Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)[C:7]([CH3:19])=[CH:6][CH:5]=2.[Li:20]CCCC>CCCCC>[CH3:1][C:2]1[CH-:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:7]([CH3:19])=[CH:6][CH:5]=2.[Li+:20]
Reactant: [Li]CCCC
Reactant: CC1=Cc2c(ccc(C)c2-c2cc(C)cc(C)c2)C1
Solvent: CCCCC
Product: Cc1cc(C)cc(-c2c(C)ccc3[cH-]c(C)cc23)c1
Product: [Li+]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,5-Dimethyl-4-(3,5-dimethylphenyl)indene (2.1 g, 8.4 mmol), prepared as described under (f) above, was dissolved in 60 ml of pentane. To this solution was added 3.4 ml of nBuLi (2.5 M in hexane) and the reaction was stirred for two hours at room temperature. A white solid precipitated from solution and was collected by frit filtration and washed with additional pentane. Yield: 1.6 g (74%).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([F:19])[C:11]=3[F:20])[CH2:6][CH2:5]2)[O:3]C1.C(O)=O>C1(C)C=CC=CC=1>[F:20][C:11]1[C:12]([F:19])=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:10]=1[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: CCOc1ccc(C2CCC3(CC2)OCCO3)c(F)c1F
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Yield: 100 %

Procedure:
Crude 4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexanone monoethylene acetal (50.3 mmol) obtained in Step 1 was dissolved in 200 ml of toluene, 87% formic acid (503 mmol) was added, and the solution was heated to reflux for 4 hours. The reaction solution was washed twice with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate, then three times with 100 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to form crude 4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexanone (50.3 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:49])[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:48])=[C:23]([C@:25]34[CH2:33][O:32][C@H:31]([C:34]([F:37])([F:36])[F:35])[C@H:30]3[C:29](=[O:38])[N:28]([CH3:39])[C:27]([NH:40]C(=O)OC(C)(C)C)=[N:26]4)[CH:24]=2)=[O:17])=[N:14][CH:15]=1>C(Cl)Cl>[NH2:40][C:27]1[N:28]([CH3:39])[C:29](=[O:38])[C@@H:30]2[C@@H:31]([C:34]([F:37])([F:36])[F:35])[O:32][CH2:33][C@:25]2([C:23]2[CH:24]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([CH:9]([F:49])[F:8])=[CH:15][N:14]=3)=[O:17])[CH:20]=[CH:21][C:22]=2[F:48])[N:26]=1
Reactant: CN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1N
Yield: 95.5 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-(5-(difluoromethyl)pyrazine-2-carboxamido)-2-fluorophenyl)-3-methyl-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (92 mg, 0.15 mmol) in DCM (2 mL) at RT. After 1 h at this temperature the volatiles were removed in vacuo and the residue was azeotroped with PhMe (×2). The residue was then taken up in MeOH and loaded on to a SCX cartridge (5 g). The cartridge was eluted with MeOH (2×20 mL) and then 2M NH3 in MeOH (2×20 mL). The relevant fraction was evaporated to give the title compound (72 mg, beige solid). 1H NMR (400 MHz, MeOH-d4) δ ppm 3.25 (s, 3H) 3.80 (d, J=8.34 Hz, 1H) 4.29-4.34 (m, 1H) 4.35-4.40 (m, 1H) 4.62-4.71 (m, 1H) 6.95 (t, J=54.30 Hz, 1H) 7.18 (dd, J=11.62, 8.84 Hz, 1H) 7.80 (ddd, J=8.72, 4.17, 2.78 Hz, 1H) 7.89 (dd, J=6.82, 2.53 Hz, 1H) 9.02 (s, 1H) 9.40 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH3:33])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]1([CH3:49])[CH2:43][O:42][CH:41]([CH2:44][CH2:45][CH2:46][CH:47]=O)[O:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:47][CH2:46][CH2:45][CH2:44][CH:41]3[O:40][CH2:39][C:38]([CH3:37])([CH3:49])[CH2:43][O:42]3)[CH2:32][CH3:33])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CCNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CC1(C)COC(CCCC=O)OC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(CCCCC1OCC(C)(C)CO1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(ethylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (68.2 mg, 0.129 mmol) in dichloroethane (2 mL) was added 4-(5,5-dimethyl-1,3-dioxan-2-yl)butanal (119 mg, 0.643 mmol) and NaBH(OAc)3 (136 mg, 0.643 mmol). The reaction was stirred at room temperature for 72 hours and then diluted with EtOAc (30 mL), quenched with saturated NH4Cl solution (10 mL), and washed with water and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl](ethyl)amino]-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.62 (25% EtOAc/hexanes). LCMS=701.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ7.97 (s, 1H), 7.85 (s, 2H), 7.23-7.19 (m, 3H), 5.79 (d, J=8.1 Hz, 1H), 4.79 (d, J=16.0 Hz, 1H), 4.62 (d, J=16.0 Hz, 1H), 4.43 (t, J=4.9 Hz, 1H), 4.11-4.01 (m, 1H), 3.61 (d, J=1.1 Hz, 2H), 3.44 (d, J=10.8 Hz, 2H), 3.06-3.00 (m, 4H), 1.71-1.41 (m, 6H), 1.12 (s, 3H), 1.05-1.01 (t, J=7.0 Hz, 3H), 0.77 (s, 3H), 0.74 (d, J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 45.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.57 g) described in Preparation Example 119 and 2-pyrrolidone (0.33 g), the title compound (0.72 g) was obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].[C:27]([CH2:29][C:30]([NH2:32])=[O:31])#[N:28].C(O)(=[O:35])C.N1CCCCC1>C(#N)C>[CH3:6][C:5]1[NH:28][C:27](=[O:35])[C:29]([C:30]([NH2:32])=[O:31])=[CH:3][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(=CN(C)C)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: Cc1[nH]c(=O)c(C(N)=O)cc1-c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
A mixture of 2.6 g of 4-(dimethylamino)-3-[4-(4-phenyl-1-piperidinyl)phenyl]-3-buten-2-one, a mixture of 0.75 g of cyanoacetamide, 0.8 ml of piperidine acetate in 25 ml of acetonitrile is refluxed for 24 hours. The solid is collected, washed with CH3CN7 ether, and dried to give 0.80 g beige solid, mp 335°-338° C. (d).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ICCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCOc3ccccc3)cc12
Yield: 38.1 %

Procedure:
A mixture of 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) (150 mg, 0.43 mmol), cesium carbonate (280 mg, 0.85 mmol) and (2-Iodo-ethoxy)-benzene (413 mg, 3.87 mmol), in dimethylformamide (6 rill) was stirring at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with a saturated solution of ammonium chloride, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-10%) to yield the title compound (77 mg, 38%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16]N(C=O)C.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1>C(Cl)Cl.CO>[CH3:16][O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in CH2Cl2 (250 mL) at 0° C. was added DMF (0.100 mL) followed by (COCl)2 (2M in CH2Cl2, 36.23 mL, 72.46 mL) over a period of 10 min. The reaction was stirred at 0° C. for 1 h and then at room temperature for 30 min. The reaction solvent was removed under a reduced pressure, dried under high vacuum and again suspended in CH2Cl2 (250 mL). The solution was cooled to 0° C., were added pyridine (4.8 mL, 48.03 mmol) followed by MeOH (10 mL, excess) and stirred overnight. The extractive work-up with CH2Cl2 gave the expected 2-methoxycarbonyl-5-nitrobenzofuran (R926609). 1H NMR (CDCl3): δ 8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: ret. time: 26.94 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(O)c2cc(S(C)(=O)=O)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a mixture of (4-methanesulfonyl-phenyl)-(3-nitro-benzylidene)-amine (10 g, 33 mmol) and ytterbium(III) triflate hydrate (2.05 g, 3.3 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (3.3 mL, 36.3 mmol) and water (0.6 mL, 33 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 6-methanesulfonyl-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (10 g, 92%) as a light yellow oil: LC/MS m/e calcd for C18H20N2O5S (M+H)+: 377.43, observed: 376.8.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.C[Si](Br)(C)C.C(Cl)[Cl:18]>>[Cl:18][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: ClCCl
Agent: C[Si](C)(C)Br
Product: Clc1ncnc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the quinazoline 2 (0.168 g, 0.29 mmol) in DCM (1.5 mL) was added TMSBr (0.079 mL, 0.61 mmol) at 0° C. The reaction was stirred for 1 h at 0° C., then for 1 h at RT. The reaction was quenched with water (3 mL) and stirred for 15 min. The aqueous layer was washed with EtOAc (5 mL), and dried with lyophilizer overnight to give desired product 3 as white foam (0.14 g. 100% yield). LC/MS (10-99%) M/Z 406.0 retention time 3.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:26])[N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: C1CCNCC1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CC1(C)CN(CC(=O)N2CCCCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 90 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and piperidine in 90% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:27]=1[CH:28]=O.CO[Si](OC)(OC)OC>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:19])([CH3:20])[C:13](=[CH:28][C:27]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:26]=1[O:25][CH3:24])[C:12]2=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Agent: CO[Si](OC)(OC)OC
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1C=C1C(=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 5.0 g (17.7 mmole) of the product of Example 100, 1.1 g (19 mmol) potassium fluoride, 3.5 g (19.5 mmole) 2-methoxy-5-nitrobenzaldehyde and 2.9 mL (2.97 g, 19.5 mmole) tetramethylortho-silicate in 15 mL dimethylformamide was heated at 80° C. for 7 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was and washed successively with 1N HCl, 5% NaHCO3, water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes gave 6.23 g (79%) of a foam. Recrystallization from ethyl acetate in hexanes yielded the title product as a solid m.p. 110°-112° C. NMR (CDCl3): δ1.70 (s, 6H); 3.82 (s, 3H); 5.02 (s, 2H). Analysis calculated for C20H23NO6 : C, 70.10; H, 5.20; N, 3.14. Found: C, 70.19; H, 5.21; N, 3.14.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=2)=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(N(CC)CC)C.C1COCC1>[C:7]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:20])=[CH:17][N:16]=2)=[CH:9][CH:8]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)CCNC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of N,N-dimethylethylenediamine (160 mg) in acetonitrile (5 ml)/THF (10 ml) were added 6-(4-biphenylylmethoxy)nicotinic acid (450 mg), WSC (340 mg), HOBt (230 mg), and triethylamine (0.7 ml) at room temperature. After stirring at room temperature for 12 hr, the reaction mixture was diluted with 10% aqueous potassium carbonates and extracted with ethyl acetate/THF. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent; THF) and recrystallized from ethyl acetate/diisopropyl ether to obtain the titled compound (400 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:21]3[N:20]=[C:19]([C:11]4[N:10]=[N:9][N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[C:12]=4[C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)[O:23][N:22]=3)=[CH:25][CH:26]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: C1CNC1
Agent: Cl
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc(CN4CCC4)cc3)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and azetidine hydrochloride (45.4 mg; 0.48 mmol) to give Example 138 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.6, 1.6 Hz), 7.96-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.6, 1.6 Hz), 7.51 (4H, t, J=8.1 Hz), 3.67 (2H, s), 3.22 (4H, t, J=6.9 Hz), 2.04 (2H, m). LC/MS (Method C): 454 (M+H)+. HPLC (Method E) Rt 2.19 min (Purity: 96.2%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:20]=[O:21])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CN1CCCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 1-methyl-1,2,3,4-tetrahydroquinoline (4.4 g, ca. 30.0 mmol) in DMF (30 mL) was added POCl3 (2.8 mL, 30.0 mmol, 1.0 eq) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice then extracted with Et2O (3×50 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was purified by flash column chromatography (0-20% EtOAc in hexanes) to afford the title compound (2.17 g, 12.4 mmol, 41% over two steps).
Reaction SMILES: C([C:4]([C@H:6]([C@@H:8]([C@@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][OH:12])[OH:9])[OH:7])=[O:5])C=C.O>CO.[Pd](Cl)Cl>[N:13]([C@@H:10]([CH2:11][OH:12])[C@@H:8]([OH:9])[C@H:6]([OH:7])[CH:4]=[O:5])=[N+:14]=[N-:15]
Reactant: C=CCC(=O)[C@@H](O)[C@H](O)[C@H](CO)N=[N+]=[N-]
Agent: Cl[Pd]Cl
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@@H](CO)[C@@H](O)[C@H](O)C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.7 %

Procedure:
1-allyl-4-azido-4-deoxy-L-xylose 36 (496 mg, 2.3 mmol) was dissolved in 99:1 methanol:water (10 mL), followed by the addition of palladium (II) chloride (81.7 mg, 0.46 mmol). The reaction mixture was stirred for 24 h at room temperature, and then filtered through a pad of Celite® with methanol wash (100 mL). The combined filtrates were purified by silica gel flash chromatography (DCM to 9:1 DCM:MeOH) to give of 37 as a yellow oil (249 mg, 1.42 mmol, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:36][NH2:37]>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:36][NH2:37])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)OCCn2c1nc(C(=O)NN)c(OCc1ccccc1)c2=O
Reaction time: 3 h
Yield: 27 %

Procedure:
To a stirred suspension of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid (prepared according to the procedure in Naidu, B. N. et al WO2005118593) (0.66 g, 2 mmol) in CH2Cl2 (10 mL) containing catalytic DMF was added oxalyl chloride in CH2Cl2 (2 M, 2 mL, 4 mmol) at room temperature. After 3 h, the resulting clear reaction solution was concentrated to remove excess oxalyl chloride. The resulting residue was re-dissolved in CH2Cl2 (20 mL) and treated with anhydrous hydrazine (0.34 mL, 10 mmol). After 2 h at room temperature, the reaction mixture was concentrated and the residue was taken up in EtOAc (100 mL) and washed with sat. NaHCO3 (10 mL), water (10 mL), brine (10 mL) then dried (Na2SO4), filtered and concentrated to give a white solid. This was digested with Et2O (20 mL) and filtered. Concentration of filtrate provided the title compound (0.17 g, 27% yield). 1HNMR (500 MHz, CDCl3) δ: 8.35 (1H, s), 7.55 (2H, d, J=7.3 Hz), 7.38-7.31 (3H, m), 5.30 (2H, s), 4.03-3.97 (6H, m), 1.60 (6H, s). HRMS (M+H) calcd for C17H21N4O5: 345.1563. found: 345.1577.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C.[Mo].[Mo]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: [Mo]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a dimolybdenum carbide from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 6.0%, wherein 5.1 g of phenyl chloroformate and 5.8 g of diphenyl carbonate were formed. Selectivity for carbonates was 97.3%.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[N:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[CH:9][CH:8]=1.O1CCCC1.B.[OH-].[Na+]>O>[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc(Cl)n1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(Cl)n1
Temperature: 10 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
A dry flask was charged with 25 mL of anhydrous tetrahydrofuran and 6-chloropyridine-2-carboxylic acid (2.00 g, 12.69 mmol) and then cooled to 10° C. This was treated dropwise with tetrahydrofuran-borane (1.0 M solution in THF, 38.1 mL) over 10 minutes under nitrogen. This was stirred with cooling for 15 minutes, then at ambient temperature for 4 h. The reaction was then cooled to 0° C., and 10 mL of water were added slowly. The resultant mixture was poured into 50 mL of 1 M aqueous sodium hydroxide and extracted 2×75 mL of ethyl acetate. The organic extracts were combined and washed with brine, then dried over sodium sulfate and filtered. Concentration in vacuo yielded 589.1 mg of a white solid as the title compound (I-5a).