Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[OH:23][N:24]1C2C=CC=CC=2N=N1.Cl.[CH3:34]N(C)CCCN=C=NCC.CN1CCOCC1.NO>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:34])[CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH:24][OH:23])=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: C=C=CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Product: C=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)C(C)C)cc1
Yield: 57.2 %

Procedure:
The procedure of Example 13 was followed using the product from Example 15 (250 mg, 0.74 mmol), 1-hydroxybenzotriazol (119 mg, 0.88 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodimide hydrochloride (199 mg, 1.04 mmol), N-methylmorpholine (0.122 mmol, 1.11 mmol), and hydroxylamine (0.226 ml, 3.7 mmol) to give 150 mg (57%) of the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[C:17]([O:25][C:26]([F:29])([F:28])[F:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([CH:33]1[CH2:38][N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH2:36][CH2:35][NH:34]1)(=[O:32])[NH2:31].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:29][C:26]([F:28])([F:27])[O:25][C:17]1[CH:16]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[CH2:21][C:22]([N:34]1[CH2:35][CH2:36][N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH3:45])[CH2:38][CH:33]1[C:30](=[O:32])[NH2:31])=[O:24]
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OC(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2OC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetic acid (0.50 g, 1.15 mmol) from Step 9 above and 2-carbamoyl-4-(2-methyl-phenyl)piperazine (0.28 g, 1.1 mmol) from Step 4 of Example 1 in DMF (20 mL) was added HOBT (0.175 g, 1.15 mmol), EDC (0.53 g, 1.8 mmol), and DIEA (0.26 mL, 1.5 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (75 mL). The organic phase was separated and washed with H2O (25 mL), saturated aqueous NaHCO3 (75 mL), and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using EtOAc as eluant. The product-containing fractions were evaporated under reduced pressure to give 1-(1-(2-trifluoromethoxy-4-(N-tert-butyoxycarbonyl-4-piperidinyloxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine as an amorphous solid (HPLC retention time=11 min (method A); TLC Rf =0.5 (7:3 EtOAc:hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[CH:38][O:37][N:36]=2)=[CH:31][CH:30]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCCCC[C@H]2CO)(=O)=O)=CC=1>>[O:37]1[CH:38]=[N:39][C:35]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][N:11]([C@@H:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH2:19][OH:20])[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:30][CH:31]=2)=[N:36]1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@@H]1CO)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncon2)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCCC[C@@H]1CO
Yield: 6.6 %

Procedure:
The title compound was synthesized from 4-chloro-N-(cis-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (119 mg, 0.38 mmol), cesium carbonate (244 mg, 0.75 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (99 mg, 0.41 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 40) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(cis-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (12 mg, 7%). 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (1H, s), 8.05 (2H, d, J=8.56 Hz), 7.68-7.70 (1H, m), 7.66-7.68 (1H, m), 7.47 (2H, d, J=8.56 Hz), 7.43-7.45 (1H, m), 7.41-7.43 (1H, m), 4.67 (1H, d, J=16.62 Hz), 4.44 (1H, d, J=16.62 Hz), 4.23-4.35 (1H, m), 3.60 (1H, dd, J=11.33, 8.56 Hz), 3.35 (1H, dd, J=11.46, 5.41 Hz), 1.99 (1H, br. s.), 1.38-1.81 (6H, m), 1.09-1.32 (5H, LC/MS R.T.=3.09 min; [M+H]+=476.23.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1CC#N.[OH-:23].[Na+].N.[CH2:26]([OH:28])[CH3:27]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:27][C:26]([OH:23])=[O:28]
Reactant: [OH-]
Reactant: CCO
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: N
Agent: [Na+]
Product: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Yield: 95 %

Procedure:
1.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile, 10 ml of ethanol and 1.4 g of sodium hydroxide are heated at boiling point for 4 hours until the evolution of ammonia is terminated. The alcohol is distilled in vacuo, treated with ether, purified with active charcoal and the aqueous phase is acidified with hydrochloric acid to pH 3. With a yield of 95 % 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; F 179.5°-181°.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17])=O.[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23]CCCC.C(O)CCCCCCCC=C>>[CH2:4]([OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC=CCCCCCCCCOC=O
Reactant: CCCCC=CCCCC
Agent: C=CCCCCCCCCO
Product: C=CCCCC
Product: CCCCC=CCCCCCCCCO

Procedure:
FIG. 18 shows a synthesis of 9-tetradecenyl formate, in which 5-decene is cross-metathesized with 9-decenol to produce 9-tetradecenol while 1-hexene is removed from the reaction under vacuum, and in which the metathesis product, 9-tetradecenol, is reacted with formyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[CH:18][N:17]=[N:16]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:16]2[N:17]=[CH:18][CH:19]=[N:15]2)[CH3:13])[CH2:11][O:10]1
Reactant: c1c[nH]nn1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nccn1)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (202 mg) and 1H-1,2,3-triazole (0.17 ml), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-1,2,3-triazol-2-yl) ethyl]oxirane (172 mg) was obtained by the same way as in Reference Example 10.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].N1C=CC=CC=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1c(F)cc(Br)cc1F
Yield: 83.6 %

Procedure:
252 g (1.95 mol) of 2,6-difluoroaniline and 170 g (2.15 mol) of anhydrous pyridine were dissolved in 780 cm3 of chloroform, and a solution of 328 g (2.05 mol) of bromine dissolved in 390 cm3 of chloroform was added dropwise for 2 hours on an ice water bath while stirring, after which it was stirred for 2 hours at room temperature. After washing the reaction solution with water, the chloroform was removed, the residue was distilled under reduced pressure (b. p. 100° C./30 mmHg), and the crystals obtained were recrystallized from hexane to obtain 340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([N+:37]([O-])=O)=[C:26]([N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:37][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)=[CH:27][C:26]=1[N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccc(O)cc3)cc2)ccc1N
Yield: 89.6 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4′-benzyloxybiphenyl-4-yloxy)-2-nitrophenyl]-N-methylcarbamate (14.75 g), palladium on carbon (10%, 0.86 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (10.2 g).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>[Ni](Br)Br.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Agent: Br[Ni]Br
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), nickel bromide (1.1 mg, 1 mol %), and Xantphos (2.9 mg) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 32 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 39%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 25 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 93%.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][C:46]([CH3:51])([CH2:49][OH:50])[CH2:47][OH:48].NCCN1CC[O:58][CH2:57]C1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:57]([NH:45][C:46]([CH2:49][OH:50])([CH3:51])[CH2:47][OH:48])=[O:58])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCCN1CCOCC1
Reactant: CC(N)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cc(OCCNC(=O)NC(C)(CO)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 19 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 4-(2-aminoethyl)morpholine, respectively.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:13])[C:5]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=2.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:14][C:15]1[N:16]=[C:17]([C:21]2[N:25]([CH2:2][C:3]3[N:4]([CH3:13])[C:5]4[C:10]([N:11]=3)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=4)[CH:24]=[CH:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: Cc1ncc2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc2nc(Cn3ccnc3-c3cccc(F)n3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 8-Chloromethyl-2,9-dimethyl-9H-purine (40 mg, 0.2 mmol), 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine (40 mg, 0.25 mmol) and K2CO3 (55 mg, 0.4 mmol) in 2 mL of DMF is stirred at room temperature for four hours. The mixture is diluted with water (10 mL), and extracted with ethyl acetate three times. The combined extract is washed with brine, dried and concentrated. The residue is purified by preparative thin layer chromatography to give the title compound. 1H NMR(CDCl3): δ 8.92 (s, 1H), 8.18 (dd, 1H), 7.88 (q, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.83 (dd, 1H), 6.22 (s, 2H), 3.89 (s, 3H), 2.8 (s, 3H). LRMS calcd 323, found 324 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([O-:38])=[O:37]>O1CCCC1>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][C@H:11]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
5.0 g (13.9 mmol) of di-tert-butyl Boc-glutamate (Journal of Peptide Research (2001), 58, 338) were dissolved in 30 mL of tetrahydrofuran and cooled to −70° C. 30.6 mL (30.6 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise over a period of 85 min at this temperature and the mixture was stirred at −70° C. for another 2 hours. 9.0 g (41.7 mmol) of 4-nitrobenzyl bromide in 30 mL of tetrahydrofuran were than added dropwise, and after 1.5 h at this temperature, the cooling bath was removed and 100 mL of 2N aqueous hydrochloric acid and 450 mL of dichloromethane were added. The organic phase was separated off, washed with water (3×150 mL), dried over sodium sulfate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[S:10])[NH:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: S=c1[nH]c2cc(Br)ccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSc1nc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
5-Bromo-3H-benzooxazole-2-thione (530 mg, 2.30 mmol) was dissolved in DMF (5.75 mL). Potassium carbonate (318 mg, 2.30 mmol) and iodomethane (172 μL, 2.76 mmol) were added and the reaction mixture was allowed to stir at RT for 3.5 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (4×10 mL). The combined organic extracts were washed with water (3×10 mL), brine (10 mL) and dried (Na2SO4), filtered and concentrated to afford 538 mg (96%) of the title compound as a dark brown solid: 1H NMR (CDCl3, 400 MHz) δ 7.72 (d, 1H, J=2.1 Hz), 7.36-7.26 (m, 2H), 2.75 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.6, 151.2, 143.8, 126.9, 121.6, 117.3, 111.2, 14.8; MS (Cl) m/z 244.0 (M+1); HPLC retention time=5.10 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Br:17]>CN(C)C=O.C(OCC)(=O)C>[BrH:17].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:10]1[CH:9]=[C:8]([CH3:11])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1]
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1cnc(N)c(C(N)=O)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: Cc1cc(C(N)=O)c(=N)n(Cc2cccc(Cl)c2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 42.4 %

Procedure:
To a solution of 2-amino-5-methylnicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-chlorobenzylbromide (0.31 g), and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (0.15 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28](Cl)(=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>ClCCl>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Reactant: CCCCCCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNCCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{[4-(3-Aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.16 g) synthesized in Example 33 and triethylamine (1.68 mL) were dissolved in dichloromethane (50 mL), heptanoyl chloride (1.62 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (10 mL), 1 M-borane/tetrahydrofuran complex (26.6 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (30 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (30 mL) was added, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound (2.86 g) as a colorless oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1(C)C=CC=CC=1>[C:38]([N:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:8]([O:16][N:17]1[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]1([CH3:24])[CH3:23])=[N:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)N(C(C)=O)C2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 22.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.55 ml, 11 mmol) and acetyl chloride (0.78 ml, 11 mmol). The mixture is stirred at room temperature for 7 hours, then washed with water (2×10 ml), dried over MgSO4 and evaporated. The residue is chromatographed over silica gel with hexane-ethyl acetate (4:1) and the pure fractions are recristallized from pentane to afford 1.05 g of the title compound as a white solid, mp. 125-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:49][CH2:50][CH2:51][NH2:52]>C(Cl)Cl.O>[F:49][CH2:50][CH2:51][NH:52][C:19]([C:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:22])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: NCCF
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NCCF)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
See FIG. 16(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (250 mg, 0.84 mmol) was taken in a 100 ml single necked flask equipped with an air condenser connected to nitrogen source. DCM (10 mL) was added to get a suspension. Triethyl amine (1.162 mL, 8.38 mmol) was added to get a clear solution. 1-Propanephosphonic acid cyclic anhydride (1.497 mL, 2.51 mmol) was added followed by the addition of 2-fluoroethanamine hydrochloride (83 mg, 0.84 mmol). The reaction mass was stirred at RT for overnight, suspension was observed. After completion of the reaction, diluted with DCM, added water, and separated the DCM layer washed with brine solution. The DCM layer was dried over sodium sulphate, evaporated and purified the compound by column chromatography. Yield-52%. ES+MS m/z: 344 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.25 (s, 20 H) 3.67 (d, J=5.46 Hz, 7 H) 3.77 (d, J=5.46 Hz, 7 H) 4.50 (t, J=4.90 Hz, 7 H) 4.66 (t, J=4.99 Hz, 7 H) 5.69 (s, 13 H) 7.26 (dd, J=8.29, 4.71 Hz, 7 H) 7.94 (d, J=8.48 Hz, 7 H) 8.28 (s, 7 H) 8.41 (s, 6 H) 8.49 (d, J=4.52 Hz, 7 H) 8.95 (t, J=5.84 Hz, 7 H).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.O.OS([O-])(=O)=O.[K+]>CS(C)=O>[CH:1]1([CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC1CCCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C=O)CC1CCCCC1
Temperature: 0 °C

Procedure:
A solution of Example 3A (25.8 g, 100 mmol), sulfur trioxide pyridine complex (79.6 g, 500 mmol), and triethylamine (69.7 mL, 500 mmol) in DMSO (70 mL) at room temperature was stirred for 30 minutes, cooled to 0° C., treated with water and saturated aqueous KHSO4, and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO4 and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.