portion wise (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-oxo-acetic acid methyl ester (0.34 g, 1.46 mmol). After stirring at room temperature overnight, the solvent is removed in vacuo and the resulting residue is neutralized with saturated sodium bicarbonate solution. The solution is extracted with DCM (3×20 ml) and the organic portions are combined, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM/MeOH (100:0 increasing to 98:2) to yield the titled compound as a yellow powder. (MH+ 219)
Reaction SMILES: Br[CH:2]([CH:8](Br)[CH3:9])[C:3]([O:5]CC)=O.[NH2:11][C:12]1[N:16]=[C:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][N:13]=1>N1C=CC=CC=1>[CH2:18]([S:17][C:15]1[N:16]=[C:12]2[N:11]=[C:3]([OH:5])[CH:2]=[C:8]([CH3:9])[N:13]2[N:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(Br)C(C)Br
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: c1ccncc1
Product: Cc1cc(O)nc2nc(SCc3ccccc3)nn12
Temperature: 65 °C

Procedure:
Ethyl 2,3-dibromobutyrate (1.33 g, 48.5 mmol) was added dropwise over 15 minutes to a solution of 10 g (49 mmol) of 3-amino-5-benzylthio-1,2,4-triazole in 20 ml of pyridine heated to 65° C. After the addition was complete, the reaction mixture was heated at 65° C. for 20 hours, cooled to room temperature and filtered. The filtrate was concentrated by evaporation at reduced pressure. The residue was triturated with methanol to separate 1.64 g (13%) of the desired product as a colorless crystalline solid, m.p. 219°-220° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:18][C:19]1[CH:23]([CH3:24])[CH:22]=[C:21]([CH3:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].Cl>>[CH3:18][C:19]1[CH:23]([CH3:24])[CH:22]=[C:21]([CH3:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=CC(C)C(C)=C1c1ccccc1N
Agent: Cl
Solvent: c1ccncc1
Product: CC1=CC(C)C(C)=C1c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Yield: 63.9 %

Procedure:
0.131 g (1.505 mmol) of pyridine and 0.316 g (1.656 mmol) of p-toluenesulfonyl chloride were added to 0.300 g (1.505 mmol) of 2-(2,3,5-trimethylcyclopenta-1,4-dienyl)phenylamine melted in 3 mL of MC, and then reacted at room temperature for 12 hours. 3 mL of 2 N HCl was added to the reaction product and strongly stirred for a few minutes. The organic layer was collected. The collected organic layer was neutralized with 3 mL of H2O without delay and dried over MgSO4. The product was filtered using a column chromatography with hexane/ethylacetate (v/v=3:1). The solvent contained in the puried product was dried in vacuum, thereby obtaining white solid (0.340 g, 64%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12](NNC(C)(C)C)=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.CC1C(C(N(C(C)(C)C)N)=O)=CC=C2C=1CCC[O:26]2.Cl>O>[CH3:1][C:2]1[C:11]([C:12]([OH:13])=[O:26])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: Cc1c(C(=O)N(N)C(C)(C)C)ccc2c1CCCO2
Reactant: Cc1c(C(=O)NNC(C)(C)C)ccc2c1CCCO2
Agent: Cl
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1CCCO2
Yield: 16.8 %

Procedure:
To a mixture of 57.8 g of a solid containing 80% of 1-(5-methylchroman-6-carbonyl)-2-t-butyl hydrazine and 20% of 1-(5-methylchroman-6-carbonyl)-1-t-butyl hydrazine and 900 ml of water was added 100 ml of concentrated hydrochloric acid at room temperature and then the the resultant was heated under reflux for 30 minutes. After cooling with ice and water, the resulting crystals were filtered to obtain 7.11 g of 5-methyl-6-chromanic acid in a yield of 16.8% (which had a purity of 99.5% by peak area from HPLC analysis and a melting point of 207° to 208° C.). An 50% aqueous solution of sodium hydroxide was added to the filtrate to pH 8 followed by extraction with dichloromethane to obtain 45.8 g of 1-(5-methylchroman-6-carbonyl)-2-t-butyl hydrazine in a yield of 79.1% (which had a purity of 99.8% by peak area from HPLC analysis and a melting point of 146° to 148° C. while which contained not more than 0.1% by peak area of 1-(5-methylchroman-6-carbonyl)-1-t-butyl hydrazine from HPLC analysis).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (10 g, 62 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 20.7 mL, 62 mmol). After stirring at room temperature for 15 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-methoxy-N-methylbenzamide (9.46 mL, 62 mmol) was added dropwise. The mixture was stirred for 2 h at room temperature. After standing for one night at room temperature, the mixture is worked-up by addition of water (150 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (2×100 mL), the organic layers were washed with water (100 mL) then dried over MgSO4 and concentrated in vacuo. The resulting orange solid was washed with pentane to afford (1-methyl-1H-imidazol-5-yl)(phenyl)methanone [8.50 g, yield 66%; HPLC/MS: m/z=187 (M+H); log P(HCOOH)=0.79].
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1>>[NH:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:23][C:2]2[N:11]=[C:10]([N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:30]=[CH:29]1
Reactant: NCCc1c[nH]cn1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Product: COc1ccc(N(C)c2nc(NCCc3c[nH]cn3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (10 mg, 0.033 mmol) and histamine hydrochloride (16 mg, 0.10) by a procedure similar to example 10 and was isolated as white solid (7 mg, 70%). 1H NMR (CDCl3): 7.52 (s, 1H), 7.49 (brd, J=3.9 Hz, 2H), 7.20-7.15 (m, 2H), 7.03-6.96 (m, 3H), 6.83 (ddd, J=8.4, 4.5 and 3.9 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.88 (s, 3H), 3.85 (t, J=6.6 Hz, 2H), 3.63 (s, 3H), 3.03 (t, J=6.6 Hz, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37]([OH:39])=O)=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:96]([OH:98])=[O:97])[CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]([O:91][C:92]([CH3:95])([CH3:94])[CH3:93])=[O:90])=[O:81]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:96]([OH:98])=[O:97])[CH2:84][CH2:85][CH2:86][CH2:87][NH:88][C:89]([O:91][C:92]([CH3:94])([CH3:95])[CH3:93])=[O:90])=[O:81])=[O:39])=[CH:33][CH:32]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)CN)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 0.08 h

Procedure:
{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (15.1 mg, 0.021 mmol) was dissolved in DMF (1 ml, dry). N-methylmorpholine (7 μl, 0.064 mmol) was added and the reaction mixture was stirred at 30° C. for five minutes. TBTU (10.8 mg, 0.034 mmol) was added and the reaction mixture was stirred at the same conditions for 1 hour. Glycyl-N6-(tert-butoxycarbonyl)-D-lysine (10.0 mg 0.033 mmol) was added and the reaction mixture was stirred for 2 hours. The mixture was purified with preparative HPLC on a C8 column. A gradient from 10 to 100% MeCN in a 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and most of the MeCN was removed under reduced pressure. The residue was lyophilised to give the title compound. M/z: 996.74 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[C:16]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH:25]1[C:12]2=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:15]=3[N:11]2[CH2:10][CH2:9][CH2:8][N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35]
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCNC(=O)OC(C)(C)C)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc2nc3n(c12)CCCN(C(=O)OC(C)(C)C)C3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a stirred solution of tert-butyl(3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propyl)carbamate (Reference example 228, 500 mg, 0.959 mmol) and triphenylphosphine (377 mg, 1.44 mmol) in tetrahydrofuran (30 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 0.655 mL, 1.44 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h, concentrated in vacuo, and purified by column chromatography on silica gel eluting with a 10-20% ethyl acetate/n-hexane gradient mixture to give a colorless amorphous solid (138 mg, 0.274 mmol, 29%).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([O-:5])=[O:4].[Br:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH2:37][CH2:38][CH2:39]Br)[C:28]3[C:33]([C:34]=2[CH:35]=1)=[CH:32][C:31]([Br:36])=[CH:30][CH:29]=3>CN(C=O)C.CCOC(C)=O>[Br:36][C:31]1[CH:30]=[CH:29][C:28]2[N:27]([CH2:37][CH2:38][CH2:39][N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N+:3]([O-:5])=[O:4])(=[O:14])=[O:13])[C:26]3[C:34]([C:33]=2[CH:32]=1)=[CH:35][C:23]([Br:22])=[CH:24][CH:25]=3
Reactant: BrCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCCn1c2ccc(Br)cc2c2cc(Br)ccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Crushed KOH (0.0024 g, 0.0431 mmol) was added to 2-nitro-N-phenylbenzenesulfonamide (0.0100 g, 0.0359 mmol) in 0.2 mL DMF solution and the mixture was stirred for 30 min. 3,6-dibromo-9-(3-bromopropyl)-9H-carbazole (Example 35, 0.0240 g, 0.0538 mmol) in 0.3 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The crude reaction mixture was diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0082 g white solid as impure product, purity 66.9% (impurity is starting Ns-aniline; used without additional purification), yield 35.5%.
Reaction SMILES: C([N:8]([C@@H:16]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:17]([OH:33])[C:18]([N:20]1[CH2:31][C@@H:30]([Cl:32])[CH2:29][C@H:21]1[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])CC1C=CC=CC=1)C1C=CC=CC=1>C(O)=O.CO.[Pd]>[NH2:8][C@@H:16]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:17]([OH:33])[C:18]([N:20]1[CH2:31][C@@H:30]([Cl:32])[CH2:29][C@H:21]1[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A solution of 20.0 g (35.6 mmol) of (4S)-1-[(2S,3S)-3-(N,N-dibenzylamino)-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide dissolved in 200 ml of a 4.5% by volume solution of formic acid in methanol was stirred in the presence of 3 g of palladium black at room temperature for 3 hours and then at 40° C. for 2 hours. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in benzene. Hexane was added to the resulting solution, to obtain 13.1 g of the title compound as a colorless powder, melting at 126°-130° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:17])=[CH:7][N:6]=1
Reactant: O=Cc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: OC(c1ccccc1)c1cnc(Cl)nc1Cl
Yield: 79 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and benzaldehyde (Aldrich) in 79% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 7.36 (m, 5H), 6.06 (d, 1H, J=3.0 Hz), 2.48 (br m,1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:16][CH2:15][CH2:14][C@@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:33]=[CH:32][N:31]=1
Reactant: C=C(C)C[C@@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=C(C)C[C@@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccnc(OC)c3)cc2)C(=O)O1

Procedure:
(R)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following conditions analogous to those described in Example 6 using PdCl2(dppf) as catalyst. tR=2.28 min, m/z 457 (M+1). 1H NMR (CD3OD) δ 8.13 (m, 2H), 7.83 (d, 1H), 7.71 (d, 2H), 7.49 (t, 3H), 7.33 (t, 2H), 7.24 (m, 2H), 7.06 (d, 1H), 5.41 (q, 1H), 4.56 (s, 1H), 3.85 (d, 3H), 3.17-2.99 (m, 2H), 2.39 (dt, 1H), 2.09 (m, 1H), 1.45 (s, 3H), 1.38 (d, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:17]=2[CH:18]=1)[CH3:13]>C(Cl)Cl>[C:12]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:17]=2[CH:18]=1)(=[O:11])[CH3:13]
Reactant: COC(=O)c1ccc2cc(C(C)O)oc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2cc(C(C)=O)oc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Oxalyl chloride (0.1 ml, 1.15 mmol) is dissolved in CH2Cl2 (2 ml) in a dry flask under nitrogen and cooled to −78° C. DMSO (0.16 ml, 2.3 mmol) is added drop-wise, and the mixture stirred for 30 min, while maintaining the temperature. Methyl 2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate (220 mg, 1.0 mmol) is dissolved in CH2Cl2 (2 ml) and added drop-wise to the mixture, and the solution stirred for 1 h at −78° C. TEA (0.69 ml, 5.0 mmol), is added drop-wise and the reaction is stirred for an additional 30 min. The reaction is then warmed to 0° C. and stirred for another 30 min. The reaction is washed with saturated NaHCO3 (40 ml), and the organics are dried (K2CO3), filtered, and concentrated to a yellow solid. The crude material is chromatographed over 25 g slurry-packed silica gel, eluting with 20% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 174 mg (80%) of methyl 2-acetyl-1-benzofuran-6-carboxylate as a pale yellow solid. HRMS (FAB) calcd for C12H10O4+H: 219.0657, found 219.0667 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([NH:10][C:11]1[N:16]=[C:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH:14]=[CH:13][CH:12]=1)=[O:9].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1>>[CH3:7][C:5]1[S:6][C:2]([NH:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[C:3]([C:8]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH:14]=[CH:13][CH:12]=2)=[O:9])[N:4]=1
Reactant: Nc1cccnc1
Reactant: CC(=O)OCc1cccc(NC(=O)c2nc(C)sc2Br)n1
Product: CC(=O)OCc1cccc(NC(=O)c2nc(C)sc2Nc2cccnc2)n1

Procedure:
A solution of 5-bromo-2-methyl-thiazole-4-carboxylic (prepared as described in example 119, steps A to B) (0.13 g, 0.60 mmol) in dichloromethane (5.00 ml) and DMF (0.10 ml) was treated with thionyl chloride (0.08 g, 0.66 mmol) and stirred at room temperature for 4.5 h. After this time, 6-amino-pyridin-2-ylmethyl ester (0.10 g, 0.60 mmol) and DIPEA (0.16 g, 1.20 mmol) were added, and the mixture stirred for 30 min. The solvents were then evaporated and the residue purified by flash chromatography (heptane/ethyl acetate) to yield acetic acid 6-[(5-bromo-2-methyl-thiazole-4-carbonyl)-amino]-pyridin-2-ylmethyl ester (0.17 g, 76%) as a white solid, MS (ISP): m/e=372.0, 370.0 (M+H+). Acetic acid 6-[(5-bromo-2-methyl-thiazole-4-carbonyl)-amino]-pyridin-2-ylmethyl ester was then coupled with pyridin-3-ylamine in step B to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([O:30][CH2:31][O:32][CH3:33])[CH2:29][CH2:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:42]I>O1CCCC1>[Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([O:30][CH2:31][O:32][CH3:33])[CH2:29][CH2:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[C:9]([I:42])[N:8]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:12])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 5-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1E) (5.0 g, 9.92 mmol) in tetrahydrofuran (50 mL) was added a solution of lithium diisopropylamide (13.9 mmol) in tetrahydrofuran (15 mL). The reaction was stirred at −78° C. for 1 hour, and a solution of iodine (3.52 g, 13.89 mmol) in tetrahydrofuran (10 mL) was added. The cold bath was removed, and, after 15 minutes, the reaction was quenched by the addition of saturated aqueous sodium thiosulfate and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 586 [M+H]+;