Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1.CCOC(C)=O>CN(C=O)C.O>[CH3:8][O:7][C:5]([CH2:4][O:3][C:10]1[N:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1)=[O:6]
Reactant: COC(=O)CO
Reactant: N#Cc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Dissolve sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL). Cool at 0° C., add dropwise methyl 2-hydroxyacetate (0.7 mL, 9.5 mmol) and stir at this temperature for 30 min. Add a solution of 6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70° C. overnight. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (461 mg, 63%). MS (ES+) m/z: 193 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].C[Si]([C:43]#[N:44])(C)C.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][C:48]=1[O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58]>ClCCl>[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH:51]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:43]#[N:44])=[CH:49][C:48]=1[O:55][Si:56]([CH:57]([CH3:58])[CH3:59])([CH:63]([CH3:64])[CH3:65])[CH:60]([CH3:61])[CH3:62]
Reactant: COc1ccc(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: C[Si](C)(C)C#N
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: COc1ccc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After adding 3.19 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 10g of MS3A, 1.56 g of Yb(OTf)3 and 4.84 ml of trimethylsilyl cyanide to a solution of 5.6 g of 4-methoxy-3-triisopropylsilanyloxybenzaldehyde [CAS No. 179260-96-6] in 98 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give a white solid (5.59 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=1.C([O-])(O)=O.[Na+].[CH:31]([OH:34])([CH3:33])[CH3:32]>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=[C:2]([O:34][CH:31]([CH3:33])[CH3:32])[N:7]2[N:8]=1
Reactant: CC(C)O
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(OC(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 80 °C

Procedure:
To a suspension of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 150 mg, 0.384 mmol) in isopropanol (5 ml) was added solid NaHCO3 (129 mg, 1.5 mmol), and the mixture was heated at 80° C. overnight. After cooling, the suspended solids (150 mg) were collected by filtration and the filtrate was concentrated, in vacuo, to give a solid (95 mg). The suspended solids were extracted from saturated aqueous NaHCO3 with ethyl acetate, the organic layers were dried (MgSO4) and then concentrated, in vacuo, to give a solid. The combined solids were then purified on a Biotage™ Flash 12M column using 0-10% ethyl acetate in hexanes to afford 13A-1 (91 mg, 60%) as an off-white solid: +ESI MS (M+1) 413.4; 1H NMR (400 MHz, CD2Cl2) δ 7.50-7.34 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 5.73 (septuplet, J=6.2 Hz, 1H), 2.62 (s, 3H), 1.55 (d, J=6.2 Hz, 6H).
Reaction SMILES: [NH:1]([C:5]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C(C)=O.[ClH:22].N>C(O)C>[ClH:22].[NH2:1][C:5]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CN(CC)CC)c1
Agent: Cl
Agent: N
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(CN(CC)CC)c1

Procedure:
19 gm of 2-acetamino-5-carbethoxy-N,N-diethyl-benzylamine were dissolved in 100 ml of ethanol, and after addition of 60 ml of concentrated hydrochloric acid the mixture was refluxed for 1 hour. Thereafter the mixture was poured over ice, made alkaline with ammonia and extracted three times with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated in vacuo, and the residue was purified by chromatography on silicagel (elution agent: ethyl acetate); by addition of isopropanolic hydrochloric acid, 2-amino-5-carbethoxy-N,N-diethyl-benzylamine hydrochloride was obtained, which was recrystallized from ethanol and then had a melting point of 138°-142°C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.O[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:32][C:33](=[O:34])[N:35]([CH3:37])[CH3:36])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: CN(C)C(=O)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 14.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.1 g, 2.90 mmol) dissolved in 40 mL of anhydrous dichloromethane (DCM) was reacted with 1.74 mL (3.48 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, an aliquot (ca. 1.45 mmol) of the acid chloride was reacted with 455 mg (4.41 mmol) of 2-hydroxy-N,N-dimethylacetamide (36b) and 352 μL mL of pyridine (344 mg, 4.35 mmol) in 10 mL of anhydrous dichloromethane (DCM). After work-up, the crude material was purified by silica gel column chromatography using mixtures of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=2:3→EtOAc/Hxn=1:1) to provide 200 mg (30% yield) of the title compound (36c) as an opaque, viscous oil. Rf=0.28 (EtOAc/Hxn=1:1). MS (ESI) m/z 464.2 (M+H)+, 486.1 (M+Na)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:18]
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)C1CCNCC1

Procedure:
The above compound was prepared similarly to Preparation C starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2-methoxybenzylamine and had an m.p. of 139°-140°.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:19]([CH3:20])[CH2:18][C:17]2[C:16]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:31]([O:35][C:36]([N:38]1[C:42]([NH:43][C:44](OC2C=CC=CC=2)=[O:45])=[CH:41][C:40]([C:53]2([CH3:56])[CH2:55][CH2:54]2)=[N:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[C@@H:19]([CH3:20])[CH2:18][C:17]2[C:16]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:44](=[O:45])[NH:43][C:42]3[N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[N:39]=[C:40]([C:53]5([CH3:56])[CH2:55][CH2:54]5)[CH:41]=3)[CH:26]=[CH:25]4)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: C[C@H]1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1nc(C2(C)CC2)cc1NC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C4(C)CC4)nn3C(=O)OC(C)(C)C)c2)CN1C(=O)OC(C)(C)C

Procedure:
Sodium hydride (0.024 g, 0.990 mmol; 60% in oil) is added to a solution of (S)-4-(1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, Example 53-B-1, (0.126 g, 0.330 mmol) and DMF (7.5 mL) at it. After 5 min 3-(1-Methyl-cyclopropyl)-5-phenoxycarbonylamino-pyrazole-1-carboxylic acid tert-butyl ester, Example 5-D, (0.178 g, 0.495 mmol) is then added. After 1 h the mixture is quenched by the addition of saturated aqueous NH4Cl and then concentrated. The residue is separated directly via FCC (20-70% EtOAc/heptane). MS (ESI) m/z 644.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[CH2:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH3:19]>C(O)C>[CH2:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CCN1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 41.8 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (15 mL) was treated with pyrrolidine (0.65 mL, 9.250 mmol), N-ethyl-4-piperidone (0.8 mL, 6.167 mmol) at room temperature and the resulting solution was refluxed for 3 days. The reaction was brought to room temperature and solvent was evaporated. The crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95), and washed with ether (3×10 mL) to obtain compound 60 (0.35 g, 42%) as a solid. mp 188-190° C.; 1H NMR (DMSO-d6) δ: 1.07 (t, 3H, J=7.2 Hz), 2.41-2.50 (m, 4H), 2.63 (t, 2H, J=5.1 Hz), 3.10-3.15 (m, 2H), 6.18 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 7.65 (s, 1H), 8.01 (dd, 1H, J=2.1, 9.0 Hz), 8.69 (d, 1H, J=2.1 Hz), 11.86 (s, 1H)— ESI-MS m/z (%): 272 (M+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][C:15]([CH3:17])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[CH3:14][C:15]1([CH3:17])[O:1][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4](=[O:6])[O:5]1
Reactant: CC(C)=O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A mixture of 2-hydroxy-5-nitrobenzoic acid (50.0 g. 0.27 mol), acetone (40 mL, 0.54 mol) and trifluoroacetic anhydride (100 mL, 0.71 mol) in TFA (300 mL) was heated at reflux. After 1 hour, a supplementary amount of acetone (60 mL, 0.82 mol) was added and the reaction mixture was refluxed for 48 hours. The solvents were evaporated under reduced pressure. The residual brown solid was dissolved in DCM (800 mL) and washed with a mixture of saturated aqueous NaHCO3 (400 mL) and water (400 mL). The aqueous layer was extracted with DCM (2×400 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residual brown oil was taken up in cold pentane (300 mL, 0° C.) and a yellow solid precipitated off. Filtration and washing with pentane gave 53.8 g (88%) of the title compound as a yellow solid. HPLC, Rt: 2.9 min (purity: 99.8%). 1H NMR (CDCl3) δ: 8.88 (d, J=2.8 Hz, 1H), 8.44 (dd, J=9.0, 2.8 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 1.80 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)(=[O:23])=[O:22])([O-:14])=[O:13].[CH2:33]([N:35]1[C:41](=[O:42])[C:40]([CH3:44])([CH3:43])[C:39](=[O:45])[N:38]([CH3:46])[C:37]2[CH:47]=[C:48]([O:51][CH2:52][CH2:53][CH2:54]I)[CH:49]=[CH:50][C:36]1=2)[CH3:34]>C(OCC)(=O)C.O>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]([CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:54][CH2:53][CH2:52][O:51][C:48]1[CH:49]=[CH:50][C:36]2[N:35]([CH2:33][CH3:34])[C:41](=[O:42])[C:40]([CH3:44])([CH3:43])[C:39](=[O:45])[N:38]([CH3:46])[C:37]=2[CH:47]=1)(=[O:22])=[O:23])([O-:14])=[O:13]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
Potassium carbonate (1.89 g, 13.7 mmol) was added to a DMF solution (50 ml) of 2-nitro-N-(2-pyridin-3-ylethyl)benzene sulfonamide (1.40 g, 4.56 mmol) and 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.16 g, 5.0 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure to thereby obtain 2.99 g (yield: quantitative) of 2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[C:9]([Br:24])[C:8]1=[O:25].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>ClCCl>[Br:24][C:9]1[C:8](=[O:25])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH:28]=[CH:27][CH:26]=2)[CH2:2][NH:1][C:36](=[O:37])[O:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)[C:12]([CH3:13])=[CH:11][C:10]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CN)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (EXAMPLE 161) (2.00 g, 4.45 mmol) was suspended in dichloromethane (15 mL). Pyridine was added (0.43 mL, 5.34 mmol). After stirring for 10 minutes at room temperature, a stock solution of 4-nitrophenyl chloroformate (10.0 mL, 0.50 M) in dichloromethane was added dropwise. After stirring for 4.5 hours at room temperature, a stock solution of 4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane was again added dropwise and stirring continued at 40° C. overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford a yellow solid (1.11 g, 66%). 1H NMR (400 MHz, DMSO d6) δ 8.56 (app t, J=6.10 Hz, 1H), 8.24-8.21 (m, 2H), 7.62 (app q, J=7.88 Hz, 1H), 7.40-7.27 (m, 7H), 6.98 (d, J=7.52 Hz, 1H), 6.54 (s, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 4.25 (d, J=6.18 Hz, 2H), 2.30 (s, 3H). ES-HRMS m/z 614.0753 (M+H C28H22BrF2N3O6 requires 614.0733).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9]N=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.[CH3:29]CN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C.[Cu]I>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:14]#[C:13][C:10]2[CH:9]=[CH:29][C:7]([N:5]3[CH2:6][C:2]([CH3:1])([CH3:20])[CH2:3][C:4]3=[O:19])=[N:12][CH:11]=2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(I)cc1
Reactant: CC1(C)CC(=O)N(c2ncc(C#C[Si](C)(C)C)cn2)C1
Reactant: CCN(CC)CC
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccc(F)cc3)cn2)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidin-2-one (Example 120, step 2) (30 mg, 0.1 mmol) was dissolved in DMF (1 ml). 1-Fluoro-4-iodobenzene (32 mg, 0.14 mmol, 1.4 equiv.), Et3N (43 μl, 0.31 mmol, 3 equiv.), Bis-(triphenylphosphine)-1-palladium(II)dichloride (4 mg, 5.2 μmol, 0.05 equiv.) and copper(I)iodide (0.6 mg, 3.1 μmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (115 μl, 0.115 mmol, 1.1 equiv.) was added dropwise in 20 minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70° C. and evaporated with isolute to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired 1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one (24 mg, 73% yield) was obtained as a white solid, MS: m/e=310.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH2:23][C:24]([OH:26])=O)=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[S:11][C:5]=2[N:4]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:3]1=[O:31].[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>CN1CCCC1=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>[OH:36][CH2:35][CH2:34][N:33]([CH3:32])[C:24](=[O:26])[CH2:23][C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:31])[N:4]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:20])[F:21]
Reactant: CNCCO
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(CC(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(CC(=O)N(C)CCO)c(Cc3ccccc3C(F)(F)F)sc21
Reaction time: 18 h

Procedure:
The product of step b) (98 mg) was dissolved in 1-methyl-2-pyrrolidinone (NMP) (1 ml) to which EDCl (1 ml), HOBT (1 ml) and N-methyl ethanolamine (1 ml) was added. The reaction was stirred for 18 hrs before being concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic phase was adsorbed onto silica and purified by chromatography eluting with 0-10% methanol in dichloromethane to yield the title compound (62 mg).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[CH2:33][C:34]([C:36]1([CH3:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:35].CC1(C(O)=O)CCCCC1>C1COCC1>[CH3:42][C:36]1([C:34](=[O:35])[CH2:33][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC1(C(=O)CCl)CCCCC1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: CC1(C(=O)O)CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C1(C)CCCCC1
Yield: 78.8 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (164 mg, 0.51 mmol), and triethylamine (355 uL, 5.0 eq) in THF (2 mL), was treated with 180 mg (2.0 eq) of 1-chloro-2-(1-methyl-cyclohexyl)-2-oxoethane (prepared from 1-methyl-1-cyclohexanecarboxylic acid using the procedure described in example 1) to provide 183 mg (93%) of L-isoleucine, N-[1-(2-(1-methyl-cyclohexyl)-2-oxoethyl)-L-prolyl] benzylamide as a colorless residue.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[CH:2]=1.[Br:11]Br.CCOCC>O1CCOCC1>[Br:11][CH2:8][C:7]([C:3]1[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C)c1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-m-tolyl-ethanone (6.0 g, 44.72 mmol) in dioxane (5 ml), bromine (7.14 g, 44.72 mmol) in dioxane (10 ml) and ether (15 ml) was added and stirred at room temperature for 5 hr. The reaction mixture was poured into ice water and the compound was extracted using ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and then evaporated to give crude 2-bromo-1-m-tolyl-ethanone, 7.6 g (80%). The crude compound obtained was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]5[NH:36][C:35]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)=[N:34][N:33]=5)[CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([NH:17][NH2:18])[N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:43](OOC)(OOC)OOC.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO.C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:8]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[NH:36][C:35]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)=[N:34][N:33]=5)[CH2:30][CH2:31]4)=[CH:23][CH:24]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:43]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COOC(OOC)OOC
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3c(ccn4cnnc34)nc2-c2ccc(CN3CCC(c4nnc(-c5ccccn5)[nH]4)CC3)cc2)cc1

Procedure:
To a solution of 8-9 (4.5 g, 8.1 mmol) in 20 mL methanol and 60 mL toluene was added trimethoxy orthoformate (3.5 g, 32.5 mmol) and toluenesulfonic acid (0.1 g, 0.8 mmol). The mixture was refluxed for 10 hrs. Upon removal of the solvent, the residue was purified by flash column chromatography (100% CHCl3 to 50% CHCl3 and 50% methanol) to afford the desired product 8-10.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.C([Mg]Cl)(C)C.C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N>O1CCCC1>[CH2:27]([O:26][C:24]([C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1)=[O:25])[CH3:28]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Reactant: CCOC(=O)C#N
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a solution of 2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.55 g, 1.8 mmol) (as prepared in the previous step) in tetrahydrofuran (THF) (6 mL) at −40° C. was added drop wise a solution of 2 M isopropylmagnesium chloride (i-PrMgCl) in THF (1 mL). The reaction was allowed to stir for 10 min at −40° C. and then cooled to −78° C., and ethyl cyanoformate (0.30 g, 3.0 mmol) was added. The reaction allowed to attain RT and stirred for 1 h. The reaction was quenched with satd aq NH4Cl, diluted with EtOAc (20 mL), washed with brine (2×20 mL). The organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.40 g (74%) of a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C13H21N3O3Si, 296.1 (M+H), found 296.1.