Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]N(C)C=O.S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(CC(=O)O)c1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C#N)ccc1OCc1ccccc1

Procedure:
10.0 g (0.037 mol) of (2-benzyloxy-5-cyano-phenyl)-acetic acid are refluxed for two hours in 65 ml dichloromethane, 0.1 ml of dimethylformamide and 8.1 ml (0.11 mol) of thionyl chloride. Then the mixture is concentrated by evaporation, the residue is combined with 55 ml of methanol and refluxed for one hour. After cooling the mixture is suction filtered, washed with ether/petroleum ether and dried at 50° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][N:20]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.ICCC.CCOC(C)=O>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:20]1[CH:21]=[C:17]([C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=2)[CH:18]=[N:19]1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: Oc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCI
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(-c2cc(O)ccn2)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To solution of 2-bromopyridin-4-ol (0.4 g, 2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.99 g, 3 mmol) in Dioxane/H2O (3 ml/1.5 ml) was added PEPSI-IPr catalyst (0.078 g, 0.115 mmol) and followed by the addition of Cs2CO3 (1.65 g, 5 mmol). The reaction mixture was stirred at 90° C. for 30 minutes. The reaction mixture was diluted with EtOAc and washed with HCl (1N). Two phases were separated and the aqueous phase was extracted with EtOAc (3×). Organic phase were combined and concentrated down under vacuo. The residue was purified by silicone gel column. And 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-4-ol was obtained (0.61 g, 91.1%). LCMS-ESI+ (m/z): [M+H]+ calcd. for C26H30N5O3: 292.42; found: 292.11.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[N+:29]([C:32]1[CH:51]=[CH:50][C:35]([CH2:36][O:37][C:38]([CH:40]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41](O)=[O:42])=[O:39])=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:41](=[O:42])[CH:40]([C:38]([O:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:51][CH:50]=2)=[O:39])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: O=C(O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)c1ccccc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccccc2)[C@H]1O)c1ccccc1
Yield: 59.2 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-[2-(4-nitrobenzyloxycarbonyl)-2-phenylacetylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (315 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (300 mg) prepared in Example 1 with N-hydroxysuccinimide ester of 2-(4-nitrobenzyloxycarbonyl)-2-phenylacetic acid (386 mg) according to a similar manner to that of Example 5, mp. 168°-175° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:42])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4C(=O)C5=CC=CC=C5C4=O)=[C:13]([F:32])[CH:12]=3)=[CH:8][C:7](=[O:33])[C:6]=2[C:34]=1[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C)C=O.CO.O.NN>[NH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:5]3[C:4]([F:42])=[CH:3][C:2]([F:1])=[C:34]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:6]=3[C:7](=[O:33])[CH:8]=2)=[CH:12][C:13]=1[F:32]
Reactant: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)c(F)c3)cc(=O)c12
Agent: NN
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN)c(F)c3)cc(=O)c12
Reaction time: 4.3 h

Procedure:
60 mg of Compound 32 was dissolved in 30 ml of a mixed solvent of dimethylformamide and methanol, 0.050 ml of hydrazine monohydrate was added and the mixture was stirred at 60° to 70° C. for 4.3 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (chloroform:methanol:aqueous ammonia=9:1:1) to give Compound 33 which was dissolved in chloroform. A 5.5N hydrochloric acid-isopropylalcohol solution was added, the solvent was distilled off under reduced pressure and the residue was treated with isopropyl ether to form the slurry from which 33.6 mg (67%) of hydrochloride of Compound 33 was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
To a slurry of 6-chloronicotinic acid (5.0 g, 31.73 mmol) in anhydrous toluene (35 ml), was added dropwise with stirring triethylorthoacetate (15.45 g, 95.2 mmol). The mixture was warmed to reflux for two hours, allowed to cool to ambient temperature, and then the resultant solution was washed with saturated NaHCO3 solution (50 ml). The organic phase was dried (MgSO4) and the solvent removed in vacuo to afford the titled compound as a clear, colorless oil (5.43 g, 29.27 mmol, 92.3% yield).
Reaction SMILES: CN(C=O)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:31][C:32]1[C:37]([CH2:38]Br)=[C:36]([O:40][CH3:41])[C:35]([O:42][CH3:43])=[C:34]([O:44][CH3:45])[C:33]=1[O:46][CH3:47].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:38][C:37]2[C:32]([Br:31])=[C:33]([O:46][CH3:47])[C:34]([O:44][CH3:45])=[C:35]([O:42][CH3:43])[C:36]=2[O:40][CH3:41])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
A DMF (120 ml) suspension of ethyl 2-(4-benzyloxyphenyl)-2-ethoxycarbonylacetate (12.0 g, 35.1 mmols), 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (16.9 g, 45.6 mmols) and potassium carbonate (14.5 g, 105 mmols) was stirred at room temperature for 6 hours, and then 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (2.60 g, 7.02 mmols) was added thereto stirring was continued at room temperature for further 6 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (11.0 g) as crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:16]=[C:15]4[CH:29]=[O:30])[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.[C:34]([Si:38]([CH3:41])([CH3:40])Cl)([CH3:37])([CH3:36])[CH3:35].N1C=CN=C1>CN(C=O)C.O>[Si:38]([O:26][CH2:25][C:24]([CH3:27])([CH3:28])[CH2:23][N:17]1[CH:16]=[C:15]([CH:29]=[O:30])[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([C:10]3[CH:11]=[C:6]([CH:7]=[C:8]([F:32])[C:9]=3[CH3:31])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:33])[CH:13]=2)[C:18]1=[O:22])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:41])[CH3:40]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide (Example 26e, 14.54 g) in DMF (120 mL) was treated with tert-butyldimethylchlorosilane (4.86 g) and imidazole (2.19 g) under nitrogen. The resulting mixture was stirred at room temperature for 1 h. More tert-butyldimethylchlorosilane (1.2 g) was added and the reaction mixture stirred at room temperature for 30 min, diluted with water (300 mL) and extracted with DCM (250 mL×2). The organics were dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with 100% diethyl ether) to give the subtitle compound (15.20 g) as a gum.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39](I)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:39]3[CH:40]=[C:35]4[N:34]=[C:33]([CH2:32][CH2:31][C:27]5[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[CH:29][N:28]=5)[NH:42][C:36]4=[N:37][CH:38]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: O=S(=O)(NC1CCCCC1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)NC5CCCCC5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
A mixture of 0.477 g of N-cyclohexyl-4-bromobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 22-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate/acetonitril (1:1) gives 0.27 g of the title compound as a solid of m.p. 199-200° C. The mass spectrum shows the molecular peak MH+ at 492.4 Da.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>C(#N)C>[N:1]1[N:2]([CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[N:3]=[N:4][CH:5]=1
Reactant: c1nnn[nH]1
Reactant: ClCC1CO1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OC(CCl)Cn1ncnn1

Procedure:
6.905 g of tetrazole (100 mmol) and 1.75 ml of diisopropylethylamine (10 mmol) and 11.73 ml of epichlorohydrine (150 mmol) in anhydrous acetonitrile (30 ml) was stirred at 60° C. for 4 hours. The obtained solution was evaporated, dried on highvac and purified on a column of silica in chloroform-methanol 100:8. The first fraction provided pure 3-(2-H-tetrazol-2-yl)-2-hydroxy-1-chloropropane, 6.215 g (colorless oil, 38% Y), the second fraction yielded 9.208 g of pure 3-(1-H-tetrazol-1-yl)]-2-hydroxyl-1-chloropropane (sticky gum; 57% Y).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C@H:10]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18](OC)[CH:17]=1)[N+:9]([CH2:32]C)(CCCO)[CH2:8][CH2:7]2.[CH2:34](I)C.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.ClCCCO>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C@@H:10]([CH2:16][C:17]1[CH:34]=[CH:21][C:20]([O:22][CH3:23])=[C:19]([O:24][CH3:25])[CH:18]=1)[N:9]([CH3:32])[CH2:8][CH2:7]2
Reactant: CCI
Reactant: CC[N+]1(CCCO)CCc2cc(OC)c(OC)cc2[C@@H]1c1cc(OC)c(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: OCCCCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H]2c3cc(OC)c(OC)cc3CCN2C)cc1OC

Procedure:
(1S,2RS)-6,7-Dimethoxy-2-ethyl-2-(3-hydroxypropyl)-1-(3,4,5-trimethoxyphenyl )-1,2,3,4-tetrahydroisoquinolinium chloride [(1S,2R)/(1S,2S), 2:1] was prepared by alkylation with ethyl iodide/potassium carbonate/dimethylformamide followed by quaternization with 3-chloropropanol (see Synthetic Example 1, procedure a).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7](=O)[CH3:8])[C:3](=O)[CH3:4].[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH2:14]>>[CH3:10][O:11][C:12](=[O:15])[CH2:13][N:14]1[C:7]([CH3:8])=[CH:6][C:2]([CH3:1])=[C:3]1[CH3:4]
Reactant: COC(=O)CN
Reactant: CC(=O)CC(C)C(C)=O
Product: COC(=O)Cn1c(C)cc(C)c1C

Procedure:
By a procedure analogous to Example 1, 3-methylhexan-2,5-dione (J. Amer. Chem. Soc., 1929, 51, 3514) is reacted with glycine methyl ester to give methyl(2,3,5-trimethyl-1H-pyrrol-1-yl)acetate.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:4]1[N:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:3]([CH3:2])[C:4]2[N:5]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:16][CH:15]=3)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=2)[CH2:29]1)=[O:40].[ClH:1]
Reactant: CN(c1cnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1)[C@@H]1CCCNC1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)N1CCC[C@@H](N(C)c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (42 mg, 0.25 mmol), DIEA (150 μL, 0.84 mmol) and then PyBOP (88 mg, 0.17 mmol). The mixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (94) as an HCl salt (29 mg). MS found for C28H38N8O4 as (M+H)+ 551.3, (M−H)− 549.3. UV: λ=274, 281, 313, 344, 369 nm.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1Nc1ccc(Br)nc1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
A mixture of 6-bromopyridin-3-amine (27.27 mmol, 4.70 g), 2,5-dichlorobenzoic acid (54.34 mmol, 10.38 g), Cu (2.71 mmol, 0.2 g), Cu2O (1.36 mmol, 0.2 g) and K2CO3 (54.27 mmol, 7.5 g) in 1,2-dimethoxiethane (40 ml) was heated in a microwave oven at 130° C. for 14 hours, under nitrogen atmosphere. Water was added and the mixture was filtered through celite and extracted with AcOEt. The organic phase was washed with saturated K2CO3 aqueous solution and brine. The solvent was evaporated to afford 3.08 g (yield 31%) of the expected product.
Reaction SMILES: [Si](O[C@@:9]1([Cl:37])[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([NH:20][CH:21]([C:24]2[O:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[N:27][N:28]=2)[CH2:22][CH3:23])[CH:14]=[CH:13][C@@H:10]1[C:11]#[N:12])(C(C)(C)C)(C)C.C[OH:39].[F-].[NH4+]>O.CCOC(C)=O.CC(OC)(C)C>[Cl:37][C:9]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([NH:20][C@@H:21]([C:24]2[O:25][C:26]([C:29]3[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=3)=[N:27][N:28]=2)[C@@H:22]([OH:39])[CH3:23])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CO
Reactant: CCCC1=C(NC(CC)c2nnc(-c3ccc(C#N)cc3)o2)C=C[C@H](C#N)[C@@]1(Cl)O[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C

Procedure:
A 100 mL round bottom was charged with 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino-2-chloro-3-propylbenzonitrile (intermediate 1119-D) (0.344 g, 0.64 mmole) and methanol (10 mL) at room temperature. Ammonium fluoride (0.119 g, 3.20 mmol) was then added in one portion and the reaction mixture was brought to reflux. The reaction stirred at reflux for 65 h before being cooled to room temperature. To the resulting reaction mixture was added water (50 mL), TBME (30 mL), EtOAc (50 mL) and more water (40 mL). The biphasic mixture was separated and the aqueous layer was extracted with EtOAc (50 mL). The organic extracts were then combined, washed with water (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a brown solid. The brown solid was then purified by flash chromatography over silica gel [EtOAc-hexanes (50%:50%)→EtOAc-hexanes (100%:0%) as eluent] to provide the title compound with other minor impurities (200.7 mg, 74%). 1H NMR (400 MHz, CDCl3 δ in ppm): 8.07 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 5.45 (d, J=8.0 Hz, 1H), 4.80 (d, J=2.0, 8.0 Hz, 1H), 4.60 (m, 1H), 2.79 (t, J=8.0 Hz, 2H), 1.64 (sextet, J=8.0 Hz, 2H), 1.46 (d, J=4.0 Hz, 3H), 1.07 (t, J=8.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[C:16]([CH2:17][NH2:18])=[CH:15][N:14]=[C:13]([CH3:19])[N:12]=1>O>[NH2:10][C:11]1[C:16]([CH2:17][N:18]2[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]2=[O:9])=[CH:15][N:14]=[C:13]([CH3:19])[N:12]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1ncc(CN)c(N)n1
Solvent: O
Product: Cc1ncc(Cn2c(C)cc(O)cc2=O)c(N)n1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (0.9 g, 0.007 mol) and 4-amino-5-aminomethyl-2-methylpyrimidine (1.0 g, 0.007 mol) in water (10.0 ml) was heated at 100° C. for 1 h under argon atmosphere. The reaction mixture was cooled, and filtered the yellow precipitate. It was washed successively with cold water, ethanol, and dried in vacuo to afford the title compound (1.01 g, 51%) as a pale yellow powder: 1H NMR (DMSO-d6/400 MHz) δ7.62 (s, 1H), 7.04 (s, 1H), 5.83 (d, 1H, J=2.0 Hz), 5.58 (d, 1H, J=2.0 Hz), 4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H); ES-HRMS m/z 325.0304 (M+H C12H14N4O2Br requires 325.0295).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:18])(=[O:7])[CH3:6]>S(=O)(=O)(O)O>[C:5]([NH:8][C:9]1[C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:18])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1C
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(C)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 60% nitric acid in sulfuric acid (410 mL) was added 4-acetamido-3-methylbenzoic acid (43 g, 0.22 mol) in small portions over 40 min while cooling with an ice bath. After addition of all amide was complete, the reaction mixture was stirred for 1 h at 0° C. and then very slowly poured over 1500 mL of ice. The yellow solid was collected by filtration and washed with ice cold water to give the title compound (38 g, 72% yield). 1H-NMR (CD3OD, 300 MHz) δ 8.29 (s, 1H), 8.18 (s, 1H), 2.39 (s, 3H), 2.16 (s, 3H). Mass spec.: 237 (MH)+.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)([C:6]([O:8]C)=[O:7])[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[F:16][C:2]1([F:1])[CH2:5][C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)([C:6]([OH:8])=[O:7])[CH2:3]1
Reactant: COC(=O)C1(c2cccnc2)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2cccnc2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.2 %

Procedure:
To a solution of Intermediate 311D (250 mg, 1.100 mmol) in THF (2 mL) and water (1 mL) was added NaOH (132 mg, 3.30 mmol) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was concentrated; the pH of the residue was adjusted to 2 with a 1.5N aq. solution of HCl and extracted with EtOAc (3×15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford Intermediate 311E as a colorless semi-solid (160 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (br. s., 1H), 8.65-8.54 (m, 1H), 8.53-8.46 (m, 1H), 7.83-7.74 (m, 1H), 7.46-7.35 (m, 1H), 3.47-3.35 (m, 2H), 3.23-3.08 (m, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([C:14](=O)[CH3:15])[C:9](OCC)=[O:10].[NH2:17][C:18]([NH2:20])=[S:19]>O1CCCC1.C(O)C>[CH3:7][C:8]1[C:9](=[O:10])[NH:17][C:18](=[S:19])[NH:20][C:14]=1[CH3:15]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1[nH]c(=S)[nH]c(=O)c1C
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a stirred solution of potassium tert-butoxide (15.71 g, 0.140 mol) in tetrahydrofuran (200 mL) was added a solution of ethyl 2-methyl-3-oxobutanoate (20.0 g, 0.14 mol) and thiourea (10.55 g, 0.14 mol) in dry ethanol (150 mL). The resulting mixture was refluxed for 15 minutes and cooled down to ambient temperature. The formed precipitate was collected by filtration, washed with tetrahydrofuran (200 mL), and dissolved in water (200 mL). Acetic acid (100 mL) was added in to the resulting solution. The formed precipitate was collected by filtration and dried to yield 17 g (78.5%) of the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 3H) 2.09 (s, 3H) 12.19 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[I-].[Na+].[C-:13]#[N:14].[Na+]>CN(C=O)C>[C:13]([CH2:2][CH2:3][CH2:4][CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7])#[N:14]
Reactant: CNS(=O)(=O)CCCCCl
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCCC#N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-N-methylbutane-1-sulfonamide (Example 5; 86.7 mmol), and sodium iodide (95.4 mmol) in DMF (175 ml) was stirred for 10 min at room temperature. Sodium cyanide (191 mmol) was added and the mixture was stirred overnight at 60° C. The mixture was filtered off and the filtrate was extracted with AcOEt/water. The crude product was concentrated and was used without further purification in the next step (Examples 10 and 20).