Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]=[C:23]=[O:24]>C(Cl)Cl.C(N(CC)CC)C>[CH3:21][NH:22][C:23]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:24]
Reactant: CN=C=O
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=NC(=O)NC)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.0 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate are placed in 10 ml of methylene chloride. After the addition of one drop of triethylamine, 0.41 g of methyl isocyanate in 5 ml of methylene chloride is added dropwise. The mixture is then left to stir at room temperature for 2 days. The reaction mixture is poured on to ice-water and extracted twice with methylene chloride. The extracts are washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oily residue is chromatographed on silica gel with n-hexane-acetone (4:1) as the eluent, and there is obtained ethyl 5,7-dihydro-N-methylcarbamoyl-6H-dibenz[c,e]azepine-6-carboximidate in 2 isomeric forms: isomer A (eluted first), m.p. 176°-178° C.; isomer B: m.p. 137°-139° C.
Reaction SMILES: Cl.[CH:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[P:13]([Cl:18])(Cl)(Cl)(Cl)[Cl:14].C(O)=[O:20]>C(Cl)(Cl)(Cl)Cl>[Cl:14][P:13]([Cl:18])([NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[O:20]
Reactant: O=CO
Reactant: NC(=O)/C=C/c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(C=Cc1ccccc1)NP(=O)(Cl)Cl

Procedure:
Heated at 70° for 25 min. at which time the HCl gas evolution had ceased, a mixture of 59 g (0.4 mole) of cinnamide, 83.5 g (0.4 mole) of phosphorus pentachloride and 500 ml of AR carbon tetrachloride. After cooling to 30°, added dropwise, 19 g (0.4 mole) of 97% formic acid. Chilled to 0° and filtered. Air-dried to give 107.5 g, m.p. softens 82°, melts 83°-90°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9]>O1CCOCC1.O.O1CCOCC1>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[O:9])[CH2:2]1
Reactant: OC1CCNC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)C1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A solution of 3-pyrrolidinol (4.0 g) in dioxane-water (10:1, 50 ml) mixed solvent was cooled to 5° C., and into which a solution of 4-nitrobenzyl chloroformate (10.9 g) in dioxane (20 ml) was added dropwise, while maintaining the pH at 8-9, followed by 10 minutes' stirring at 5° C. Distilling the solvent off under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure. Washing the residue with ethyl acetate, 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (6.6 g) was obtained as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1Cl.[N-:15]=[N+]=[N-].[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1[NH2:15]
Reactant: Nc1nc(-n2cccn2)nc(Cl)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(-n2cccn2)nc(N)c1Br
Reaction time: 0.5 h

Procedure:
A solution of 0.10 g (0.37 mmol) of 5-bromo-6-chloro-2-(1H-pyrazol-1-yl)pyrimidine-4-amine (Intermediate 5) and 0.05 g (0.77 mmol) of sodium azide in dioxane (10 mL) was stirred at 80° C. for 6 h. The solvent was then evaporated, and the residue dissolved in methanol, Pd on charcoal added (10 mg) and hydrogenated for 30 min. The solvent was again evaporated and the residue crystallizes from ethanol.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].Cl[Si](C)(C)C.CN1CCOCC1.Cl[CH:25]([O:27][C:28](Cl)=[O:29])[CH3:26].[C:31]([OH:34])(=[O:33])[CH3:32]>ClCCl>[C:31]([O:34][CH:25]([O:27][C:28]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:29])[CH3:26])(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: CC(Cl)OC(=O)Cl
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general procedure for the one pot synthesis, tranexamic acid (786 mg, 5.0 mmol) was reacted with chlorotrimethylsilane (1.396 mL, 1.195 g, 11.0 mmol) in anhydrous dichloromethane (10 mL) and in the presence of N-methylmorpholine (1.374 mL, 1.264 g, 12.5 mmol). Subsequent reaction of the intermediate with 1-chloroethylchloroformate (0.82 mL, 1.07 g, 7.5 mmol) followed by a mixture of NMM (2.75 mL, 2.53 g, 25 mmol) and acetic acid (2.86 mL, 3.00 g, 50 mmol) yielded the title compound 8 (320 mg, 22% yield) as a very slightly orange-colored oil after aqueous work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.17-1.35 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.66-1.73 (br. m, 2H), 1.84-1.91 (br. m, 2H), 1.99 (s, 3H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.74-2.88 (m, 2H), 6.62 (q, J 5.2 Hz, 1H), 7.44 (t, J 6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 310.12 (M+Na)30; 286.08 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:30][CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCC1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: O=c1[nH]c2cc(CNC3CCCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and cyclopentylamine to give a yellow solid. MS m/z: 403.2 (M+1).
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:29](=[O:67])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:66])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([N:43]4[C:46](=[O:47])[CH:45]([CH2:48][CH2:49][CH:50]([OH:57])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[CH:44]4[C:58]4[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=4)=[CH:39][CH:38]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C.OC(C1C=CC=CC=1)CCC1C(=O)N(C2C=CC(NC(=O)CCCCN)=CC=2)C1C1C=CC(OC)=CC=1>CN(C)C=O>[OH:57][CH:50]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:49][CH2:48][CH:45]1[C:46](=[O:47])[N:43]([C:40]2[CH:39]=[CH:38][C:37]([NH:36][C:35](=[O:66])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29](=[O:67])[CH:18]([NH2:17])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=3)=[CH:42][CH:41]=2)[CH:44]1[C:58]1[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(Cc3ccc(N=[N+]=[N-])cc3)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Agent: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCNC(=O)C(N)Cc3ccc(N=[N+]=[N-])cc3)cc2)cc1
Yield: 18.5 %

Procedure:
300 mg (0.33 mmol) of product 11 and 0.8 ml of diethylamine are solved in 4 ml DMF (dimethylformamide) and reacted according to production of compound 9. 42 mg (19%) of compound 12 is obtained in form of an amorphic solid compound: C39H43N7O5 (689.82) MS (ESI+) 690.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]2[O:23][C:10]3[C:11](=[O:22])[N:12]([C@@H:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15](O)=[O:16])[CH2:13][C:9]=3[CH2:8][C:7]=2[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.ON1[C:38]2C=CC=[CH:42][C:37]=2N=N1>C(Cl)Cl.O>[CH:19]1([CH2:18][C@H:14]([N:12]2[CH2:13][C:9]3[CH2:8][C:7]4[C:6]([O:25][CH3:26])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:24]=4[O:23][C:10]=3[C:11]2=[O:22])[C:15]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:16])[CH2:20][CH2:42][CH2:37][CH2:38][CH2:21]1
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: On1nnc2ccccc21
Reactant: Nc1nccs1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2nccs2)C1
Yield: 67 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (Example 13, step 2c) (100 mg, 0.21 mmol), commercially available 2-aminothiazole (30 mg, 0.30 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (52 mg, 0.27 mmol), and N-hydroxybenzotriazole (HOBt) (37 mg, 0.27 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-cyclohexyl-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-N-thiazol-2-yl-propionamide (68 mg, 56.6%), as a white solid. 1H NMR (DMSO-d6) δ: 12.55 (br. s., 1H), 7.50 (d, J=2.9 Hz, 1H), 7.25 (br. s., 1H), 6.92 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.06 (d, J=5.4 Hz, 1H), 4.35 (d, J=18.6 Hz, 1H), 4.04 (d, J=18.6 Hz, 1H), 3.76 (s, 6H), 3.56 (br. s., 2H), 1.45-1.91 (m, 7H), 0.76-1.30 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12](/[CH:21]=[CH:22]/[C:23]([O:25]C)=O)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.FC1C=CC([CH2:34][NH:35][C:36](C2C(O)=C3C(C=CC=N3)=C(CCC(OC)=O)N=2)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12](/[CH:21]=[CH:22]/[C:23]([N:35]([CH3:36])[CH3:34])=[O:25])[N:11]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: COC(=O)CCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reactant: COC(=O)/C=C/c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Product: CN(C)C(=O)/C=C/c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12

Procedure:
The title compound was prepared using a procedure similar to that described in Example 147, Step 2, except that methyl (2E)-3-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)-2-propenoate (Example 137, Step 1) was substituted for methyl 3-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)propanoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:18]1[C:22]2([CH2:27][CH2:26][CH:25]([NH:28][C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:28]([CH:25]2[CH2:26][CH2:27][C:22]3([O:18][CH2:19][CH2:20][O:21]3)[CH2:23][CH2:24]2)[C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)[C@@H](C)NC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirred mixture of 2,4-dichloro-5-nitropyrimidine (4, 12 g, 62.1 mmol), potassium carbonate (11.7 g, 84.78 mmol) in acetone (100 mL) was added methyl N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate (13.8 g, 62.1 mmol) at rt. The reaction mixture was stirred for 16 h at rt. The bulk of solvent was removed under reduced pressure to give a residue, which was diluted with ethyl acetate (100 mL), washed with water, dried over sodium sulfate. The solvent was evaporated to give a crude material, which was then purified by silica gel flash chromatography (eluent: ethyl acetate-hexane mixture (v:v=5:95)) to afforded the desired product (10.1 g). 1HNMR (300 MHz, CDCl3): δ 1.55-1.64 (m, 3H), 1.70-1.99 (m, 6H), 2.05-2.20 (m, 3H), 3.06-3.15 (m, 1H), 3.75 (s, 3H), 3.99 (t, 4H), 8.61 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:6][C:7]([CH2:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].I[CH3:21]>O1CCCC1>[CH:16]1([C:5]2[C:4]([C:1](=[NH:2])[S:3][CH3:21])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:14][CH3:15])[CH:6]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: CI
Reactant: CCc1cc(C2CCC2)c(C(N)=S)cc1C(=O)OC
Solvent: C1CCOC1
Product: CCc1cc(C2CCC2)c(C(=N)SC)cc1C(=O)OC
Reaction time: 15 h
Yield: 114.2 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate (compound 181.6, 1.50 g, 5.41 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). This was followed by the addition of iodomethane (3.80 g, 26.8 mmol, 5.00 equiv) dropwise with stirring. The resulting solution was stiffed at 25° C. for 15 h, then concentrated in vacuo. This resulted in 1.80 g (97%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[OH-].[K+].[CH3:15]I>CN(C=O)C.O.CCOC(C)=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2[Cl:11])[N:4]([CH3:15])[N:3]=1
Reactant: CI
Reactant: Nc1nc(Cl)c2c(Br)n[nH]c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(Br)c2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (580 mg, 2.3 mmol) is dissolved in DMF (40 ml), potassium hydroxide (131 mg, 2.3 mmol) is added and the reaction mixture is stirred at room temperature for 15 minutes. Methyl iodide (0.133 ml, 2.3 mmol) is then added and the reaction is continued stirring overnight. The reaction mixture is diluted with water (60 ml) and EtOAc (60 ml), the layers are separated and the organic portion is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[NH:14][C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[CH3:21]I>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:21])[C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(-c2cc(=O)[nH]c(=O)[nH]2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (1.0 g) in a mixture of water (5 ml) and methanol (5 ml) was added potassium hydroxide (0.57 g), and to an almost dissolved mixture was added methyl iodide (5 ml). The mixture was stirred at ambient temperature for 18 hours. The resulting precipitates were filtered and washed successively with water, ethanol and diisopropyl ether to afford 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (0.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[O:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:40][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])([OH:18])[CH3:40])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(=O)c3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1F)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: -20 °C

Procedure:
To a solution of 3-{4-(5-chloropyridin-3-yl)-2-[(2-fluorophenyl)carbonyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (Example 8.1, 44 mg, 0.08 mmol) in tetrahydrofuran (0.8 mL) at −78° C. was added dropwise methyl magnesium bromide (0.054 mL of 3.0 M in diethyl ether, 0.161 mmol). The reaction was stirred and slowly warmed to −20° C. over 3 hours. The reaction was then quenched via the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-10% methanol/DCM) to afford 3-{4-(5-chloropyridin-3-yl)-2-[1-(2-fluorophenyl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one as a white solid. MS ESI calcd. for C29H28ClFN6O3 [M+H]+ 563. found 563.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[S:23][C:22]([C:24]([O:26]CC)=O)=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:29]1([CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[S:23][C:22]([C:24]([N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][CH2:34][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:42][CH2:41]3)=[O:26])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: C1CCN(CCCN2CCNCC2)C1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCN(CCCN4CCCC4)CC3)s2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-thiadiazole-2-carboxylate (30 mg, 0.07 mmol), 1-[3-(pyrrolidin-1-yl)propyl]piperazine (31 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [NH:1](/[CH:8]=[C:9](/[C:15]1C=CC=CC=1)\C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1.C1([O:39]C2C=CC=CC=2)C=CC=CC=1>>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:9][C:8]1=[O:39]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)/C(=C\Nc1ccccc1)c1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1ccc2ccccc2[nH]1
Temperature: 250 °C
Reaction time: 0.17 h
Yield: 144 %

Procedure:
Compound 1 (1.10 g, 4.11 mmol) is added portionwise and rapidly with stirring, to a solution of biphenyl (1.70 g) and diphenyl ether (13.10 g) heated to 250° C. After 10 minutes, the heating is stopped. During the cooling, the quinolone 2 precipitates out in the reaction medium. This product is collected by filtration and then rinsed with petroleum ether. After drying, 859 mg (94%) of compound 2 are obtained in the form of white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:25][CH2:26][CH2:27][CH3:28])[O:7][CH2:8][C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:39]([C@H:8]([O:7][C@H:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH3:28])[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: BrCc1ccccc1
Reactant: CCCCC(OCC(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCC[C@H](O[C@@H](Cc1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Temperature: 0 °C

Procedure:
Benzhydryl 4-(2-furyl)-3-oxaoctanoate (2.0 g, 5.28 mmol) was dissolved in 20 mL freshly distilled THF and cooled to -80°±5° C. under dry argon. Sodium bis(trimethylsilyl)-amide (1.0M in THF, 5.6 mL, 5.6 mmol) was slowly added keeping the temperature at -80°±5° C. After 15 m, freshly distilled and filtered (through basic alumina) benzyl bromide (0.7 mL, 5.81 mmol) in HMPA (4 mL) was added dropwise maintaining the reaction temperature at -75°±5° C. After 15 m, the reaction was allowed to warm to 0° C. for 1 h before quenching with water and extraction with ether. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, brine,dried over MgSO4, and purified by flash silica gel chromatography to give 771.3 mg (31%): [α]25D -65.5°; 1H NMR (300 MHz, CDCl3) δ0.81 (t, 3H, J=7 Hz), 1.22 (m, 4H), 1.80 (m, 2H), 2.91 (m, 2H), 4.12 (dd, 1H, J=9 Hz), 4.30 (t, 1H, J=7 Hz), 5.86 (m, 1H), 6.19 (m, 1H), 6.69 (s, 1H), 7.2 (m, 16H); mass spectrum (FAB): 486 (M+NH4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:17][CH2:18][N:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=2)[C:20]1=[O:33]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:18][N:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[C:20]2=[O:33])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(CCBr)c(=O)c2c1
Reactant: COc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCOc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxyphenol (74 mg, 0.59 mmol) in THF (2.5 mL) was added potassium tert-butoxide (52 mg, 0.46 mmol). The reaction mixture was stirred at rt for 3 h, then methyl 2-(2-bromoethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (80 mg, 0.26 mmol) in DMF (2.5 mL) was added and the resulting mixture was stirred at rt overnight. The mixture was then concentrated to afford methyl 2-[2-(4-methoxyphenoxy)ethyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate. LC-MS: (FA) ES+354.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.[O:18]=[S:19]1(=[O:36])[CH2:24][CH2:23][N:22]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:21]2=[N:20]1>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:35][C:32]2[CH:31]=[CH:30][C:29]([C@H:28]3[C:21]4=[N:20][S:19](=[O:36])(=[O:18])[CH2:24][CH2:23][N:22]4[CH2:25][CH2:26][CH2:27]3)=[CH:34][CH:33]=2)=[CH:11][CH:10]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(Cl)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.9 %

Procedure:
Diacetoxycopper (1037 mg) was added to a mixture of triethylamine (1.983 mL), 4-chlorophenylboronic acid (1339 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (800 mg) and in DMF (dry) (30 mL). The mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 15 hr. Then 4-chlorophenylboronic acid (1339 mg) and diacetoxycopper (1037 mg) were added and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 2 days. The insoluble material was removed by filtration, and the filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with 0.1N NaOH aq., dried over anhydrous magnesium sulfate. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then crystallized from THF/IPE to give the title compound (177 mg) as an off-white solid.