Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[C:20](Cl)(Cl)=[S:21]>O1CCOCC1>[F:11][C:10]([F:12])([F:13])[CH2:9][O:8][C:6]1[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:3]=[C:2]([N:1]=[C:20]=[S:21])[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Solvent: C1COCCO1
Product: FC(F)(F)COc1cc(OCC(F)(F)F)nc(N=C=S)n1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
2-Amino-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (20.0 g, 68.7 mmol) was added to a solution of thiophosgene (15.7 mL, 206 mmol) in anhydrous dioxane (100 mL) under an N2 atmosphere. The resulting solution was heated to reflux. After 18 h the heat was removed and the reaction cooled to room temperature. The dioxane was evaporated to give a dark oil. The dark oil was distilled to afford the product as a light yellow oil (13.7 g, 60% yield); by 83-86° C., (ca 0.2 mmHg): 1H NMR (CDCl3) δ 6.24 (s 1H), 4.78 (q, 4H, J=8.2 Hz); GCMS (EI, 70 eV) m/z 333 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (3.50 g) in dimethyl sulfoxide (60 mL) were added L-valine (3.16 g) and cesium carbonate (9.53 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 5.69 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[O:4][N:3]=1.C([Sn](=O)CCCC)CCC.[N:53]([Si](C)(C)C)=[N+:54]=[N-:55].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH2:6][CH:5]([CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:55][N:54]=[N:53][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[O:4][N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-[(4-{trans-4-[(3-methyl-4,5-dihydroisoxazol-5-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.4 g), dibutyltin oxide (0.088 g), azidotrimethylsilane (2.4 g) and toluene (25 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:4]([Cl:6])([Cl:5])[C:3]=1[Cl:7].[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]2[O:8][CH:12]([C:4]([Cl:6])([Cl:5])[C:3]=1[Cl:7])[CH:11]=[CH:10]2
Reactant: c1ccoc1
Reactant: ClC1=C(Cl)C1(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=C(Cl)C(Cl)(Cl)C2C=CC1O2

Procedure:
A stirred mixture of 1,2,3,3-tetrachlorocyclopropene (60 g) and furan (22.97 g) in dry toluene (600 ml) was heated to reflux for 30 hours. The solvent was evaporated under reduced pressure to afford the required product, 75.4 g. 1H NMR (CDCl3) δ: 6.90 (1H, dd), 6.45 (1H, dd), 5.41 (1H, d), 4.93 (1H, d).
Reaction SMILES: NN.[N:3]1[NH:4][C:5](=[O:14])[NH:6][C:7](=[O:13])[C:8]=1[C:9]([NH:11][NH2:12])=[O:10].Cl.[N:16]([O-])=[O:17].[Na+]>O.CN(C)C=O>[N-:16]=[N+:11]=[N-:12].[N:3]1[NH:4][C:5](=[O:14])[NH:6][C:7](=[O:13])[C:8]=1[C:9]([OH:17])=[O:10]
Reactant: O=N[O-]
Reactant: NNC(=O)c1n[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1n[nH]c(=O)[nH]c1=O
Product: [N-]=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
A solution of 1.01 g. (0.005 mole) of 1,2,4-triazine-3,5-dione-6-carboxylic acid hydrazide hydrazine salt in 50 ml. of water, 20 ml. of 1N hydrochloric acid and 70 ml. of N,N-dimethylformamide was cooled to -3° C. A solution of 0.83 g. (0.012 mole) of sodium nitrite in 4 ml. of water was added to the hydrazide solution and the mixture was stirred at -3° C. to -5° C. for 30 minutes to give in solution the acid azide of 1,2,4-triazine-3,5-dione-6-carboxylic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[OH-].[Na+].Cl[C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CS(C)=O>[CH2:14]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:19]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=2[C:21]#[N:22])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:15]
Reactant: CCN(CC)S(=O)(=O)c1ccc(O)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 60 °C
Yield: 87.8 %

Procedure:
To a solution of 6.73 g (0.0294 moles) of N,N-diethyl-4-hydroxybenzenesulfonamide in 150 ml of DMSO was added 1.18 g (0.0294 moles) of NaOH. The mixture was heated to 60° C. and 4.88 g (0.0267 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 3 hrs. The reaction mixture was cooled and poured into a solution of 400 ml of 2 N aqueous NaOH and 300 ml of water. The product was collected by filtration, washed well with water and dried to obtain 8.8 g of product (88% yield). Recrystallization from ethanol afforded purified N,N-diethyl-4-(2-cyano-4-nitrophenoxy)benzenesulfonamide, mp 163°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[CH:5]=[N:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[CH:20]([Mg]Br)=[CH2:21].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH:20]=[CH2:21])[CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=1
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[S@](=O)N=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
To a solution of (S)-N-(3-bromo-5-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (20 g, 56.1 mmol) in DCM (300 mL) was drop wise added vinylmagnesium bromide (84 mL, 1 M in THF, 84 mmol) at −60° C. The reaction mixture was stirred at room temperature for 5 h and poured into aqueous NH4Cl solution. The resulting mixture was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (12 g, yield: 56%); m/z (ES+): 384 [M+H]+.
Reaction SMILES: COC([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:19])=O>CC#N.O>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH2:5][C:6]1=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1C(=O)CCN(Cc2ccccc2)C1=O
Solvent: O
Solvent: CC#N
Product: O=C1CCN(Cc2ccccc2)C(=O)C1
Yield: 98.4 %

Procedure:
A solution of 1-benzyl-2,4-dioxo-piperidine-3-carboxylic acid methyl ester (2.09 g, 8.0 mmol) in MeCN (250 mL) and water (20 mL) was heated at reflux for 76 hours. The cooled reaction mixture was concentrated under vacuum to afford 1.60 g (98%) of 1-benzyl-piperidine-2,4-dione as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.36-7.24 (m, 5H), 4.69 (s, 2H), 3.48 (t, 2H), 3.43 (s, 2H), 2.54 (t, 2H).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@H:76]([NH:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C:77](OCC#N)=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([C:63]1[CH:92]=[CH:91][C:66]([CH2:67][O:68][C:69]([NH:71][CH2:72][CH2:73][CH2:74][CH2:75][C@@H:76]([NH:83][C:84]([O:86][C:87]([CH3:88])([CH3:89])[CH3:90])=[O:85])[C:77]([O:40][C@H:39]2[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36][C@H:35]2[CH2:34][O:33][P:30]([O:29][C@H:28]2[CH2:27][C@H:26]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:25][C@@H:24]2[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:78])=[O:70])=[CH:65][CH:64]=1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 18.7 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (47.9 mg, 0.075 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk36) (104 mg, 0226 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (14 mL), and the mixture was stirred at room temperature for 1.75 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk37) (14.6 mg, 19%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]CC(OC)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:20][Mg+].[Br-].CC[O:25][CH2:26][CH3:27]>>[OH:25][C:26]([CH3:27])([CH3:20])[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C[Mg+]
Reactant: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOCC
Agent: [Br-]
Product: CC(C)(O)CC1CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.69 g (2.7 mmol) of 1-t-butoxycarbonyl-4-(methoxycarbonylethyl)piperidine (Example 22, Step 2) in 26 mL of ether at 0° C. was added dropwise 2.8 mL (8.4 mmol) of CH3MgBr (3 M in ether) and the reaction mixture was warmed slowly to rt. After stirring at rt for 6 h, the reaction was quenched by addition of 20 mL of sat'd NH4Cl solution and the mixture was stirred overnight. The mixture was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes-:ethyl acetate, 3:1) to give 0.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][CH:12]([F:29])[C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:27][NH2:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH2:27][C:19]1([C:16]2[CH:15]=[N:14][C:13]([CH:12]([F:29])[F:11])=[N:18][CH:17]=2)[CH2:24][CH2:23][C:22]([F:25])([F:26])[CH2:21][CH2:20]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and (1-(2-(difluoro methyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine. LCMS (MH+): m/z=416.1, tR (minutes, Method F)=2.83
Reaction SMILES: C(O[C:4](=[NH:19])[C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:10]=1)C.O.[NH2:21][NH2:22]>C(O)C>[NH:21]([C:4](=[NH:19])[C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:10]=1)[NH2:22]
Reactant: NN
Reactant: CCOC(=N)c1ccc2nc(C(=O)OCC)cn2c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn2cc(C(=N)NN)ccc2n1
Reaction time: 2 h

Procedure:
To a solution of 625 mg of ethyl 6-[ethoxy(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate in 12 mL of ethanol is added dropwise at 0-5° C. 0.2 mL of hydrazine hydrate. The reaction mixture is stirred for 2 hours, a further 73 μL of hydrazine hydrate are added and the mixture is stirred for a further 2 hours while allowing the temperature to rise to 25° C. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dried to give 600 mg of ethyl 6-[hydrazino(imino)methyl]imidazo[1,2-a]pyridine-2-carboxylate, which is used without further purification in the rest of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:30]([C:32]1[C:37]([CH3:38])=[CH:36][C:35]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=1)#[N:31]>C(O)(C)(C)C.ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([C:15]([NH:42][S:39]([C:35]3[CH:36]=[C:37]([CH3:38])[C:32]([C:30]#[N:31])=[CH:33][C:34]=3[CH3:43])(=[O:40])=[O:41])=[O:17])[N:14]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1cc(S(N)(=O)=O)c(C)cc1C#N
Reactant: O=C(O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c(C)cc1C#N
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-c]pyridine-2-carboxylic acid (2.5 g, 9.5 mmol, prepared as described in Example 1 Step C) in t-butanol (70 mL) and dichloromethane (70 mL) was added 4-(dimethylamino)pyridine (3.47 g, 28.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.54 g, 23.7 mmol). The reaction mixture was stirred for 15 min after which time 4-cyano-2,5-dimethylbenzenesulfonamide (1.85 g, 8.85 mmol) was added, and stirring was continued at room temperature overnight. Dichloromethane (200 mL) was then added, the mixture was washed with 1 N hydrochloric acid (3×100 mL), the organic phase was collected and dried over magnesium sulfate and then concentrated under reduced pressure to afford a solid. The solid was isolated by filtration, rinsed with diethyl ether, and recrystallized from hexane/ethyl acetate to afford 1.5 g of the title compound, a compound of the present invention, as a solid, m.p. 228-229° C. 1H NMR (CDCl3) δ 9.97 (br s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 2.71 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C@@H:11](O)[CH2:12][CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C@H:13]([CH2:12][CH:11]=[CH2:10])[CH3:14]
Reactant: Oc1cc(F)ccc1Br
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 2-bromo-5-fluorophenol (1.46 g, 7.64 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.94 mL, 9.17 mmol, 1.2 equiv), and PPh3 (2.40 g, 9.17 mmol, 1.2 equiv) in THF (26 mL) was added DIAD (1.78 mL, 9.17 mmol, 1.2 equiv). After stirring 2 h, the yellow solution was diluted with ether, washed with 1 N NaOH, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (hexane) to provide the product (1.18 g, 60%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J=8.7, 6.3 Hz, 1H), 6.67 (dd, J=10.6, 2.8 Hz, 1H), 6.62-6.56 (m, 1H), 5.91 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.22-5.12 (m, 2H), 4.49-4.38 (m, 1H), 2.62-2.52 (m, 1H), 2.49-2.40 (m, 1H), 1.39 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:2][C:1]1[O:8][C:6](=[O:7])[C:5](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[CH:13][CH:14]=2)[N:4]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc(OC(F)(F)F)cc2)C(=O)O1
Temperature: 120 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A mixture of N-acetylglycine (5.00 g, 42.7 mmol), 4-trifluoromethoxybenzaldehyde (9.30 g, 47.0 mmol), sodium acetate (4.55 g, 55.5 mmol), and acetic anhydride (20 mL, 213 mmol) was stirred at 120° C. for 1 hour, and then was cooled to room temperature. After further ice-cooling, the precipitated yellow solid was suspended in water. The insoluble substance was collected by filtration, washed with water, and dried by heating under reduced pressure to give 10.7 g of the title compound (yellowish brown crystal, yield: 92%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:29])([C:23]2[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=2)[C:10](O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)=[O:11])=[CH:5][CH:4]=1)#[N:2].[Li+].[BH4-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:29][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([C:23]1[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=1)[CH2:10][OH:11]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(O)(c1ccc(C#N)cc1)c1cncn1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(CO)c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of Example 93B (2.15 g, 78% potency, 4.24 mmol) in THF (6.5 mL) was treated with a solution of 2M LiBH4 in THF (3.3 mL, 6.1 mmol), heated to 55° C. for 3 hours, cooled to room temperature, treated with 20% citric acid (12 mL), warmed to 50° C. for 30 minutes, and extracted with MTBE (2×20 mL). The aqueous phase was adjusted to pH >10 with 50% NaOH and extracted with 5:1 THF/ethyl acetate (2×30 mL). The combined organic phases were concentrated, treated with citric acid (1.0 g), and concentrated to a volume of approximately 6 mL. The solution was adjusted to pH >10 with 50% NaOH, stirred for 2 hours, and filtered. The filter cake was washed with water (2 mL) and dried under vacuum with an air bleed to provide 670 mg (61% potency, 40% potency adjusted yield) of the desired product as one enantiomer in high excess. MS (ACPI) m/e 244 (M+H)+; 1H NMR (CD3OD) δ 7.70 (d, 2H) 7.55 (s, 1H) 7.54 (d, 2H) 7.18 (s, 1H) 4.00 (d, 1H) 3.89 (d, 1H) 3.30 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][Si:12](Cl)([CH3:14])[CH3:13].C(N(CC)CC)C.CCCCCC>O1CCCC1>[Cl:1][CH2:2][C:3]([O:10][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=C(CCl)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 4-chloro-3-oxobutanoate (30 g, 0.183 mol, 24.7 mL) and trimethylsilyl chloride (30.2 mL, 0.234 mol) in tetrahydrofuran (360 mL) was added dropwise triethylamine (30.61 mL, 0.23 mol) at -20° C. with mechanical stirring. After the addition was complete (~15 minutes), the mixture was stirred for an additional 30 minutes at -20° C., 30 minutes at 0° C., and then one hour at room temperature. The reaction was diluted with a large excess of hexane (1 L). The resulting precipitate was filtered and the solution was concentrated on a rotavap to an oily residue. It was diluted with hexane (400 mL), filtered and the filtrate was concentrated on a rotavap to an oily residue. This process was repeated until no further precipitation occurred. Distillation of the residue (b.p. 70° C. to 78° C./1 mm Hg) gave the title compound (33 g, 80%) as a mixture of cis,trans isomers.
Reaction SMILES: CC1C=CC(C)=CC=1[NH:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18](=[S:20])[NH2:19])[CH2:14][CH2:13]1)=O.Br[CH2:22][C:23]([C:25]1[CH2:29][C@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)=O.[C:36](=[O:39])(O)[O-].[Na+]>CC(C)=O>[C:30]1([C@@H:28]2[O:27][N:26]=[C:25]([C:23]3[N:19]=[C:18]([CH:15]4[CH2:14][CH2:13][N:12]([C:10]5([NH:9][CH:36]=[O:39])[CH:31]=[C:30]([CH3:35])[CH:28]=[CH:29][CH:25]5[CH3:23])[CH2:17][CH2:16]4)[S:20][CH:22]=3)[CH2:29]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(C)c(NC(=O)N2CCC(C(N)=S)CC2)c1
Reactant: O=C(CBr)C1=NO[C@@H](c2ccccc2)C1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1=CC(NC=O)(N2CCC(c3nc(C4=NO[C@@H](c5ccccc5)C4)cs3)CC2)C(C)C=C1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
A mixture of N-(2,5-dimethylphenyl)-4-thiocarbamoylpiperidine carboxamide (i.e. the product of Example 14, Step B) (291 mg, 1.0 mmol) and 409 (i.e. the product of Example 12, Step E) (268 mg, 1.0 mmol) in acetone (10 mL) was vortexed for 16 h and then heated at 45° C. for 1 h. The reaction mixture was allowed to cool to room temperature, treated with solid sodium bicarbonate (168 mg, 2.0 mmol), and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated under reduced pressure to give the title product as a pale-yellow foam. The sample was dissolved in methyl acetate (2 mL) and allowed to sit at room temperature and then at 0° C. to give 220 mg of colorless crystals melting at 120-125° C. A second preparation was crystallized from methanol to give large prisms melting at 121-124° C.