Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:19]([C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCNCC2
Yield: 43.8 %

Procedure:
A mixture of 3-(tert-butoxycarbonyl)-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (765 mg, 2.81 mmol) and trifluoroacetic acid (2 ml), in dichloromethane (20 ml) was stirred at 40° C. for 1 h. The reaction mixture was evaporated to dryness in vacuo and partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was basified using potassium carbonate and re-extracted with ethyl acetate (2×30 ml). The combined basic organic extracts were dried over sodium sulfate and evaporated in vacuo to give the title compound as a colourless oil (212 mg, 44%).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[NH:15][N:14]=[CH:13][C:12]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4](=O)[O:3]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O)C>C(Cl)Cl>[CH2:19]([O:18][C:16]([C:12]1[CH:13]=[N:14][N:15]2[C:4]([OH:3])=[C:5]([C:6]([OH:7])=[O:8])[CH:9]=[N:10][C:11]=12)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cn[nH]c1NC=C1C(=O)OC(C)(C)OC1=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Ethyl 5-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-ylidene)methylamino]1H-pyrazole-4-carboxylate (14.9 g, 45.6 mmol) obtained in step 1 was suspended in methylene chloride (227 mL), and triethylamine (25 mL, 182 mmol) was added. Trimethylsilyl trifluoromethanesulfonate (33.2 mL, 182 mmol) was added dropwise over about 10 min under ice-cooling while maintaining the reaction inside temperature at not more than 10° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to 0° C., and ethanol (75 mL) was added dropwise over 10 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 10 hr. The precipitated crystals were collected by filtration, washed with cold ethanol (50 mL), and dried under reduced pressure at 40° C. overnight to give the title compound (10.5 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1)[C:5]#[N:6].[NH2:16][OH:17]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1)/[C:5](=[N:16]/[OH:17])/[NH2:6]
Reactant: NO
Reactant: N#Cc1ccc(O[C@H]2CCOC2)c(Cl)c1
Solvent: CCO
Product: N/C(=N\O)c1ccc(O[C@H]2CCOC2)c(Cl)c1
Yield: 41.2 %

Procedure:
Under an atmosphere of nitrogen, (S)-3-chloro-4-(tetrahydrofuran-3-yloxy)benzonitrile (11.2 g, 50.1 mmol) and 50% aqueous hydroxylamine (3.31 g, 50.1 mmol) in EtOH (150.0 mL) was heated at 60° C. for 18 hr. Solvents removed in vacuo and the residue was azeotroped with MeOH. The residual solid was purified by precipitation from an ethyl acetate/30-60° C. pet/ether mixture (1:2) to give (S,Z)-3-chloro-N′-hydroxy-4-(tetrahydrofuran-3-yloxy)benzimidamide (5.3 g) LCMS (Table 1, Method b) Rt=1.52 min, m/z 257.09 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][CH2:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:31][CH:32]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[N:31][CH:32]=[C:27]([CH2:26][O:25][CH3:24])[CH:28]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COCc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 5-(methoxymethyl)pyridine-3-boronic acid pinacol ester (PepTeck, Burlington, USA, 32 mg, 0.128 mmol) to give the title compound as a white solid. (HPLC: tR 2.08 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.70-8.67 (m, 1H), 8.56-8.54 (m, 1H), 8.19-8.13 (m, 2H), 8.02-7.98 (m, 1H), 7.82-7.80 (m, 1H), 7.62-7.59 (m, 1H), 4.53 (s, 2H), 3.94 (s, 3H), 3.60 (s, 3H), 3.37 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [F:1][CH:2]([F:26])[CH2:3][N:4]1[CH2:21][CH:20]([C:22](=O)[CH2:23][CH3:24])[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5]1.C[N:28]([CH:30](OC)OC)C.[NH2:35]N>CO>[F:26][CH:2]([F:1])[CH2:3][N:4]1[CH2:21][CH:20]([C:22]2[NH:35][N:28]=[CH:30][C:23]=2[CH3:24])[O:19][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Solvent: CO
Product: Cc1cn[nH]c1C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 1 h
Yield: 33.4 %

Procedure:
tert-Butyl 8-(2,2-difluoroethyl)-10-propanoyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (225 mg, 0.598 mmol) and DMF-DMA (1.0 mL, 7.53 mmol) were heated in a sealed vial at 105° C. overnight. The reaction mixture was concentrated and then diluted with methanol (1 mL). Hydrazine (60 μL, 1.9 mmol) was added in 3 aliquots every hour over 3 hours and then the reaction mixture was stirred for an additional 1 hour. The reaction mixture was diluted with methanol, microfiltered and purified by preparative LCMS (10-99% ACN/Water, HCl modifier) to give tert-butyl 8-(2,2-difluoroethyl)-10-(4-methyl-1H-pyrazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 0.2 mmol, 33.42%) as a yellow oil. ESI-MS m/z calc. 400.2. found 401.5 (M+1)+; Retention time: 1.36 minutes (3 min run).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15].C([BH3-])#N.[Na+]>CO.O>[C:9]([CH:8]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:11])=[O:10]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](NC(Cc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A mixture of phenylpyruvic acid (753 mg) and L-alanyl-L-proline (171 mg) in methanol-water are adjusted to pH 6.8 and treated with sodium cyanoborohydride (173 mg) at room temperature until reaction is complete. The product is absorbed on strong cation exchange resin and eluted with 2% pyridine in water to give 294 mg of crude diastereomeric product, N-(1-carboxy-2-phenylethyl)-L-alanyl-L-proline. A portion is purified by gel filtration (LH-20) for spectrographic analysis. The nmr spectrum shows a broad singlet at 7.2, complex absorption from 3.0 to 4.6, a multiplet at 2.1 and a pair of doublets at 1.5 ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([Cl:27])[C:21]=2[NH:20][C:19]1=[O:28])[CH:16]=[CH2:17].O>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([Cl:27])[C:21]=2[N:20]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:19]1=[O:28])[CH:16]=[CH2:17]
Reactant: BrCc1ccccc1
Reactant: C=CCn1c(=O)[nH]c2c(Cl)nccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCn1c(=O)n(Cc2ccccc2)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.6 %

Procedure:
Potassium carbonate (0.76 g) and benzylbromide (0.94 g) were added to a solution of 1-allyl-4-chloro-1,3-dihydroimidazo[4.5-c]pyridin-2-one (1.05 g) in N,N-dimethylformamide (50 mL). This was stirred at room temperature for 14 hours. Water (300 mL) and ethyl acetate (300 mL) were added, and the organic layer was washed three times with 100 mL of water and then once with 100 mL of saturated aqueous sodium chloride solution, then was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.57 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][C:8](=[O:11])[N:9]=2)[C:5]([Br:12])=[C:4]([Br:13])[C:3]=1[Br:14].[Cl-].[Li+].[CH2:17]1[O:19][CH2:18]1.[CH3:20][C:21](N(C)C)=[O:22]>>[OH:22][CH2:21][CH2:20][N:9]1[C:10]2[C:2]([Br:1])=[C:3]([Br:14])[C:4]([Br:13])=[C:5]([Br:12])[C:6]=2[N:7]([CH2:18][CH2:17][OH:19])[C:8]1=[O:11]
Reactant: C1CO1
Reactant: CC(=O)N(C)C
Reactant: O=C1N=c2c(Br)c(Br)c(Br)c(Br)c2=N1
Agent: [Cl-]
Agent: [Li+]
Product: O=c1n(CCO)c2c(Br)c(Br)c(Br)c(Br)c2n1CCO
Temperature: 80 °C

Procedure:
44.96 g (0.1 mol) of 4,5,6,7-tetrabromobenzimidazolone are stirred with 250 ml of dimethylacetamide and 2.5 g of lithium chloride. A solution of 13.2 g of ethylene oxide (0.3 mol) in 100 ml of dimethylacetamide is added to this mixture at room temperature. The mixture is stirred slowly and heated to 80°C over the course of 2.5 hours. It is then stirred for a further 2 hours at 100°C. During the course of the reaction the starting material dissolves completely.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C.C(Cl)(=O)C(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[Lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (100 mg, 455 μmol) was dissolved in CH2Cl2(5 mL) with one drop of DMF and oxalyl chloride (2 mL) was added. The mixture was stirred at RT for one hour then concentrated and dried under high vacuum. Morpholine (60 μl, 683 μmol) was then added to the mixture with N-ethyl-N-isopropylpropan-2-amine (238 μl, 1366 μmol) and the mixture was stirred for 20 hours. The mix was then concentrated and purified using 0 to 100% 90/10/1 CH2Cl2/MeOH/ammonium hydroxide in CH2Cl2 to afford (7-chlorothieno[3,2-b]pyridin-2-yl)(morpholino)methanone.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CO>[C:3]([CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CCCCCCBr
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC(C(C)=O)C(=O)OC
Yield: 62.3 %

Procedure:
465 g of methyl acetoacetate were added dropwise under nitrogen and stirring to 720 g of 30% sodium methylate solution in 1200 ml of methanol. Then, 727 g of 1-bromohexane were added and the reaction mixture was boiled at reflux for 20 hours. The majority of the methanol was distilled off and the residue was poured on to ice-water. The mixture was extracted with n-hexane and then with water. The organic phases were combined and dried over sodium sulphate. The solvent was evaporated and the crude ester was distilled. There were obtained 499.4 g of methyl 2-acetyloctanoate, b.p. 124°-128°/15 Torr.
Reaction SMILES: [NH2:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[F:20].CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1>C(O)(=O)C>[OH2:17].[F:20][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19])[CH:10]([CH3:15])[CH2:11][CH2:12][C:13]=3[C:2]=1[N:1]1[CH:23]=[CH:27][CH:26]=[CH:25]1
Reactant: COC1CCC(OC)O1
Reactant: CC1CCc2c(N)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC(=O)O
Product: CC1CCc2c(-n3cccc3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: O

Procedure:
To a suspension of 1.0 g of 8-amino-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 20 ml of warm galcial acetic acid was added 1.0 g 2,5-dimethoxytetrahydrofuran. The mixture was heated at reflux for 30 minutes. The product which precipitated was separated by filtration and washed with water to provide yellowish-white crystals of 6,7-dihydro-9-fluoro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrate, m.p. 300° C. Analysis: Calculated for C18H15FN2O3.1/3H2O: %C, 65.0; %H, 4.7; %N, 8.4; Found: %C, 64.8; %H, 4.5; %N, 8.4. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: N[C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([N:26](CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@:3]([NH2:26])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](c1ccccc1)[C@@](N)(O)c1ccccc1
Temperature: 25 °C

Procedure:
(1R,2S)-2-amino-1,2-diphenylethanol (2.10 g) was dissolved in dichloromethane (30 ml) and stirred at room temperature. Ethyl bromoacetate (2.00 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (1.5 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (2.60 g, 88%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure. Yield 2.20 g (75%); mp 123-125° C.; [α]D18 +2.4° (c 1.00, EtOH). IR (KBr): 3180, 1745, 765, 705 cm- 1. 1H-NMR (CDC13): 1.17 (t, 3H, J =7 Hz), 2.35 (bs, 2H), 3.16 (pseudo s, 2H), 3.98 (q, 2H, J =7 Hz), 4.15 (d, 1H, J =6 Hz), 4.76 (d, 1H, J =6 Hz), 7.20 (s, 10H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9](OC1C=CC(S(C)(=O)=O)=CC=1)=[O:10])=[O:4].[CH2:23]1[CH2:28][CH2:27][C:26]([CH2:33][NH2:34])([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24]1.C(=O)(O)[O-].[K+]>C(#N)C.C(OCC)C>[CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9]([NH:34][CH2:33][C:26]1([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:28][CH2:27]1)=[O:10])=[O:4]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(C)C(=O)OCCOC(=O)Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)C(=O)OCCOC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A 50 mL, single-neck, round-bottomed flask equipped with a magnetic stir bar and a nitrogen inlet was charged with sulfone D3 (300 mg, 1 mmol) and gabapentin (171 mg, 1 mmol) in acetonitrile (1 mL). To the resulting slurry, saturated aqueous potassium bicarbonate (1 mL) was slowly added over a period of two minutes. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into a separatory funnel, diluted with diethyl ether (20 mL), washed with 5% aqueous sulfuric acid (10 mL), water (10 mL), and brine (100 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum to give a viscous oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E4 as a viscous oil (250 mg, 75% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (d, J=6.8 Hz, 6H), 1.35-1.55 (m, 10H), 1.46 (d, J=5.2 Hz, 3H), 2.32 (s, 2H), 2.52 (m, 1H), 3.23 (d, J=6.8 Hz, 2H), 5.27 (t, J=6.4 Hz, 1H, —NH) 6.76 (q, J=5.6 Hz, 1H).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH2:9][CH:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=O)=O>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:10]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][C:1]#[N:2])=[CH:12][CH:13]=1
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CC#N)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Sodium cyanide (105 mg, 2.14 mmol) was added to 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl methanesulfonate (Intermediate 23) (300 mg, 0.86 mmol) in DMF (5 mL) at 20° C. The resulting suspension was stirred at 80° C. for 3 hours. The reaction mixture was evaporated to dryness and redissolved in water (10 mL), and washed sequentially with DCM 3× (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-2-cyanoethylcarbamate (209 mg, 87%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ1.38-1.42 (9H, s), 2.82-2.89 (2H, m), 4.89 (1H, d), 7.38-7.45 (4H, m), 7.76 (1H, d). m/z (ESI+) (M−H)−=279; HPLC tR=2.42 min.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](/B(O)O)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1CCc1ccccc1
Reaction time: 96 h

Procedure:
Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 mL) at 90° C. for 24 hours. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd—C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:13][C:14]([NH2:16])=[NH:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+].C(OCC)(=O)C>CO.CCCCCC>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: N=C(N)Cc1ncccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a stirred solution of 2-(3-phenyl-pyridin-2-yl)-acetamidine (162) (300 mg, 1.10 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester (4) (511 mg, 1.66 mmol) in methanol (5 mL) was added sodium methoxide (1.3 mL, 3.32 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature, stirred for 16 h. Silica thin layer chromatography was performed (50% ethyl acetate in hexane, Rf=0.3). After completion of the reaction, it was quenched with water, methanol was evaporated and water (30 mL) was added. The mixture was extracted with ethyl acetate (3×30 mL) and the separated organic part was dried and concentrated to get a crude product, which was purified by a CombiFlash column (eluted at 90% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (163) (250 mg, 48.1%) as a yellow sticky product.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:79][CH2:78][CH2:77][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([N:38]1[CH2:76][CH2:75][CH2:74][C@H:39]1[C:40]([NH:42][C@H:43]([C:49]([NH:51][C@H:52]([C:57]([N:59]1[CH2:73][CH2:72][CH2:71][C@H:60]1[C:61]([N:63]1[CH2:70][CH2:69][CH2:68][C@H:64]1[C:65]([OH:67])=[O:66])=[O:62])=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH2:44][CH2:45][C:46](=[O:48])[NH2:47])=[O:41])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8].[N+](=[CH2:82])=[N-].C(O)(=O)C>CO>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:79][CH2:78][CH2:77][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([N:38]1[CH2:76][CH2:75][CH2:74][C@H:39]1[C:40]([NH:42][C@H:43]([C:49]([NH:51][C@H:52]([C:57]([N:59]1[CH2:73][CH2:72][CH2:71][C@H:60]1[C:61]([N:63]1[CH2:70][CH2:69][CH2:68][C@H:64]1[C:65]([O:67][CH3:82])=[O:66])=[O:62])=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH2:44][CH2:45][C:46](=[O:48])[NH2:47])=[O:41])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8]
Reactant: C=[N+]=[N-]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC
Reaction time: 7 h

Procedure:
Pyroglutamyl-tryptophyl-prolyl-arginyl-prolyl-glutaminyl-isoleucyl-prolyl-proline (1.6 g) is dissolved in 80 ml of methanol. To this, excess ethereal diazomethane is added and the solution is kept for 7 hours at room temperature. Acetic acid is added to destroy the excess diazomethane and the resulting mixture is concentrated to dryness in vacuo.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:11]([C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].CO.O1CCCC1>[Cl:26][C:23]1[CH:24]=[C:25]2[C:17]([C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]=3[O:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:16])=[CH:18][NH:19][C:20]2=[N:21][CH:22]=1
Reactant: O=C(c1cccc(OCc2ccccc2)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1cccc(O)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of [3-benzyloxy-2-cyclopropylmethoxy-phenyl]-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (132, 0.92 g, 2.13 mmol) and palladium on carbon (100 mg, 10%, 0.5 mmol) in methanol (60 mL) and tetrahydrofuran (60 mL) was stirred under an atmosphere of hydrogen overnight. After filtering off of catalyst and removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (133, 236 mg, 32%).