Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C)C.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]([NH:28][C@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][C:4]([CH3:7])([CH:30]([OH:31])[C@H:29]([NH:28][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:32][CH3:33])[CH3:6]
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added tert-butyllithium (1.5 M in pentane, 8.0 mL, 4 eq, 12.0 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −55° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring, and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel gradient column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.57 g (49%). (55% de 3S,4R: 45% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.36 & 0.86 (2×t, 3H, J=7.42 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 0.57 & 0.71 (2×s, 9H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.38-1.52 (m, 2H, —NHCH (CH2CH3)CH(C(CH3)3)OH), 1.99 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.27 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.95 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.22 & 4.77 (2×d, 1H, J=4.42 5.21 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.14-7.52 (m, 15H, 3×Ph).
Reaction SMILES: N1CCOCC1.[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S-:23])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:29][C:30]([NH2:32])=[O:31]>C1COCC1>[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S:23][CH2:29][C:30]([NH2:32])=[O:31])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: NC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c([S-])c1C#N
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Reaction time: 2 h
Yield: 360.4 %

Procedure:
To a solution of 0.940 g (2.28 mmol) of the above morpholine salt in THF (15 mL), cooled to 0° C., was added 0.315 g (0.280 mmol) of 2-bromoacetamide as a solid in one portion. The mixture was stirred and allowed to slowly warn to room temperature over a 2 h period during which time salts precipitated from solution. The mixture was filtered through diatomaceous earth to remove solids and the filter pad was washed with EtOAc. The mixture was concentrated under reduced pressure to provide 0.385 g (44%) of 2-{4-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-3-cyano-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl}-acetamide as an orange foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: O
Product: Cc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Yield: 100 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (3.0 g, 17.3 mmol) in pyrrolidine (50 mL) was stirred at 80° C. for 12 hr. The mixture was concentrated in vacuo to give a residue which was poured into water and extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (3.6 g, 17.3 mmol, 100%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH2:51]1>CN(C=O)C>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:50]5[CH2:53][CH:52]([N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)[CH2:51]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reactant: C1CN(C2CNC2)CCO1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reaction time: 18 h
Yield: 44.8 %

Procedure:
To a mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (500 mg, 1.19 mmol), 2-chloro-1-methylpyridinium iodide (729 mg, 2.86 mmol) and DIPEA (500 μL, 2.87 mmol) in DMF (10 mL) was added 4-azetidin-3-ylmorpholine (288 mg, 2.0 mmol) and the resulting mixture allowed to stir at r.t for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc which was washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) affording 799 as a cream solid (290 mg, 45%). LCMS (method G): RT 5.90 min, [M+H]+ 544.5. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.67-7.67 (1 H, m), 7.28-7.20 (2 H, m), 4.73-4.72 (1 H, m), 4.70-4.00 (4 H, brd s), 4.53-4.51 (1 H, m), 4.29-4.21 (1 H, m), 4.18-4.08 (4 H, m), 3.87 (4 H, t, J=4.67 Hz), 3.78 (4 H, t, J=4.60 Hz), 3.30-3.30 (1 H, m), 2.88-2.88 (1 H, m), 2.47-2.45 (4 H, m), 1.35-1.34 (2 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH3:6][C:7]1([CH3:15])[CH2:13][C:12](=O)[O:11][C:9](=[O:10])[CH2:8]1.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(OCC)C>[CH3:3][CH:2]([CH3:4])[CH2:1][N:5]1[C:9](=[O:10])[CH2:8][C:7]([CH3:15])([CH3:6])[CH2:13][C:12]1=[O:11]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CC(C)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)CN1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isobutylamine (7.3 g, 0.1 mol) was added slowly to 3,3-dimethylglutaric anhydride (14.2 g, 0.1 mol) stirring at room temperature in a two neck round bottom flask fitted with a water condenser. After 30 minutes, acetic anhydride (20.4 g, 0.2 mol) was added, and the resulting mixture was boiled for two hours. After cooling, the mixture was poured slowly on to an aqueous NaOH solution (2N, 100 ml) stirring at room temperature. After one hour, the mixture was diluted with diethyl ether (50 ml), and the organic layer was separated. The aqueous layer was washed with more diethyl ether (2×50 ml), and the combined organic layer dried and concentrated to give the title compound as a pale yellow oil which solidified on standing, m.p. 48°-52° C., yield 18.5 g (94%). The product was suffuciently pure by NMR spectroscopy to be used directly in the following procedure.
Reaction SMILES: [CH:1]1([N:4]([CH3:31])[C:5](=[O:30])[CH2:6][NH:7][C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:9]=2)[CH2:3][CH2:2]1.[Cl:32]N1C(=O)CCC1=O>>[Cl:32][C:13]1[C:8]([NH:7][CH2:6][C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:31])=[O:30])=[N:9][C:10]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)=[N:11][C:12]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1)C1CC1
Product: CN(C(=O)CNc1nc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2)c1Cl)C1CC1

Procedure:
N-Cyclopropyl-N-methyl-2-[6-phenyl-2-(4-trifluoromethyl-phenyl)-4-pyrimidinylamino]acetamide and N-chlorosuccinimide are treated in the same manner as in Example 1, and the resultant is recrystallized from ethanol to give the desired compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[CH3:52][O:53][C:54](=[O:65])[CH2:55][CH:56]([NH2:64])[C:57]1[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([NH:64][CH:56]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[CH2:55][C:54]([O:53][CH3:52])=[O:65])=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: COC(=O)CC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 63.7 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (84 mg, 0.22 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (72.3 mg, 0.20 mmol), 3-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride (50 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.104 mL, 0.60 mmol) in N-methyl-2-pyrrolidinone (1.5 mL) at 20° C. under argon. The resulting solution was stirred for 5 h. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) with decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (71.0 mg, 63.8%) as a white crystalline solid.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[Cl:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([CH2:27]Cl)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:29].O>CN(C)C=O>[C:1]1([S:7]([NH:10][CH2:27][C:24]2[CH:25]=[CH:26][C:21]3[N:20]=[C:19]([CH3:29])[N:18]([CH2:17][C:16]4[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=4[Cl:14])[C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccccc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(CNS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 0.667 g of benzenesulfonic acid amide in 5 ml of N,N-dimethylformamide were added 0.127 g of 60% sodium hydride at room temperature, and the mixture was stirred for 1 hour. Further, 0.648 g of 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride were added thereto, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution to stop the reaction, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and with water. The organic layer was concentrated, and was purified through silica-gel column chromatography (eluent: ethyl acetate) to give 0.240 g of 6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methylbenzimidazole (264).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]1=2.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12][C:11]2[CH:15]=[C:16]([NH:19][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])[CH:17]=[CH:18][C:10]1=2
Reactant: CN1CCCC1CCN1CCSc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CCCC1CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
A suspension of 4-(2-(1-methylpyrrolidin-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.7 g, 2.52 mmol) and methyl thiophene-2-carbimidothioate hydroiodide (1.439 g, 5.05 mmol) in dry ethanol (15 mL) was stirred at room temperature overnight (16 hours) under an argon atmosphere. At this time, the solvent was evaporated, and the residue was partitioned between saturated NaHCO3 solution (50 mL) and dichloromethane (25 mL). The mixture was transferred to a separatory funnel, and the organic layer was removed. The aqueous layer was extracted into dichloromethane (2×25 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was subjected to column chromatography on silica gel (sequence of eluents: 2:98 methanol:dichloromethane, 5:95 methanol:dichloromethane, and 5:95 (2M ammonia in methanol):dichloromethane) to give compound 13 as yellow syrup (0.48 g, 49%). 1H-NMR (DMSO-d6) δ 7.69 (brd, J=2.7 Hz, 1H), 7.57 (brd, J=4.5 Hz, 1H), 7.07 (dd, J=3.9, 4.8 Hz, 1H), 6.52 (dd, J=1.8, 8.1 Hz, 2H), 6.47 (brd, J=1.8 Hz, 1H), 6.38 (brs, 2H), 3.51-3.47 (m, 2H), 3.28-3.22 (m, 2H), 3.05-3.02 (m, 2H), 2.99-2.93 (m, 1H), 2.24 (s, 3H), 2.12-2.06 (m, 2H), 1.94-1.87 (m, 2H), 1.68-1.63 (m, 2H), 1.51-1.42 (m, 2H); ESI-MS (m/z, %): 387 (MH+, 90), 276 (100), 194 (50).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:24])[C@@H:13]2C(=O)[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(CC(N(C)[C@@H]2C(=O)CCC[C@H]2N2CCCC2)=O)C=CC=1Cl.C(O[CH:53]([O:57][CH2:58][CH3:59])[O:54][CH2:55][CH3:56])C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:24])[C@@H:13]2[C:53]([O:54][CH2:55][CH3:56])([O:57][CH2:58][CH3:59])[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C(=O)Cc1ccc(F)c(F)c1)[C@@H]1C(=O)CCC[C@H]1N1CCC1
Reactant: CCOC(OCC)OCC
Agent: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1C(=O)CCC[C@H]1N1CCCC1
Solvent: CCO
Product: CCOC1(OCC)CCC[C@@H](N2CCC2)[C@@H]1N(C)C(=O)Cc1ccc(F)c(F)c1

Procedure:
Following the procedure of Example 3, substituting trans-(±)-3,4-difluoro-N-methyl-N-[6-oxo-2-(1-azetidinyl)cyclohexyl]benzeneacetamide for the trans-(±)-3,4-dichloro-N-methyl-N-[6-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide in 50 ml of dry ethanol instead of methanol and 5.0 ml of triethylorthoformate instead of trimethylorthoformate, there is formed as product trans-(±)-3,4-difluoro-N-methyl-N-[6,6-diethoxy-2-(1-azetidinyl)cyclohexyl]benzeneacetamide, which is converted to a hydrochloride salt.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=3[CH3:30])=[CH:19][S:20][CH:21]=2)=[CH:13][CH:12]=1.CN(C)[CH:33]=[O:34]>O1CCCC1>[CH:33]([C:19]1[S:20][CH:21]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)[C:18]=1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[CH3:30])=[O:34]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cscc2-c2ccc(C#N)cc2C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2csc(C=O)c2-c2ccc(C#N)cc2C)cc1
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
A solution of freshly prepared LDA (0.8 mL, 1.64 mmol) in anhydrous tetrahydrofuran (7 mL) was added slowly a solution of 4-(4-(4-methoxyphenyl)thiophen-3-yl)-3-methylbenzonitrile (Scheme I, 3, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (500 mg, 1.637 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen at −78° C. After being stirred for 15 min., a solution of dimethylformamide (0.14 mL, 1.804 mmol) in anhydrous tetrahydrofuran (3 mL) was dropwise added. The resulting mixture was stirred for 1 h at −78° C., and at room temperature for 3 h. The reaction was quenched with water (50 mL), and extracted with ethyl acetate (40 mL×3). The combined organic extracts were washed with water (30 mL), brine (50 mL), dried over anhydrous sodium sulfate, evaporated, and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to afford 4-(2-formyl-4-(4-methoxyphenyl)thiophen-3-yl)-3-methylbenzonitrile (Scheme I, 4A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.16 g, yield 29.3%) as a white solid (confirmed by NOE). 1H NMR (DMSO-d6 400 MHz): δ 9.46 (s, 1H), 8.31 (d, J=1.2 Hz, 1H), 7.83 (s, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 3.77 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[O:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.S(=O)(=O)(O)O.[N+:29]([O-])([OH:31])=[O:30]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:19])[C:13]3[CH:14]=[C:15]([N+:29]([O-:31])=[O:30])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(c2ccc(Cl)cc2)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Yield: 32 %

Procedure:
To a stirred suspension of 4-(4-chlorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.15 g, 18.80 mmol) in a mixture of glacial acetic acid (15 mL) and concentrated sulfuric acid (15 mL) was slowly added concentrated nitric acid (3 mL). After 10 minutes the reaction was poured over ice and brine (100 mL) and filtered. Trituration of the solid with ethyl acetate/ether gave 4-(4-chlorophenyl)-4-methyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one as a tan solid (1.92 g, 32%). 1H NMR (DMSO-d6): δ 11.04 (s, 1H), 8.29 (m, 2H), 7.47 (dd, J=6.6, 2.0 Hz, 2H), 7.32 (dd, J=6.7, 2.1 Hz, 2H), 7.13 (d, J=9.5 Hz, 1H), 2.06 (s, 3H); MS (ESI) m/z [M+H]+(319/321); MS (ESI) m/z [M−H]− (317/319); Anal. calcd for C15H11ClN2O4: C, 56.53; H, 3.48; N, 8.79. Found: C, 55.43; H, 3.37; N, 8.78.
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:36].F[P-](F)(F)(F)(F)F.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([N:35]([CH3:36])[CH3:34])=[O:25])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)N(C)C)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid (40 mg, 0.09 mmol), HATU (34 mg, 0.090 mmol), N,N-dimethylamine hydrochloride (7.3 mg, 0.090 mmol) and iPr2NEt (62 μL, 0.36 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield 1′-(4-ethyl-3-methoxybenzoyl)-N,N-dimethylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide. ESI-MS m/z calc. 473.6. found 474.5 (M+1)+; Retention time: 1.80 minutes (3 min run).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:18]=[CH:17][C:13]3[CH:14]=[N:15][S:16][C:12]=3[CH:11]=2)=[N:7][N:6]=1)(=O)=O.C([O-])(=O)C.[NH4+:23].CO>C(Cl)Cl>[S:16]1[C:12]2[CH:11]=[C:10]([C:8]3[S:9][C:5]([NH2:23])=[N:6][N:7]=3)[CH:18]=[CH:17][C:13]=2[CH:14]=[N:15]1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3cnsc3c2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: Nc1nnc(-c2ccc3cnsc3c2)s1
Temperature: 140 °C
Yield: 70.3 %

Procedure:
A mixture of 6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)benzo[d]isothiazole (0.16 g, 0.54 mmol) and excess ammonium acetate (1.93 mL, 26.9 mmol) was heated in a microwave-safe reaction vessel at 140° C. for 30 minutes under microwave irradiation. The mixture was cooled, 5% MeOH in DCM (with NH3) was added, and the mixture was adsorbed onto silica gel. The residue was purified by flash column chromatography (DCM—10% MeOH in DCM) to obtain the desired product as an off-white solid (89 mg, 71%). LCMS (API-ES) m/z (%): 235.3 (100%, M+H+); 1H-NMR (400 MHz, CD3OD) δ ppm 9.02 (s, 1 H) 8.49 (s, 1 H) 8.25 (d, J=8.53 Hz, 1 H) 7.98 (d, J=9.03 Hz, 1 H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:16](O)[CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][O:12][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:15][CH:14]=1
Reactant: OCCO
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Yield: 57.4 %

Procedure:
Dry HCl gas was passed through a mixture of (4-nitrophenoxy) acetic acid 22 (100 g, 507 mmol) and ethylene glycol (300 ml) for 1 hour. During HCl gas bubbling the temperature rose to 60° C. The crude reaction mass was poured onto ice (2 kg). Crude 23 was filtered, dried and purified by column chromatography on silica gel using hexane:ethyl acetate (95:5) to give pure 23 (70 g, 57.4%) as a white powder with an m.p. between 73.5-75.5° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:5]2.[C:16]([OH:20])(=[O:19])[C:17]#[CH:18].C(N(CC)CC)C>C(#N)C.[Cu]I>[N:11]1([CH:7]2[C:8]3[C:4](=[CH:3][C:2]([C:18]#[C:17][C:16]([OH:20])=[O:19])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#CC(=O)O
Reactant: Ic1ccc2c(c1)CCC2N1CCCC1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)C#Cc1ccc2c(c1)CCC2N1CCCC1
Reaction time: 2 h

Procedure:
Under an argon atmosphere at 0° C., 0.5 g (1.59 mmol) of 1-(5-iodoindan-1-yl)pyrrolidine and 123 mL (2 mmol) of propynoic acid are dissolved in 25 mL of acetonitrile. 0.66 mL (4.79 mmol) of triethylamine, 30 mg (0.16 mmol) of copper (I) iodide, and 80 mg (0.11 mmol) of ditriphenylphosphine palladium dichloride are added to this solution and the mixture is stirred for 2 hours, while the solution is allowed to come up to ambient temperature. The purification is carried out by preparative HPLC (eluant: dichloromethane/methanol/ammonia (8:2:0.2)). Yield 0.1 g (24.5% of theory); C16H17NO2 (M=255.31); calc.: molecular ion peak (M+H)+: 256; found: molecular ion peak (M+H)+: 256.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(O)c2ccccc2n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(=O)[nH]c2ccccc12
Yield: 54 %

Procedure:
To a suspension of 2.4-dihydroxy quinoline (3.00 g, 18.6 mmol) and potassium carbonate (5.14 g, 37.2 mmol) in acetone (500 mL) was added dimethyl sulfate (2.1 mL, 22 mmol) and the resulting mixture heated at reflux during 5 hrs. The solvent was removed in vacuo and the residue triturated in water. The product was collected by filtration, washed with water and triturated from methanol to give 4-methoxy 2-quinolone 187a (1.76 g, 54%) as a white solid, that had identical 1H NMR data as reported (Reisch et al., Arch. Pharm., 1980,313, 751-755).