Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][N:16]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)CNc2ccc(C)cc2)cc1OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)CN(C(=O)OCc2ccccc2)c2ccc(C)cc2)cc1OC
Temperature: 0 °C
Yield: 84.8 %

Procedure:
A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(p-toluidino)acetamide (3.6 g) and anhydrous potassium carbonate (2.5 g) was added to anhydrous dimethylformamide (25 ml). The mixture was vigorously stirred under ice cooling and to the solution was dropwise added over 20 minutes an anhydrous chloroform solution (5 ml) containing benzyl chloroformate (2.04 g). The reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with water, dried and the solvent was distilled off. The residue was crystallized by treating with ether to give N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-toluidino)-acetamide (4.3 g), mp 81° to 85° C.
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[C:8]([O:20][CH3:21])=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)([CH3:6])=[O:5])#[N:2].[NH2:22][C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1.C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[C:1]([N:3]=[S:4]([C:7]1[C:8]([O:20][CH3:21])=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:10]([NH:22][C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1)=[O:12])([CH3:6])=[O:5])#[N:2]
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)(=O)=NC#N
Reactant: Cc1nnc(N)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1c(C(=O)Nc2nnc(C)o2)ccc(C(F)(F)F)c1S(C)(=O)=NC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.8 %

Procedure:
350 mg (80% by weight; 0.869 mmol) of 3-(N-cyano-S-methylsulfonimidoyl)-2-methoxy-4-(trifluoromethyl)benzoic acid and 151 mg (1.52 mmol) of 2-amino-5-methyl-1,3,4-oxadiazole were initially charged in 10 ml of dry pyridine and cooled in an ice bath. 207 mg (1.63 mmol) of oxalyl chloride were added, and after 30 minutes the mixture was thawed to RT. The contents were stirred at RT for 2 h, and another 51.8 mg (0.408 mmol) of oxalyl chloride were then added. The mixture was then stirred at RT for 16 h. For work-up, the contents were freed from the solvent on a rotary evaporator and the residue was taken up in water and dichloromethane. After phase separation, the organic phase was freed from the solvent on a rotary evaporator and the residue was purified chromatographically under neutral conditions, which gave 9.80 mg of product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:24])[CH3:23])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)cc1C
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)- benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 436.6 mg.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Reactant: C#C[Si](C)(C)C
Product: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 6 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and trimethylsilylacetylene: MS (m/z) 363.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH2:20]([N:27]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH:31]=[C:30]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:29]=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: O=C(O)c1csc(COc2ccc(-c3cnn(Cc4ccccc4)c3)cc2)n1

Procedure:
2-[4-(1-Benzyl-1H-pyrazol-4-yl)-phenoxymethyl]-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 1-benzyl-1h-pyrazole-4-boronic acid (available from Frontier Scientific, Inc., Logan, Utah). Mass spectrum MH+=392.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.Cl[C:10]1[C:11]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][C:13]2[N:14]([C:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[N:17][N:18]=2)[N:15]=1.[H-].[Na+]>CN(C=O)C.O>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[C:16]1[N:14]2[N:15]=[C:10]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][N:5]=3)[C:11]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][C:13]2=[N:18][N:17]=1
Reactant: Cn1ncnc1CO
Reactant: CC(C)(C)c1cc2nnc(-c3cc(F)ccc3F)n2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nn2c(-c3cc(F)ccc3F)nnc2cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.1 %

Procedure:
To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.069 g, 0.4 mmol) and 6-chloro-3-(2,5-difluorophenyl)-7-(1,1-dimethylethyl)-1,2,4-triazolo[4,3-b]pyridazine (0.10 g, 0.31 mmol) in DMF (10 ml) was added sodium hydride (0.015 g of a 60% dispersion in oil, 1.2 mol eq.) and the reaction mixture was stirred at room temperature for 40 minutes. After this time the reaction mixture was diluted with water (80 ml) and the solid that precipitated was collected by filtration and washed several times with water in the sinter funnel. The solid was recrystallised from ethyl acetate/hexane to give pure title compound (0.088 g, 65%). Data for the title compound: 1H NMR (360 MHz, CDCl3) δ1.41 (9H, s), 3.89 (3H, s), 5.54 (2H, s), 7.23-7.26 (2H, m), 7.64 (1H, m), 7.91 (1H, s), 8.00 (1H, s); MS (ES+) m/e 400 [MH]+. Anal. Found C, 57.36; H, 4.61; N, 24.60%. C19H19F2N7O requires C, 57.14; H, 4.79; N, 24.55%.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[CH:12]=[CH:11][N:10](C(=O)C(C)(C)C)[CH:9]=[C:8]1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[S]>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1C1=CN(C(=O)C(C)(C)C)C=CC1COC(C)(C)C
Agent: [S]
Solvent: Cc1ccccc1
Product: CN1CCCC1c1cnccc1COC(C)(C)C
Yield: 73.3 %

Procedure:
A solution of 1-[4-tert-butoxymethyl-3-(1-methylpyrrolidin-2-yl)-4H-pyridin-1-yl]-2,2-dimethyl-propan-1-one (0.194 g, 0.5 mmol), sulfur (0.02 g, 0.5 mmol) and toluene (5 mL) was refluxed for 1 day. After filtration of the mixture through a pad of Celite and evaporation of the solvent under reduced pressure, the crude material was purified by radial PLC (hexanes) to afford 0.091 g (54%) of 4-tert-butoxymethyl-3-(1-methylpyrrolidin-2-yl)-pyridine as a yellow oil. IR (thin film, neat, NaCl) 2970, 2778, 1594, 1362, 1193, 1088 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.72 (s, 1H), 8.45 (d, 1H, J=6.4 Hz), 7.40 (d, 1H, J=6.4 Hz), 4.52 (s, 2H), 3.32-3.20 (m, 3H), 2.32-2.22 (m, 2H), 2.18 (s, 3H), 1.96-1.66 (m, 4H), 1.29 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 148.3, 147.7, 146.2, 135.3, 121.4, 73.4, 65.2, 59.6, 56.5, 40.2, 33.7, 27.20, 22.4; HRMS Calcd for C15H24N2O: 249.1967 [M+H]+. Found: 249.1964 [M+H]+. [α]D28−108.2 (c 3.4, CH2Cl2).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(=O)CC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CC(=O)NCCCN1CCc2ccccc2C1
Temperature: 25 °C

Procedure:
A suspension of N-(3-bromopropyl)acetoacetamide (4.50 g, 20.3 mmol, 1.00 equiv), 1,2,3,4-tetrahydroisoquinoline (3.30 mL, 26.3 mmol, 1.30 equiv), K2CO3 (3.64 g, 26.3 mmol, 1.30 equiv), and KI (330 mg, 1.99 mmol, 0.10 equiv) in acetone (60 mL) was stirred at reflux for 14 hours. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, MeOH--EtOAc 0:1 to 1:9) to give 1.78 g (43%) of light yellow oil, which was characterized spectroscopically. N-(3-Bromopropyl)acetoacetamide (1.20 g) was also recovered.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[NH:24]1[CH:28]=[N:27][C-:26]=[N:25]1.O>CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH:16]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [c-]1nc[nH]n1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)N2CC(n3cncn3)C2)cc1
Yield: 68.9 %

Procedure:
A suspension of N-benzhydryl-3-[(methylsulfonyl)oxy]azetidine (0. 951 g, 3 mmol) and potassium-1,2,4-triazolide (0.69 g, 6.5 mmol) in 50 ml of dimethylformamide was heated at 85°-90° C. overnight. To this, water (200 ml) was added and extracted with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4) and evaporated to yield 0.9 g of the crude which upon purification over silica gel using ethyl acetate as solvent yielded 0.6 g of the desired product as a white solid. 1H NMR (CDCl3) δ: 8.22 (s, 1H), 7.97 (s, 1H), 7.57-7.12 (m, 5H), 5.13-4.9 (m, 1H), 4.53 (s, 1H), 3.8-3.4 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:20])[N:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:1][C:2]1[N:3]=[C:4]([CH3:20])[N:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Cn2c(C)nc(O)cc2=O)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(C)nc(OCc3ccc(F)cc3F)cc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of methyl 4-[(4-hydroxy-2-methyl-6-oxopyrimidin-1(6H)-yl)methyl]benzoate (0.2 g, 0.00073 mol, from step 2), potassium carbonate (0.15 g, 0.001 mol), 2,4 difluorobenzylbromide (0.15 g, 0.00073 mol), and 18-crown-6 (0.011 g) in DMF is stirred at room temperature for 1 h under argon atmosphere. The DMF was distilled in vacuo and the residue is partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase is washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel flash chromatography using 35% EtOAc in hexanes to afford the title compound (0.20 g, 69%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.98 (d 2H, J=8.4 Hz), 7.54 (m, 1H), 7.27 (d, 2H, J=8.4 Hz), 6.98 (m, 2H), 5.78 (s, 1H), 5.38 (s, 2H), 5.32 (s, 2H), 3.88 (s, 3H), and 2.44 (s, 3H); ES-HRMS m/z 401.1308 (M+H calcd for C21H19N2O4F2 requires 401.1307). 19F NMR(CD3OD/400 MHz) −111.77 (m), 116.06 (m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[Cl:17])[C:6]=1[CH:7]=O.C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[Cl:17])[C:6]=1/[CH:7]=[CH:38]/[C:39]([O:41][CH3:42])=[O:40]
Reactant: Cc1nc(Cl)c(C=O)n1Cc1ccc(I)cc1Cl
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(I)cc1Cl
Yield: 84.5 %

Procedure:
To a solution of 4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazole 5-carbaldehyde (1.01 g) in tetrahydrofuran (10 ml) was added methyl (triphenylphosphoranylidene)acetate (1.27 g) and the mixture was refluxed under heating for 4 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazol-5-yl)-2-propenate (974 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].I[CH2:35][CH3:36]>>[CH2:35]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:36]
Reactant: CCI
Reactant: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine ethyl ester was prepared from N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine and iodoethane using the general procedure described in example 27 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C26H28ClN3O5 (M+Na) 520.1610, found 520.1591.
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[N:24]=1)([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:31].CO>>[C:19]([O:18][C:16](=[O:17])[NH:15][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[N:24]=1)([CH3:14])[CH2:12][O:11][C@@:5]([C:4](=[O:3])[NH2:31])([CH3:10])[C:6]([F:7])([F:8])[F:9])([CH3:20])([CH3:22])[CH3:21]
Reactant: CCOC(=O)[C@@](C)(OCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)n1)C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(CO[C@](C)(C(N)=O)C(F)(F)F)c1cccc(Br)n1

Procedure:
A solution of (R)-2-[(RS)-2-(6-bromo-pyridin-2-yl)-2-tert-butoxycarbonylamino-propoxy]-3,3,3-tri-fluoro-2-methyl-propionic acid ethyl ester (3.0 g, 6.01 mmol) in 7N NH3/MeOH (6.5 ml) was stirred in a sealed glass vial at 55° C. for 72 h. The reaction mixture was concentrated to leave the title compound as a colourless solid that was used in the next step without further purification. HPLC RtH4=1.12, 1.14 min (diastereomers); ESIMS: 470, 472 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[N:42])[C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].CCO.C1COCC1>[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]#[N:42])[C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1
Reactant: N#Cc1ccccc1Cn1c(C2CCCC(NC(=O)OCc3ccccc3)C2)nc2ccn(Cc3ccccc3)c(=O)c21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccccc1Cn1c(C2CCCC(N)C2)nc2ccn(Cc3ccccc3)c(=O)c21
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A solution of {3-[5-benzyl-3-(2-cyano-benzyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (78 mg, 0.14 mmol) in 1:3 EtOH/THF (8 mL) was hydrogenated over 10% Pd/C (73 mg, 0.068 mmol) at room temperature. After 2 h, the catalyst was removed by filtration, rinsing with MeOH, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 94:6:0.5 CH2Cl2/MeOH/NH4OH to give 2-[2-(3-amino-cyclohexyl)-5-benzyl-4-oxo-4,5-dihydro-imidazo[4,5-c]pyridin-3-ylmethyl]-benzonitrile (45 mg, 75% yield). The HCl salt was prepared by treating the amine in EtOAc with ethereal HCl (0.2 mL). 1H-NMR (500 MHz, 1 mL CDCl3+1 δ L d-Trifluoroacetic acid: 8 (dd, 1H, J=7.8, 1.4 Hz), 7.62 (dt, 1H, J=7.8, 1.4 Hz), 7.53 (dt, 1H, J=7.8, 1.4 Hz), 7.49 (d, 1H, J=7.5 Hz), 7.37 (br m, 5H), 7.26 (dd, 1H, J=7.8, 1.4 Hz), 6.60 (d, 1H, J=7.5 Hz), 6.35 (d, 1H, J=16.3 Hz), 6.17 (d, 1H, J=16.3 Hz), 5.28 (d, 1H, J=14.0 Hz), 5.25 (d, 1H, J=14.0 Hz), 3.45 (br s, 1H), 3.34 (br t, 1H, J=11.7 Hz), 2.38 (br d, 1H, J=11.7 Hz), 2.29 (q, 1H, J=11.7 Hz), 2.15 (br d, 1H, J=11.7 Hz), 2.0 (br d, 1H, J=13.3 Hz), 1.66 (m, 2H), 1.59 (q, 1H, J=11.7 Hz), 1.48 (br t, 1H, J=11.7 Hz). MS: calculated for C27H27N5O+H 438.2; found: 438.3.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(CCl)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over one hundred minutes. The solvents were removed under reduced pressure at 40° C. and the residue dissolved in ethyl acetate (approx. 1L). The solution was washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution was removed under reduced pressure. To the resulting oil was added hexane (approx. 1L) and the mixture warmed to 60° C. with swirling. After cooling to room temperature, the solids were collected and washed with 2L of hexane. The resulting solid was recrystallized from hot ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150-151° C. and M+Li+=340.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.NN>>[NH2:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCCCCCCO
Agent: NN
Product: C=CCCCCCCCCCN
Yield: 66 %

Procedure:
Compound XXXI was prepared as described in Scheme I from 10-undecen-1-ol, 1, by a three step procedure in an overall yield of 31%. Alkylation of phthalimide with alkanol, 1, under Mitsunobu conditions, followed by reaction with hydrazine gave 1-aminoundec-10-ene, 2, in 66% yield. The amine was derivatized with O-acetylsalicyloyl chloride and the resulting alkene, 3, was oxidized to the acid using potassium permanganate. Removal of the acetate, followed by acid precipitation provided compound XXXI in 47% yield based on amine 2. Delivery Systems
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:34])=[C:15]([C@:17]34[O:25][CH2:24][CH2:23][C@H:22]3[CH2:21][S:20][C:19]([NH:26]C(=O)OC(C)(C)C)=[N:18]4)[CH:16]=2)=[O:9])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[Cl:42]CCl>>[NH2:26][C:19]1[S:20][CH2:21][C@@H:22]2[CH2:23][CH2:24][O:25][C@:17]2([C:15]2[CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([Cl:42])=[CH:7][N:6]=3)[CH:12]=[CH:13][C:14]=2[F:34])[N:18]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Br)cn4)ccc3F)OCC[C@H]2CS1
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)OCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (4aR,7aR)-7a-(5-(5-bromopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (45 mg) in dichloromethane (0.44 mL) was added TFA (103 μL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was subjected directly to preparative TLC eluting with 90% CH2Cl2/9% MeOH/1% NH4OH to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-chloropicolinamide as a white foam (29 mg). 1H NMR (500 MHz, CDCl3) δ 9.89 (1H, s), 8.70 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=8.5 Hz), 8.06 (1H, dd, J=2.0, 8.06 Hz), 8.0 (1H, m), 7.75 (1H, m), 7.09 (1H, m), 4.13 (2H, m), 3.22 (1H, m), 3.02 (1H, m), 2.89 (1H, m), and 2.22 (2H, q, J=7.5 Hz). MS (M+H)+: 453.3. Retention time: 18.96 chiralcel OJ-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol); Retention time: 11.49 chiralcel OD-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:12][C@H:13]([CH2:18]O)[C:14]([CH3:17])([CH3:16])[CH3:15]>ClC1C=CC=CC=1>[C:14]([C@H:13]1[CH2:18][O:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[N:12]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)[C@H](N)CO
Solvent: Clc1ccccc1
Product: CC(C)(C)[C@H]1COC(c2ccc(C#N)cc2)=N1
Yield: 78 %

Procedure:
Under an argon atmosphere, a mixture of 4-cyanobenzoic acid (7.2 mmol), L-tert-leucinol (6.0 mmol), Zn4(OCOCF3)6O (0.3 mmol) and chlorobenzene (10 mL) was heated under reflux for 18 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (V/V)) to give (S)-4-tert-butyl-2-(4-cyanophenyl)-1,3-oxazoline in 78% yield.