Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:22][C@@H:21]([N:43]2[CH:50]=[C:49]([F:51])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:59][O:60][C:61]1[C:69]([O:70][CH3:71])=[CH:68][CH:67]=[CH:66][C:62]=1[C:63](Cl)=[O:64]>O1CCOCC1>[CH3:59][O:60][C:61]1[C:69]([O:70][CH3:71])=[CH:68][CH:67]=[CH:66][C:62]=1[C:63]([N:46]1[C:47](=[O:48])[C:49]([F:51])=[CH:50][N:43]([C@@H:21]2[O:22][C@H:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20]2)[C:44]1=[O:45])=[O:64]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CCCCCCCCCCCCCCC
Reactant: COc1cccc(C(=O)Cl)c1OC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(OC)c3OC)c2=O)C[C@@H]1OC(=O)CCCCCCCCCCCCCCC
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
3.0 Grams of 2'-deoxy-3',5'-di-O-palmitoyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.9 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 10 minutes and then at 70° C. for 90 minutes. The reaction liquid is cooled and the precipitated triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is dissolved under heating in ethanol and the solution is allowed to stand whereby crystals are obtained which, after recrystallization from ethanol, affords 2.95 g (yield: 80.2%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-palmitoyl-5-fluorouridine. M.P. 77°-78° C.
Reaction SMILES: CC1C=C[C:5]([O:8]C)=CC=1OC1C=CC(NC(=O)[C@@H](C)N)=CC=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][C:33]1[N:38]=[CH:37][C:36]([NH:39][C:40](=[O:44])[C@@H:41]([CH3:43])[NH2:42])=[CH:35][CH:34]=1>>[CH3:43][C@H:41]1[NH:42][C:5](=[O:8])[N:39]([C:36]2[CH:37]=[N:38][C:33]([O:32][C:25]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=3[CH3:23])=[CH:34][CH:35]=2)[C:40]1=[O:44]
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Product: COc1ccc(C)c(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1

Procedure:
The title compound was made in a similar fashion to the preparation of Example 7 replacing N1-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-D-alaninamide with N1-(6-{[2-methyl-5-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-alaninamide (Intermediate 56, 118 mg) to afford the title compound (78 mg)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24](F)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.ClCCl>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc(NC(=O)OC(C)(C)C)c(F)c1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc(NC(=O)OC(C)(C)C)c(F)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Methyl 2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-fluorobenzoate (0.170 g) and piperazine (0.154 g) were dissolved in dimethylsulfoxide (2 mL) and heated to 85° C. After 1 hour, the reaction was cooled, poured into dichloromethane (75 mL), and washed with water (30 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOCC>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)Oc3ccc(C(=O)OCC[Si](C)(C)C)cc3)ccc21

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 79.0 mg, 0.280 mmol), 2-trimethylsilylethyl 4-hydroxybenzoate (73.3 mg, 0.308 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg, 0.364 mmol), and 4-N,N-dimethylaminopyridine (44.5 mg, 0.364 mmol) in 2.0 mL DMF was stirred overnight at room temperature. Et2O (100 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: [CH3:1][NH2:2].CO.[Cl:5][C:6]1[CH:19]=[C:18](F)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:7]=1[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]>CCO>[Cl:5][C:6]1[CH:19]=[C:18]([NH:2][CH3:1])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:7]=1[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]
Reactant: O=C(NC1CCCC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CN
Solvent: CO
Solvent: CCO
Product: CNc1cc(Cl)c(C(=O)NC2CCCC2)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
N-Methylamine in MeOH (2 M, 2.0 mL, 4.0 mmol) was added to 2-chloro-N-cyclopentyl-4-fluoro-5-nitrobenzamide (230 mg, 0.79 mmol) in EtOH. The mixture was heated at 50° C. for 12 h in a sealed vessel, cooled and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield: 150 mg (64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:33]([CH3:32])[C:35]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Cl)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH:16](O)[CH3:17])=[N:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Br)(Br)[Br:20]>C(Cl)(Cl)Cl>[Br:20][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][N:14]=1)[CH3:17]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanol (95 mg, 0.3 mmol) in chloroform (3 mL) was added PBr3 (0.1 mL, 1.1 mmol) at 0° C. and the reaction was stirred at 0° C. for about 3 h. The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with DCM (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude 2-(1-bromoethyl)-5-(4-nitrophenyl)pyridine as off brown liquid (95 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.98 (d, 1H), 8.31 (d, 2H), 8.22 (dd, 1H), 8.01 (d, 2H), 7.70 (d, 1H), 5.55 (dd, 1H), 2.04 (d, 3H), LC-MS m/z calcd for [M+H]+ 309.00. found 309.3.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].O.O.O.C([O-])(=O)C.[Na+].[Br:22][CH2:23][C:24](Br)=[O:25]>CC(C)=O.O>[CH3:12][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:24](=[O:25])[CH2:23][Br:22])[CH3:13]
Reactant: O=C(Br)CBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a well-stirred ice-cooled mixture of 2,6-diisopropylaniline (10.0 g, 0.056 mol) in acetone (25 mL) and water (25 mL) and sodium acetate trihydrate (15.3 g, 0.112 mol), bromoacetyl bromide (17.0 g, 0.084 mol) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is diluted with water (100 mL), the product filtered, washed with cold water, sodium bicarbonate solution, water, and finally with hexane. The product is dried in a vacuum at 40° C. to afford 14.5 g of the title compound as a white solid; mp I70° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.[Br:8][C:9]1[C:10]([CH3:16])=[N:11][C:12](Cl)=[N:13][CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Br:8][C:9]1[C:10]([CH3:16])=[N:11][C:12]([N:2]2[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]2)=[N:13][CH:14]=1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1nc(Cl)ncc1Br
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC[C@@H](O)C2)ncc1Br
Temperature: 70 °C
Yield: 89.5 %

Procedure:
In a 500 mL pear flask equipped with a magnetic stir bar were mixed (R)-pyrrolidin-3-ol hydrochloride (8.94 g, 72.3 mmol), 5-bromo-2-chloro-4-methylpyrimidine (15 g, 72.3 mmol), DIPEA (31.6 mL, 181 mmol), and EtOH (150 mL). The resulting yellow suspension was heated in a sand bath to 70° C. for 18 hours. At this time about half of the solvent was evaporated. Water (250 mL) was added to the flask while rapidly stirring the solution. An off-white precipitate formed and was filtered off, washed with water (100 mL) and dried to give the title compound (16.7 g, 89.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH:16]2[CH2:18][CH2:17]2)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Product: CC1CN(C(=O)OC(C)(C)C)CCC1NC1CC1

Procedure:
The title compound is prepared from 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 3): tR=1.30 min; Mass spectrum (ESI+): m/z=255 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[C:15]1([CH:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:15]1([CH:21]([NH:23][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Reactant: CC(N)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1ccccc1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (1.59 g, 7.57 mmol), 1-phenylethanamine (0.92 g, 7.57 mmol) and N,N-diisopropylethylamine (1.95 g, 15.1 mmol) were stirred at room temperature in dry acetonitrile (50 mL) for 20 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.28 mg, 12% yield). 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 7.80 (t, 1H), 7.31 (m, 5H), 6.33 (t, 1H), 6.22 (d, 1H), 4.58 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S(O[CH2:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:27][C:28]1([CH2:32][O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:31][O:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC2(C)COC2)cc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 5-hydroxyisophthalate (500 mg), (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (915 mg), and potassium carbonate (850 mg) in N,N-dimethylformamide (3 mL) is stirred at 50° C. for 5 h. The reaction mixture is diluted with water and the precipitate is filtered off, washed with water, and dried to give the title compound. LC (method 7): tR=0.97 min; Mass spectrum (ESI+): m/z=295 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([OH:30])=O)[CH2:24][CH:25]([CH3:27])[CH3:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH2:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34]>C(Cl)(Cl)Cl>[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([NH:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34])=[O:30])[CH2:24][CH:25]([CH3:26])[CH3:27])([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: C[C@H](N)C(=O)Cc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
23.3 ml (18.9 g=157 mMol) pivaloyl chloride and 48 ml (28.9 g=286 mMol) triethylamine are added to a solution of 35 g (143 mMol) BOC-MeLeu-OH in 500 ml chloroform and the mixture stirred for 2 hrs. at room temperature under a nitrogen atmosphere. 30.7 g (171 mMol) H-Ala-Bzl dissolved in 300 ml chloroform are then added and the reaction mixture stirred for a further 2 hrs. at room temperature, again under a nitrogen atmosphere. The product is purified in accordance with the technique of example 1a) to yield the title compound: rotation, [α]D25 =-59.4° (c=1.0 in chloroform).
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1[C:22]2[C:17](=[N:18]C=[CH:20][CH:21]=2)[S:16][N+:15]=1[O-].C(NC(C)C)(C)C>ClCCl>[Cl:12][C:2]1[N:18]=[C:17]2[S:16][N:15]=[C:14]([CH3:13])[C:22]2=[CH:21][CH:20]=1
Reactant: Cc1c2cccnc2s[n+]1[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cc1nsc2nc(Cl)ccc12
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of triphosgene (190 mmol) in dichloromethane (200 mL) was added dropwise over 20 min to a solution of 3-methylisothiazolo[5,4-b]pyridine-N-oxide (47.4 mmol) in dichloromethane (150 mL) at −20° C. A solution of diisopropylamine (190 mmol) in dichloromethane (200 mL) was added dropwise over 1 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The reaction mixture was quenched with water (40 mL) of water and the pH was adjusted to 7 by the addition of 10% sodium hydroxide. The organic layer was washed with water (100 mL). The combined aqueous layers were extracted with dichloromethane (10×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/80 ethyl acetate/petroleum ether) to provide 6-chloro-3-methylisothiazolo[5,4-b]pyridine in 46% yield as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[N:17]3[C:13]([S:14][CH:15]=[CH:16]3)=[N:12][C:11]=2[CH3:18])=[O:9])[CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32]([N:1]3[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]4[N:17]5[C:13]([S:14][CH:15]=[CH:16]5)=[N:12][C:11]=4[CH3:18])=[O:9])[CH2:2]3)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Product: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCN(C(=O)c2ccccc2-c2cccc(Cl)c2)C1

Procedure:
prepared by reaction of (R)-6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid piperidin-3-ylamide with 3′-chloro-biphenyl-2-carboxylic acid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][Cl:15].CCCCCCC>CN(C=O)C>[Cl:15][CH2:14][CH2:13][N:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=[CH:2]1
Reactant: c1cnc2[nH]cnc2c1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: ClCCn1cnc2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
6.5 g (54.56 mmol) 3H-imidazo[4,5-b]pyridine were dissolved under argon in 100 ml DMF and cooled to 0° C. in an ice bath. 4.6 g (109.1 mmol) sodium hydride were added and the mixture was stirred for 1 hour at room temperature. Then a solution of 9 ml (109.1 mmol) 1-bromo-2-chloroethane in 30 ml DMF was added over the period of an hour and the solution was stirred at room temperature during 20 hours. The brownish solution was poured onto ice water and extracted 3 times with ethyl acetate. The organic layers were combined, washed once with brine, dried over Na2SO4 and evaporated in vacuo to give a yellow oil. The oil was stirred with three times 50 ml warm heptane. Heptane was decanted, the tree fractions pooled and evaporated to give 2.08 g of light yellow crystals. MS(ISP): 182.2 [MH]+; 1H-NMR (CDCl3): 3.99 (t, 2H), 4.66 (t, 2H), 7.28-7.32 (m, 1H), 8.11-8.17 (m, 2H), 8.40-8.42 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[CH:4].[Cl:7][CH:8]([CH3:12])[C:9](Cl)=[O:10].Cl>O>[Cl:7][CH:8]([CH3:12])[C:9]([O:5][C:2]([CH3:6])([CH3:1])[C:3]#[CH:4])=[O:10]
Reactant: CC(Cl)C(=O)Cl
Reactant: C#CC(C)(C)O
Agent: Cl
Solvent: O
Product: C#CC(C)(C)OC(=O)C(C)Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.84 g of 1,1-dimethyl-2-propynol and solution F were mixed and stirred for 15 minutes at 0° C. To the mixture was added 0.97 ml of 2-chloropropionyl chloride and the solution was stirred for 5 minutes at 0° C., additional 5 hours at room temperature. Then, to the reaction mixture was added 1N hydrochloric acid and water, and extracted with ethyl acetate. The organic layer was washed successively with water and aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 1.06 g of (1,1-dimethyl-2-propynyl) 2-chloropropionate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1cnc(-c2ccc(F)cc2)o1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cnc(-c2ccc(F)cc2)o1
Yield: 15 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 15%). 1H NMR (400 MHz, MeOD) δ 8.48-8.47 (m, 1H), 8.28-8.25 (m, 1H), 8.00-7.97 (m, 3H), 7.68-7.64 (t, J=7.8 Hz, 1H), 7.21-7.16 (t, J=8.8 Hz, 2H), 7.00 (s, 1H), 3.66 (s, 2H), 1.46 (s, 6H). MS (ESI) m/z: Calculated for C23H18F4N4O3: 474.13. found: 475.2 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[S:25](=[O:33])(=[O:32])[N:24]=1>C1COCC1>[C:1]([N:5]1[C:9]([OH:10])=[C:8]([C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:32])(=[O:33])[N:24]=2)[C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CC(C)(C)N1C(=O)CC(=O)N1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)n1c(O)c(C2=NS(=O)(=O)c3ccccc32)c(=O)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
step 5—To a solution of the pyrazolone 62a (300 mg, 1.1 mmol) in THF (5 mL) was added NaH (54 mg, 1.4 mmol). The reaction mixture was stirred at RT for 20 min, and 3-chloro-benzo[d]isothiazole 1,1-dioxide (270 mg, 1.4 mmol) was added. The reaction mixture was then stirred at RT for 2 h, quenched with saturated aqueous NH4Cl and extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by reverse-phase column chromatography eluting with acetonitrile/water which afforded 15 mg (3%) of III-2; LCMS RT 2.3 min, M−H.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][C@@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(OCC)(=O)C>[CH3:15][S:16]([O:7][CH2:1][CH2:2][CH2:3][C@@H:4]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH3:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)CCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](CCCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution containing 2.5 g (24 mmol) of (S)-1,4-pentanediol produced in Example 3, 7.3 g (72 mmol) of triethylamine, and 30 mL of ethyl acetate was cooled to 5° C. Subsequently, 6.6 g (58 mmol) of methanesulfonyl chloride was added to the solution, and the solution was stirred for one hour. The solution was washed by adding 15 mL of a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was further washed with 15 mL of water, and was dried over anhydrous magnesium sulfate. The solvent was then distilled off under a reduced pressure. Thus, (S)-1,4-bis(methanesulfonyloxy)pentane was obtained as a light yellow oily substance (6.1 g, yield; 98%).