Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:28]2[N:29]=[CH:30][C:31]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(N3CCC3)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-azetidin-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 5.1.1, 39 mg, 0.150 mmol) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=426 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.25-8.18 (m, 1H), 8.14-8.09 (m, 1H), 8.06-8.02 (m, 1H), 7.89-7.81 (m, 1H), 7.62-7.53 (m, 1H), 7.42 (s, 1H), 6.48-6.42 (m, 1H), 4.01-3.93 (m, 4H), 3.91 (s, 3H), 3.56 (s, 3H), 2.36-2.28 (m, 2H), 1.96 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[C:9]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.[C:26](Cl)(=O)[O:27]C1C=CC=CC=1.C(=O)([O-])O.[Na+].C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:25][C:26](=[O:27])[O:16][C:9]2([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OC(c1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1OC(c2ccc(Cl)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Yield: 87.5 %

Procedure:
To a solution of 500 mg of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol in 1 ml of dry pyridine is added 300 mg of phenyl chlorocarbonate, and the resultant mixture is allowed to react at room temperature for 18 hours. The reaction mixture is mixed with aqueous sodium hydrogencarbonate solution and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica-gel, which is eluted with 2% methanolmethylene chloride. The eluate is concentrated and the residue is crystallized from ethyl acetate-isopropyl ether to give 466 mg of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals melting at 178° to 179° C. The yield is 87%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.BrP(Br)Br.[CH3:15][C:16]1[N:21]=[C:20]([SH:22])[N:19]=[C:18]([OH:23])[CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][S:22][C:20]2[N:19]=[C:18]([OH:23])[CH:17]=[C:16]([CH3:15])[N:21]=2)=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1ccnc(C)c1CO
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2c(C)ccnc2C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
(2,4-dimethylpyridin-3-yl)methanol was dissolved in dichloromethane (100 mL). Tribromophosphane (1.5 mL, 16 mmol) was added slowly. After 2 hours, the mixture was evaporated to dryness. The crude solid was dissolved in cold ethanol (100 mL), and 6-methyl-2-sulfanylpyrimidin-4-ol (1.13 g, 8.0 mmol) and triethylamine (4.5 mL, 32 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and the crude solid was washed with THF (200 mL). After evaporation of solvent, the crude was purified by CombiFlash (0-6% MeOH in DCM) to provide 2-{[(2,4-dimethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.5 g, 64% yield); 1H NMR (500 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.68 (s, 3H), 2.84 (s, 3H), 4.62 (s, 2H), 6.05 (br, 1H), 7.71 (s, 1H), 8.62 (s, 1H); M+232.
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH3:58])=[CH:52][CH:51]=3)=[CH:45][CH:44]=2)=[C:22]2\[CH:23]=[CH:24][C:25]([CH:40]=[C:41]\2[CH3:42])=[N+:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([O-:39])(=[O:38])=[O:37])[CH:31]=2)[CH2:27][CH3:28])=[C:17]([CH3:59])[CH:16]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([O-:14])(=[O:13])=[O:12])[CH:6]=1.[Na+].[P:61](=[O:65])([OH:64])([OH:63])[OH:62].O>C(O)C>[CH3:1][CH2:2][N:3]([C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:43]2[CH:44]=[CH:45][C:46]([NH:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH3:58])=[CH:52][CH:51]=3)=[CH:47][CH:48]=2)=[C:22]2/[CH:23]=[CH:24][C:25]([CH:40]=[C:41]/2[CH3:42])=[N+:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([OH:39])(=[O:37])=[O:38])[CH:31]=2)[CH2:27][CH3:28])=[C:17]([CH3:59])[CH:16]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([OH:14])(=[O:13])=[O:12])[CH:6]=1.[P:61](=[O:62])([OH:65])([OH:64])[OH:63]
Reactant: CCOc1ccc(Nc2ccc(/C(=C3/C=CC(=[N+](CC)Cc4cccc(S(=O)(=O)[O-])c4)C=C3C)c3ccc(N(CC)Cc4cccc(S(=O)(=O)[O-])c4)cc3C)cc2)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(Nc2ccc(/C(=C3\C=CC(=[N+](CC)Cc4cccc(S(=O)(=O)O)c4)C=C3C)c3ccc(N(CC)Cc4cccc(S(=O)(=O)O)c4)cc3C)cc2)cc1
Yield: 0.01 %

Procedure:
To 100 mg Coomassie Brilliant Blue (G-250) was added 47 g ethanol, 85 g phosphoric acid and 850 g water. This solution was mixed for 20 minutes, to ensure all components were dissolved, resulting in a reagent comprising 0.01% (w/v) Coomassie Brilliant Blue G-250, 4.7% ethanol (w/v) and 8.5% (w/v) phosphoric acid, To this solution different dextrins were added as indicated in the specific examples.
Reaction SMILES: N[C:2]1[C:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([CH3:18])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21].Cl>C(O)C.O>[CH3:18][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([C:8](=[O:17])[C:9]3[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=3)[CH:6]=1)[NH:22][C:20](=[O:21])[CH2:19]2
Reactant: CSc1ccc(C(=O)c2cc(C)cc(CC(N)=O)c2N)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(=O)c2cc(C)cc3c2NC(=O)C3)cc1
Yield: 61.7 %

Procedure:
A solution of 18.8 g (0.06 mole) of 2-amino-5-methyl-3-[4-(methylthio)benzoyl]phenylacetamide in 1700 ml of absolute ethanol with 16.6 ml (0.2 mol) of concentrated hydrochloric acid was heated at reflux for 45 min. The mixture was diluted with 50 ml of water and cooled. The precipitate was collected and recrystallized from 60% aqueous ethanol to give 11.0 g (62%) of the titled compound as tan crystals, m.p. 176.0°-177.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]=[CH:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>ClCCl>[CH3:20][C:21]([Si:24]([CH3:26])([CH3:25])[O:14][CH2:13][CH:12]=[CH:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(SC=CCO)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC=CSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
A solution of a 1.5 to 1 mixture of (E) and (Z) 3-(4-nitrophenylthio)-2-propenol (3.53 g, 16.71 mmol) (JCS, Perkin Trans. I, 1974, 25) in dichloromethane (40 mL) was treated with imidazole (2.28 g, 33.4 mmol) and TBDMSCl (2.77 g, 18.4 mmol), stirred at room temperature for 24 hours, and then partioned between dichloromethane and water. The organic phase was dried, concentrated, and purified on silica gel by flash column chromatography eluting with 8 to 1 hexanes/ethyl acetate to give 5.1 g (94%) of the desired product. Rf: 0.8 (2:1 hexane:ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].[CH:16](I)([CH3:18])[CH3:17].Cl>CO>[O:13]=[C:9]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:16]([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: CC(C)I
Reactant: O=C(O)C(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(C(=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 36 h
Yield: 48 %

Procedure:
p-Chlorophenylpyruvic acid (1.98 g, 10.0 mmoles) was dissolved in 20 ml of methanol, and a 3N aqueous solution of sodium hydroxide (8.0 ml, 24 mmoles) was added to form a solution. Then, 2.0 ml of isopropyl iodide was added, and the mixture was stirred at 35° C. for 36 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with three 30 ml portions of ether. The ether layers were dried over magnesium sulfate and concentrated under reduced pressure. The resulting pale yellowish white oil was purified by silica gel column chromatography (ethyl acetate:hexane=1:7) to obtain pure 2-oxo-3-(p-chlorophenyl)-4-methylpentanoic acid as an oil in a yield of 48 %. This product was treated with an aqueous solution of sodium hydroxide, and isolated as a pure sodium salt.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 86.3 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.10 g, 0.46 mmol), heptanoyl chloride (0.072 mL, 0.46 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (12 mL) provided N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylheptanamide (0.13 g). MS m/z 328 ([M+H]+); HRMS: calcd for C21H29NO2+H+, 328.22710; found (ESI, [M+H]+), 328.2263.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:20]1[CH:21]=[CH:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)cc1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 1 step (iii) and 4-fluorophenyl methyl sulfone.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](OC)=O)=[CH:17][C:16]=3OC)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.COC1C=C(C(OC)=O)C=CC=1CP(=O)(OCC)OCC.ClC1C=CC(C([N:57]2CCC(=O)CC2)=O)=CC=1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:57])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)c2ccc(Cl)cc2)CC1
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(OC)c1
Agent: CCOP(=O)(Cc1ccc(C(=O)OC)cc1OC)OCC
Product: N#Cc1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
1-(4-chlorobenzoyl)-4-(2-methoxy-4-methoxycarbonylbenzylidene)piperidine from diethyl 2-methoxy-4-methoxycarbonylbenzylphosphonate and N-(4-chlorobenzoyl)-4-piperidone. Colorless oil.
Reaction SMILES: [O:1]=[O+][O-].[C:4]1([CH3:21])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=CC)[C:12]=1[OH:20]>C(OCC)(=O)C.C(O)(=O)C>[OH:20][C:12]1[C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:21])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]=[O:1]
Reactant: CC=Cc1cccc(Sc2ccccc2C)c1O
Reactant: O=[O+][O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccccc1Sc1cccc(C=O)c1O

Procedure:
Ozone gas was introduced into a solution of 2-(o-tolylthio)-6-(1-propenyl)phenol (24.3 g) in a mixture of ethyl acetate (200 ml) and acetic acid (5 ml) at 3° C. for 1.5 hours. The excess of ozone was removed by air-bubbling and further decomposed with aqueous sodium hydrogen sulfite. The resultant organic layer was separated, washed with aqueous sodium hydrogen sulfite and water in turn, dried and then evaporated under reduced pressure. The oily residue was crystallized with ethanol to give yellow needles of 2-hydroxy-3-(o-tolylthio)benzaldehyde (12.2 g), mp. 42°-43° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9])([CH3:3])[CH3:2].[I:15]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:15][C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: II
Reactant: COc1ccc(C=O)cc1OC(C)C
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(I)c(C=O)cc1OC(C)C
Temperature: 61 °C
Yield: 92.8 %

Procedure:
Silver trifluoroacetate (12.3 g, 56.7 mmol) was added to a solution of isovanillin isopropyl ether (10.0 g, 51.5 mmol) in dry chloroform (120 mL) under nitrogen and the resultant slurry stirred and heated to 61° C. Iodine (14.4 g, 56.7 mmol) was then added portionwise (6 portions) over 0.6 h and the reaction allowed to reflux for a further 6.5 h. The reaction mixture was then cooled and filtered, rinsing with chloroform (50 mL). The filtrate was washed with Na2S2O5 (10% solution in water, 150 mL), NaHCO3 (sat in water, 150 mL) and water (150 mL) dried (MgSO4) and concentrated under vacuum. The solid residue was suspended in hexane (200 mL) and stirred vigoursly for 1 h, cooled in an ice bath for 1 h and filtered rinsing with ice cold hexane (200 mL) to give the title compound as a cream solid (15.3 g, 93%) mp 75–6° C. IR (KBr disc, cm−1) 3072, 2978, 2932, 1673, 1581, 1503, 1438, 1385, 1332, 1260, 1215, 1174, 1157, 1133, 1105, 1024, 939. 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H,), 7.34 (s, 1H), 7.24 (s, 1H), 4.57 (septet, J=6.0 Hz, 1H) 3.86 (s, 3H), 1.31 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 194.7 (−), 155.5 (+), 147.9 (+), 128.2 (+), 122.2 (−), 114.1 (−), 110.8 (+), 92.4 (+), 71.3 (−), 56.4 (−) 21.77 (−). MS (70 eV) m/z (%): 320 (M+•, 43), 278 (100), 249 (17), 207 (12), 150 (40). Anal. Calcd for C11H13O3I: C, 41.27; H, 4.09; I, 39.64. Found: C, 41.06; H. 3.80; I, 39.59.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][CH:30]1[C:31]([OH:33])=O>C(O)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:31](=[O:33])[CH:30]3[CH2:34][CH2:35][CH2:36][N:29]3[C:10](=[O:9])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)oc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C(O)C1CCCN1
Solvent: CC(=O)O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)C1CCCN1C2=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 65.1 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-2H-thieno[2,3-d][1,3]oxazine-1(4H)-yl)methyl]biphenyl-2-carbonitrile (1 g), D,L-proline (0.44 g) and acetic acid (50 mL) was stirred at 100° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.74 g, 65%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCCC1>[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([CH2:22][OH:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2nc(-c3ccncc3)oc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2nc(-c3ccncc3)oc12
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
Lithium aluminium hydride (53 mg, 1.42 mmol) was added to a solution of methyl ester of [2-(4-pyridyl)-benzoxazol-7-yl]carboxylic acid (360 mg, 1.42 mmol) in tetrahydrofuran (15 ml) with stirring under ice cooling in 10 min. and the mixture was stirred at the same temperature for 0.5 hrs. To the reaction mixture were added dropwise at the same temperature 10% aqueous tetrahydrofuran (2 ml) and 30% aqueous solution of sodium hydroxide (0.5 ml) in turn, and the mixture was stirred at room temperature for 2 hrs. The resultant insoluble materials were filtered off, and the solvent was distilled off from the filtrate under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine in turn and then dried. The solvent was distilled off under reduced pressure, and the resultant crystals were triturated with a mixture of n-hexane/diisopropyl ether (1/1), filtered and dried to give [2-(4-pyridyl)-benzoxazol-7-yl]methanol (216 mg, 67%) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:11])[N:3]1[O:26][S:27]([OH:30])(=[O:29])=[O:28].FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[N:3]1[O:26][S:27]([OH:30])(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NN1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 208 (0.12 g, 0.27 mmol) in DCM (12.5 mL) was added trifluoroacetic acid (1.0 mL, 12.96 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. This white solid was purified by HPLC on a prep-X Bridge-19×250 mm column and freeze-dried to give (2S,5R)-7-oxo-N-(piperazin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 100 (Table 2) (0.11 g, 88%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.[F:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19](F)[CH:18]=1.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:19]2[C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2Nc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solid from step B was added to a solution of 1,3-difluoro-4,6-dinitrobenzene (46 g) in methanol (200 L), then triethylamine (31.4 mL) was added, and stirred at rt for 4 h. The reaction mixture was filtered, and the cake was washed with methanol to give 80.6 g of red solid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCCc1ccc(F)cc1
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorophenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])[C:5]2=[CH:4][CH:3]=1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:37].[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(Cl)ccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3nc(Cl)ccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.020 g, 0.039 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-2-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.015 g, 75%).
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11]
Reactant: CC(C)COC(C)ONC(=O)c1cnc(N2CC3C(C2)C3N2CCOCC2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CC3C(C2)C3N2CCOCC2)nc1
Yield: 37.7 %

Procedure:
N-(1-Isobutoxyethoxy) 2-(6-morpholin-4-yl-3-aza-bicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide (10 mg, 0.02 mmol) was dissolved in DCM (2 ml) and treated with 4M HCl in dioxane (0.4 ml, 0.1 mmol). The resultant mixture was stirred at r.t. for 30 min, then evaporated under reduced pressure and azeotroped with MeOH (3×5 ml) to give the title compound as a white solid (2.3 mg, 40%). LCMS purity 90%, m/z 306 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 2.49 (2H, br s), 2.85 (1H, br s), 3.55-3.87 (8H, m), 4.10 (4H, m), 8.72 (2H, s).