Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])[CH3:30]>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([CH2:29][CH3:30])[CH:32]=3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCc1cccc(N)c1
Solvent: Cc1ccccc1
Product: CCc1cccc(NCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1

Procedure:
0.4 g (1.10 mmol) of 3-(1-triphenylmethyl-4-imidazolyl)propionaldehyde is treated with 0.13 g (1.10 mmol) of 3-ethylaniline in anhydrous toluene, and then reduced as described for Example 154 to yield 1-triphenylmethyl-4-[3-(3-ethylphenylamino)propyl]-imidazole in the form of a colourless oil. The latter is deprotected with HCl in tetrahydrofuran, and the oil obtained is converted to oxalate as described for Example 154, to yield the product, m.p. 189-191° C. after recrystallization in a mixture of 2-propanol and diethyl ether.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:26])[CH2:24][NH2:25])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[C:1]([NH:25][CH2:24][C:23]([NH:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)NC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of benzoyl chloride (0.060 mmol) in chloroform (0.4 mL) was added to a solution of 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give 4-(N-benzoylglycyl)amino-1-benzylpiperidine (compound No. 386) (11.3 mg, 64%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 352.0 (M++H, C21H25N3O2).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[O:17]
Reactant: CC(C)=CCO
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCOC(=O)CBr
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A 1-liter flask was charged with 43.9 g (0.51 mol) of 3-methyl-2-buten-1-ol, 51.6 g (0.51 mol) of triethylamine and 300 ml of dichloromethane, and the mixture was cooled down to 0° C. While stirring the mixture at 0° C., 100.9 g (0.50 mol) of bromoacetyl bromide were added dropwise over 1 hour, followed by stirring further for 3 hours at room temperature. Solids were separated by filtration from the resultant reaction mixture, and the filtrate was washed 3 times with water and distilled to obtain 66.5 g of 3-methyl-2-butenyl bromoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[Br:13][CH2:14][CH2:15]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:13][CH2:14][CH2:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: BrCCBr
Reactant: Clc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Clc1ccc2c(ccn2CCBr)c1
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of 1 g of 5-chloroindole in 30 ml of 1,2-dibromoethane was treated with 30 ml of 28% NaOH and 80 mg of tetrabutyl-ammonium bromide. The mixture was stirred at 50° for 3 hours. The phases were separated and the aqueous phase was extracted with toluene. The combined organic phases were washed with water and dried over sodium sulfate. The solvent was distilled off and the residue was chromatographed over 150 g of silica gel with hexane-ethyl acetate (5:1). There were obtained 1.17 g (69%) of 1-(2-bromoethyl)-5-chloroindole as white crystals with a m.p. of 71°.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[NH:5])#[N:2].Cl.C(CC(=N)OCC)#N.Br[CH:17]([CH3:27])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=O.O>C(O)C>[NH2:5][C:4]1[NH:6][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:17]([CH3:27])[C:3]=1[C:1]#[N:2]
Reactant: N#CCC(=N)N
Reactant: CC(Br)C(=O)c1ccccc1F
Agent: CCOC(=N)CC#N
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccccc2F)[nH]c(N)c1C#N

Procedure:
To an ethanolic solution of 2-cyanoacetamidine prepared from 10 g of ethyl 2-cyanoacetimidate hydrochloride as in Reference Example 2 was added a solution of 2-bromo-2′-fluoropropiophenone (7.6 g) in ethanol dropwise under ice-cooling with stirring, and the mixture was then stirred at room temperature overnight. This reaction mixture was poured into iced water (500 g) and the resulting crystals were collected by filtration. The crude crystal crop was washed well with n-hexane, air-dried, and purified by flash chromatography (Kieselgel 60H, 90 g; eluent: 30% ethyl acetate/n-hexane). Recrystallization from benzene-n-hexane (1:1) yielded the title compound as colorless crystals (4.67 g). The physical constants of this product were in agreement with those of the product obtained in Example 5-(1).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]2[C:16]([OH:31])=[C:17]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:18]([OH:25])=[C:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:12]=2[O:11][C:10]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([F:39])[CH:33]=1)C1C=CC=CC=1>CO.[Pd]>[F:39][C:34]1[CH:33]=[C:32]([C:10]2[O:11][C:12]3[C:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:18]([OH:25])[C:17]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:16]([OH:31])[C:13]=3[C:14](=[O:15])[C:9]=2[OH:8])[CH:37]=[CH:36][C:35]=1[Cl:38]
Reactant: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(Cl)c(F)c3)c(OCc3ccccc3)c(=O)c2c1O
Agent: [Pd]
Solvent: CO
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c2oc(-c3ccc(Cl)c(F)c3)c(O)c(=O)c2c1O
Reaction time: 5 h
Yield: 9 %

Procedure:
3-benzyloxy-2-(3-fluoro-4-chlorophenyl)-5,7-dihydroxy-6,8-di(3-methyl-2-buten-1-yl)-4H-benzopyran-4-one was dissolved in 10 mL methanol, and 5% Pd/C (10 mg) was added. The reaction mixture was hydrogenated at 0° C. under atmospheric pressure for 5 hr. The mixture was tilted and the filtrate was concentrated. The residue was purified by silica gel column chrotomagraphy (eluent:methol/dichloromethane, 1:50) to give the desired compound (11.3 mg, yield 9.0%). 1H NMR (400 MHz, CDCl3): δ=11.82 (s, 1H), 8.02-7.94 (m, 2H), 7.53 (dd, 1H, J1=8.4 Hz, J2=7.6 Hz), 6.80 (s, 1H), 6.46 (s, 1H), 5.27-5.24 (m, 2H), 3.56 (d, 2H, J=6.8 Hz), 3.47 (d, 2H, J=7.2 Hz), 1.86 (s, 3H), 1.81 (s, 3H), 1.78 (s, 3H), 1.76 (s, 3H); LC-MS (ESI) m/z 459.6 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:5]([O:6][CH:7]([CH3:9])[CH3:8])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:14]=[C:13]3[CH2:29][CH2:30][CH2:31][OH:32])[C:3]1=[O:33].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(N(CC)CC)C.CCCCCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[C:5]([O:6][CH:7]([CH3:9])[CH3:8])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([Si:19]([CH:23]([CH3:24])[CH3:25])([CH:20]([CH3:21])[CH3:22])[CH:26]([CH3:28])[CH3:27])[CH:14]=[C:13]3[CH2:29][CH2:30][CH2:31][O:32][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])[C:3]1=[O:33]
Reactant: CC(C)Oc1c(-c2ccc3c(c2)c(CCCO)cn3[Si](C(C)C)(C(C)C)C(C)C)c(=O)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ccc(-c4c(OC(C)C)c(=O)c4=O)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To an ice-cold solution of 5-[1,2-dioxo-4-(1-methylethoxy)-3-cyclobuten-3-yl]-3-(3-hydroxypropyl]-1-triisopropylsilylindole (12) (0.208 g, 0.44 mmol) in 5 mL of dichloromethane was added p-toluenesulfonyl chloride (0.094 g, 0.49 mmol), followed by triethylamine (68 μL, 0.49 mmol) and a small but arbitrary amount of 4-dimethylaminopyridine. The cooling bath was then removed and the mixture was stirred at room temperature under Ar for 1 h. Another 0.047 g (0.25 mmol) of p-toluenesulfonyl chloride and 34 μL (0.24 mmol) of triethylamine were added and stirring was continued at room temperature for 18 h. The mixture was then diluted with dichloromethane, washed with 10% aqueous Na2CO3, dried (Na2SO4) and evaporated to give a yellow gum. Flash chromatography (SiO2 /CH2Cl2 then hexane-ethyl acetate, 1:1) of this material afforded the title compound (0.265 g, 97%) as a bright yellow gum: IR (neat) 1782, 1738, 1585, 1390 cm-1 ; 1H NMR (CDCl3, 400 MHz) δ 8.34 (d, J=1.5 Hz, 1H), 7.81 (dd, J=8.7, 1.5 Hz, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.10 (s, 1H), 5.64 (hept, J=6.2 Hz, 1H), 4.09 (t, J=7.2 Hz, 2H), 2.87 (t, J=7.3 Hz, 2H), 2.44 (s, 3H), 2.11-2.05 (m, 2H), 1.70 (hept, J=7.5 Hz, 3H), 1.58 (d, J=6.1 Hz, 6H), 1.14 (d, J=7.5 Hz, 18H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([CH:33]3[CH2:35][CH2:34]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].CC1C=C[C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39]C=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:43]([CH2:40][CH3:39])(=[O:45])=[O:44])[N:17]=[C:16]([CH:33]3[CH2:34][CH2:35]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(C2CC2)nc1OCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCS(=O)(=O)NCCOc1nc(C2CC2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a), 250 mg 5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 100 mg 5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=5.32 min, [M−1]−=604.39.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[N:33][CH:32]=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:35][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:34]=[N:33][CH:32]=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cnccn5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cnccn5)cc4)CC3)n2CCS1
Yield: 104 %

Procedure:
A solution of the compound (217 mg, 0.43 mmol) obtained in Example 38-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (176 mg, quant.) as a colorless solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][CH:24]=3)[CH:21]=2)=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[CH:23][C:24]=3[I:1])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2ccc3ccnn3c2)cc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ccc3c(I)cnn3c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
N-iodosuccinimide (630 mg, 2.8 mmol) was added in one portion to a stirred solution of 6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridine (500 mg, 2.4 mmol) in dry DMF (6 ml) at RT under N2. After 45 minutes, the reaction was quenched with saturated aqueous sodium thiosulphate/saturated NaHCO3 (1:1, 40 ml). The mixture was stirred at RT for 15 minutes then partitioned between EtOAc/H2O. The organic layer was washed with water (×1), brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified trituration with petrol to give the title compound (635 mg, solid). 1H NMR (400 MHz, CDCl3): 8.61 (1H, s), 7.98 (1H, s), 7.57-7.51 (3H, m), 7.42 (1H, dd), 7.22-7.13 (2H, m).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][NH:9][C@H:8]([C:16](OC)=[O:17])[CH2:7][C:6]2=1.[BH4-].[Na+].C(O)C>O>[OH:17][CH2:16][C@@H:8]1[CH2:7][C:6]2[C:5]3[C:13](=[CH:14][CH:15]=[C:3]([F:2])[CH:4]=3)[NH:12][C:11]=2[CH2:10][NH:9]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Temperature: 25 °C
Reaction time: 21 h
Yield: 64.1 %

Procedure:
A mixture of 0.577 g of methyl (3S)-6-fluoro-1,2,3,4-tetrahydro-β-carboline-3-carboxylate hydrochloride, 0.32 g of sodium borohydride, 20 ml of ethanol and 10 ml of water is stirred at room temperature for 21 hours, and then further refluxed for 3 hours. After the reaction, insoluble materials are removed by filtration and washed with hot ethanol. The filtrate and washings are combined and concentrated. Water is added to the residue, and crystalline precipitates are collected by filtration and dried, whereby 286 mg of (3S)-3-hydroxymethyl-6-fluoro-1,2,3,4-tetrahydro-β-carboline are obtained as colorless needles. Yield: 65%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[C:55]([F:60])[CH:56]=2)[CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>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].ClCCl.O1CCOCC1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:50]5[CH:59]=[CH:58][C:57]6[C:52](=[CH:53][CH:54]=[C:55]([F:60])[CH:56]=6)[CH:51]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: Fc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cc(F)ccc4c3)cc2F)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Into a 5 mL microwaveable vial was placed 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.244 mmol), bis(pinacolato)diboron (0.244 mmol), potassium acetate (0.977 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.024 mmol), and 1,4-dioxane (2 mL). The vial was capped and the contents were purged with nitrogen. The solution stirred at 100° C. for 16 h. LCMS analysis displayed boronic ester intermediate present (boronic ester cleavage to acid also observed on LCMS) as well as a small amount of bromide starting material. The reaction was cooled to room temperature. Added to the vial was 2-bromo-6-fluoronaphthalene (0.244 mmol) and 2M aq potassium carbonate (1 mL). The vial was capped, purged with nitrogen, and stirred at 100° C. for 1 h. The solution was cooled to room temperature, whereby the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (2 mL). All dioxane filtrates were combined and concentrated in vacuo. Reverse phase HPLC (30-80% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (21 mg, 17%). MS(ES)+ m/e 475.1 [M+H]+.
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)OC(=O)NCCCC[C@@H](NC(=O)CN)C(=O)O
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
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
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([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])(C)(C)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.CN1CCOCC1.[NH2:35][C:36]([C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([F:52])[CH:45]=1)([C:38]1[N:39]([CH3:43])[CH:40]=[N:41][CH:42]=1)[CH3:37]>CN(C=O)C>[C:48]([C:47]1[CH:50]=[CH:51][C:44]([C:36]([NH:35][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[OH:5])=[O:13])([C:38]2[N:39]([CH3:43])[CH:40]=[N:41][CH:42]=2)[CH3:37])=[CH:45][C:46]=1[F:52])#[N:49]
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1cncc1C(C)(NC(=O)CCNC(=O)O)c1ccc(C#N)c(F)c1
Reaction time: 8 h

Procedure:
To a solution of 3-tert-butoxycarbonylamino-propionic acid (0.77 g, 4.09 mmol) in DMF (8.2 mL) at ambient temperature was added [1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAT) (0.53 g, 3.89 mmol), EDC (0.82 g, 4.30 mmol), and 4-methylmorpholine (0.41 g, 4.09 mmol), followed by (+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile (Example 1, Step I) (1.00 g, 4.09 mmol). After stirring overnight, the reaction was concentrated in vacuo to remove the DMF. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the crude title compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.C(N(CC)CC)C>C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)(=[O:5])=[O:4]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)NC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 221.2 %

Procedure:
A mixture of N-methylethenesulphonamide (45 g), 5-bromoindole (60 g), palladium acetate (0.9 g), triotolylphosphine (18.6 g) and triethylamine (90 mL) in isopropanol (300 mL) was heated at 85° under nitrogen for 18 h. The reaction mixture was cooled to ambient temperature, filtered and the filter cake washed with isopropanol (30 mL). The combined washings and filtrate were concentrated in vacuo to give a yellow-brown solid (160 g). This material was purified by column chromatography on silica gel. Eluting initially with ethyl acetate/cyclohexane (1:1) followed by ethyl acetate provided the product (26.4 g, 36% of theory) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH3:15])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CC)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a solution of 75A (228 mg, 0.85 mmol) in 3 mL THF, was added aq. LiOH (1M, 2 mL, 2 mmol), and the reaction was stirred at rt for 16 h. Water (20 mL) was added, then the mixture was acidified with 1N HCl (pH=2) and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated to afford 75B (150 mg, 73%). MS (ESI) m/z 243.0 (M+H)+.