Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O.[CH3:37][C:38]([CH:40]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:39]>C1C=CC=CC=1>[CH3:37][C:38](/[CH:40]=[CH:1]/[C:3]1[CH:8]([C:9]([O:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=[O:39]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)/C=C/C1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 25.6 %

Procedure:
A solution of diphenylmethyl 3-formyl-7β-(2-thienylacetamido)ceph-2-em-4-carboxylate (116 mg.) in benzene (3 ml.) was treated with a solution of methylcarbonylmethylenetriphenylphosphorane (150 mg.) in benzene (4 ml.) and the mixture refluxed for 5.75 hours. The organic solution was washed with 2N-hydrochloric acid and water, dried and evaporated in vacuo. The residual gum (186 mg.) was purified by preparative T.L.C. (Kieselgel HF254+366, developed five times with benzene-ethyl acetate = 8:1) to give the title compound (32 mg, 27%) as a gum, λmax. CHCl3) 318 nm. (qualitative), τ CDCl3) 3.00 and 3.86 (CH=CH, two d, J 16 Hz), 3.12 (CHPh2), 3.27 (C(2) --H, broad s), 4.47 (C(7) -H, dd, J 8 and 4 Hz), 4.73 (C(6) --H, d, j 4 Hz), 4.69 (C(4) --H, broad s), 616 (CH2CONH) and 7.91 (COCH3).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:13][C:14]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:31][CH3:32])[C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C(Cl)Cl>[CH3:13][C:14]1[CH:36]=[CH:35][C:34]([NH:37][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=2)=[CH:33][C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:31][CH3:32])[C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COc1cc2c(Nc3cc(N)ccc3C)ncnc2c(OC)c1OC
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: COc1cc2c(Nc3cc(NC(=O)c4cccc(N(C)C)c4)ccc3C)ncnc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
3-Dimethylaminobenzoyl chloride (105 mg) was added to a suspension of 4-(2-methyl-5-aminoanilino)-6,7,8-trimethoxyquinazoline (180 mg) in dry methylene chloride (4 ml) and the resulting mixture was stirred at ambient temperature for 18 hours. Methylene chloride (100 ml) was added and the mixture washed with aqueous sodium hydroxide solution (100 ml), water and brine, dried over sodium sulphate, filtered and evaporated give a yellow gum. This was purified by silica column chromatography, eluting with 2% methanol in methylene chloride to yield the title compound as a solid (30 mg, 12%); NMR (CDCl3) 2.22 (s, 3H), 2.97 (s, 6H), 3.96 (s, 3H), 4.06 (s, 3H), 4.13 (s, 3H), 6.84 (dd, 1H), 7.05 (m, 2H), 2.22 (m, 2H), 7.28 (t, 1H), 7.42 (m, 1H), 7.92 (s, 1H), 7.95 (s, 1H), 8.61 (s, 1H); m/s: M+H+ 488.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=4)=[CH:7][N:6]=3)=[CH:17][N:16]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)NCc3ccc(-c4ccnc(F)c4)nc3)nc2)c1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a tube was added 5-bromo-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)picolinamide 38-4 (38 mg, 0.10 mmol), 3-(methylsulfonyl)phenylboronic acid 43-1 (33 mg, 0.20 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), toluene (0.4 mL), ethanol (0.1 mL) and 2M Na2CO3 (0.15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the tube sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified with reverse phase HPLC to give N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)-5-(3-(methylsulfonyl)phenyl)picolinamide 43 as a white powder. MS m/z 463.10 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.63 (t, 1H, J=6.0 Hz), 9.06 (d, 1H, J=1.6 Hz), 8.75 (d, 1H, J=1.6 Hz), 8.42 (dd, J1=8.4 Hz, J2=2.0 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.31 (m, 1H), 8.20-8.15 (m, 3H), 8.03-8.01 (m, 2H), 7.94 (dd, 1H, J1=8.2 Hz, J2=2.0 Hz), 7.85-7.80 (m, 2H), 4.62 (d, 2H, J=6.4 Hz), 3.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[CH3:36][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:36])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.270 mmol) and 2N dimethylzinc in toluene (0.27 mL, 0.540 mmol), the title compound was obtained as a solid (75 mg, 47% yield). MS (ESI): 535 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:27]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:18]=2)[CH2:25][CH2:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: Nc1ccccc1
Product: COc1cc(-c2cc(CN3CCC(Nc4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.1 g) and aniline (344 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Reactant: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCOCCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.500 g of tert-butyl 3-hydroxy-4-(4-{2-[2-(2-methoxyphenyl)ethoxy]ethoxy}phenyl)piperidine-1-carboxylate (Example 100c) and 0.312 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one (Example 13b) are reacted. The title compound is obtained as an opaque oil. Rf=0.21 (1:1 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Reactant: IC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(C4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=O.O.ON1C2C=CC=CC=2N=N1.[N:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][C:6](=[O:8])[N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: COC(=O)C(CC(=O)O)Cc1ccc(OC)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COC(=O)C(CC(=O)N1CCN(c2ccncc2)CC1)Cc1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
To a solution of 2-(4-methoxybenzyl)succinic acid 1-methyl ester (3 g) in acetonitrile (60 ml) were added HOBt (1-hydroxy-1H-benzotriazole monohydrate) (1.84 g) and 1-ethyl-3-(3-dimethylamgnopropyl)carbodiide hydrochloride (2.76 g) and the solution was stirred for 10 minutes. To the solution was added 1-(4-pyridyl)-piperazine (1.96 g) and the solution was stirred for 30 minutes at room temperature. The reaction mixture was concentrated and the concentrate was made basic with an aqueous solution of sodium hydrogen carbonate to give an alkaline solution, which was extracted with ethyl acetate twice. The extract was washed with saturated brine and dried over Na2SO4. The solution was concentrated under reduced pressure and recrystallized from ethyl acetate/hexane to give the titled compound (4.25 g) as colorless needles.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][Si:7]([CH3:10])([CH3:9])Cl>C(N(CC)CC)C>[CH3:6][Si:7]([C:3]([Si:7]([CH3:10])([CH3:9])[CH3:6])=[CH:2][C:1]([NH2:5])=[O:4])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(N)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C(=CC(N)=O)[Si](C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
71 g (1 mol) of acrylic acid amide are dissolved in 750 ml of anhydrous triethylamine in a 6 liter three-necked flask equipped with a stirrer and a reflux condenser. 270 g (2.5 mols) of trimethylchlorosilane are then added dropwise over the course of 2 hours at room temperature (approximately 25° C). The temperature is then slowly raised to 60° C and the reaction mixture is stirred for about 16 hours at this temperature. The triethylamine hydrochloride which has precipitated is filtered off under protective gas and the filter cake obtained is rinsed with 200 ml of triethylamine. The triethylamine is then distilled off under a slight vacuum at 40°-45° C. The resulting concentrated filtrate is subjected to a purification distillation with addition of a little sulphur as a polymerisation inhibitor. 149 g (69% of theory) of bis-trimethylsilylacrylic acid amide, boiling at 71° C/20 mm Hg, are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: Clc1cc(-c2ccco2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3ccco3)nc3c2CCC3)cc1
Yield: 71.4 %

Procedure:
Following general procedure B1, 4-chloro-2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.064 g, 0.29 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.073 g, 0.41 mmol) to afford the title compound (0.075 g, 61%) as a white foam. MW=362.42. 1H NMR (CDCl3, 500 MHz) δ 7.45-4.43 (m, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.24 (s, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.93-6.89 (m, 1H), 6.48-6.44 (m, 1H), 5.73 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.62 (s, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 363 [M+H]+.
Reaction SMILES: O[CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:17][C:18]([NH:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:19].[CH3:30][C:31]1[C:39]([CH3:40])=[CH:38][C:34]2[N:35]=[CH:36][NH:37][C:33]=2[CH:32]=1>>[CH3:30][C:31]1[C:39]([CH3:40])=[CH:38][C:34]2[N:35]([CH2:2][CH:3]3[C:12]4[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)[CH2:6][CH2:5][N:4]3[CH2:17][C:18]([NH:20][CH:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)=[O:19])[CH:36]=[N:37][C:33]=2[CH:32]=1
Reactant: COc1cc2c(cc1OC)C(CO)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: Cc1cc2nc[nH]c2cc1C
Product: COc1cc2c(cc1OC)C(Cn1cnc3cc(C)c(C)cc31)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 2-(1-Hydroxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamide with 5,6-dimethylbenzimidazole
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[N+]([O-])(O)=O.C(O)(=O)C.[N+]([O-])(O)=O.[C:18]1([C:24]([F:27])([F:26])[F:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>S(=O)(=O)(O)O>[N+:1]([C:20]1[CH:19]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:23]=[CH:22][CH:21]=1)([O-:4])=[O:2]
Reactant: FC(F)(F)c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
The nitration step (a) may be effected by using various nitrating agents such as concentrated nitric-sulfuric acid, potassium nitrate--sulfuric acid and nitric acid-acetic acid. The preferred nitrating agent is connected nitric-sulfuric acid. The reaction is carried out by slowly adding fuming nitric acid to a mixture of benzotrifluoride in concentrated sulfuric acid while maintaining the temperature of the reaction between 0° to 40° C., preferably 20°-30° C. When the addition is complete, the reaction is allowed to continue for 1 to 2 hours, preferably 1 hour at room temperature. 3-Nitrobenzotrifluoride is isolated from the reaction mixture by conventional techniques.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH:32][CH3:33])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:35])([CH3:34])[O:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[OH:36][CH:7]1[C:6]2[C:11](=[C:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH:32][CH3:33])=[O:31])[CH:28]=5)[CH:23]=[CH:22]4)[CH2:17][CH2:16]3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][C:9]([CH3:35])([CH3:34])[CH2:8]1
Reactant: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5O)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
259 mg of 1-(1-(2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl)piperidin-4-yl)-N-methyl-1H-indole-6-carboxamide was dissolved in 5 ml of methanol. Thereafter, 60 mg of sodium borohydride was added to the reaction solution while cooling on ice. The obtained mixture was then stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) and then purified by silica gel column chromatography (ethyl acetate-methanol), so as to obtain 216 mg of the subject compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([CH2:23][CH2:24][OH:25])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2>N1C=CC=CC=1>[CH3:1][S:2]([O:25][CH2:24][CH2:23][C:9]1([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:4])=[O:3]
Reactant: OCCC1(CCO)c2ccccc2Oc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)c2ccccc2Oc2ccccc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 9,9-bis(2'-vinyloxyethyl)xanthene (57 g.) (prepared as in Example 2), water (400 ml.) and concentrated hydrochloric acid (15 ml.) is heated on the steambath with vigorous stirring for 5 hours. The cooled mixture is extracted three times with ether and the combined extracts are dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from chloroform-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-hydroxyethyl)xanthene, m.p. 144°-145° C. Methanesulphonyl chloride (588 mg.) is added dropwise over 5 minutes at 5° C. to a solution of 9,9-bis(2'-hydroxyethyl)xanthene (0.54 g.) in dry pyridine (5 ml.) with stirring. The mixture is allowed to stand at room temperature for 20 hours and is then poured into a mixture of 3N hydrocholoric acid (20 ml.) and ice (10 g.), and the resulting mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with 3N hydrochloric acid and water, dried over MgSO4, and evaporated to dryness. The solid residue is recrystallised from acetone-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-methanesulphonyloxyethyl)-xanthene, m.p. 121°-122° C.
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].O>C1COCC1>[O:12]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][N:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
n-Butyllithium (2.5 M in hexanes; 12.11 mL, 30.26 mmol) was added dropwise to a cooled (−78° C.) solution of piperidin-2-one (2.50 g, 25.22 mmol) in THF (100 mL). The mixture was stirred at −78° C. for 2.5 h. A solution of benzyl chloroformate (7.20 mL, 50.44 mmol) in THF (30 mL) was added dropwise. The mixture was stirred at −78 PC for 2 h and then was allowed to warm to rt. Water was added (200 and the mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated to dryness to afford 4.13 g (70%) of the desired product. ES-MS m/z 233.91 [M+H]+, HPLC RT (min) 2.76.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(#N)C.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 3-chloro-2-hydroxy-5-nitropyridine (36.0 g), acetonitrile (72 mL), and phosphorus oxychloride (37.5 g) was heated to 80° C. The reaction was then stirred at this temperature for about 15 hours. After cooling the reaction to 40° C., water (27 g) was added, while maintaining the temperature below 70° C. The temperature was adjusted to 45° C. and then more water (189 g) was added slowly. The reaction was then cooled to 23° C., stirred for at least 12 hours, and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/CDCl3) δ 9.10 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H)
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[N:10]([CH:12]=[N:13][N:14]=2)[CH:11]=1)C.C1C(=O)N(Br)C(=O)C1.[CH2:29]([NH:32][C:33]([NH2:35])=[S:34])[CH2:30][CH3:31]>O1CCOCC1.O>[C:15]1([C:8]2[C:9]3[N:10]([CH:12]=[N:13][N:14]=3)[CH:11]=[C:6]([C:5]3[S:34][C:33]([NH:32][CH2:29][CH2:30][CH3:31])=[N:35][CH:4]=3)[CH:7]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCNC(N)=S
Reactant: CCO/C=C\c1cc(-c2ccccc2)c2nncn2c1
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1ncc(-c2cc(-c3ccccc3)c3nncn3c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A solution of (Z)-6-(2-ethoxyvinyl)-8-phenyl-[1,2,4]triazolo[4,3-a]pyridine (13 mg, 0.049 mmol) in 1,4-dioxane (1 mL) and water (1 mL) was added NBS (9.4 mg, 0.054 mmol) and stirred at rt for 1 h. The mixture was then added 1-propylthiourea (6.4 mg, 0.054 mmol), heated to 85-90° C. for 10 h, then cooled and concentrated. The residue was dissolved in a mixture of 20% MeOH in dichloromethane and purified by 500 μm silica gel prep plate using 75% ethyl acetate in hexanes as an eluent. The product was collected (4.5 mg, 27.4% yield). LCMS: 336.55 (M+H), Tr 2.98 min, (Conditions A).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[C:27]([CH2:29][CH2:30][CH:31](O)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:28].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.CCOCC>[C:27]([CH2:29][CH2:30][CH:31]([O:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:28]
Reactant: Oc1cccnc1
Reactant: CCOC(=O)CCCC(O)CCC#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCCC(CCC#N)Oc1cccnc1
Reaction time: 0.08 h

Procedure:
To a mixture of triphenylphosphine (2.42 g, 9.2 mmol) and 3-hydroxypyridine (0.7 g, 7.3 mmol) in methylene chloride (20 ml) is added the ethyl 7-cyano-5-hydroxyheptanoate obtained above. The reaction mixture is stirred for 5 min and then diethyl azodicarboxylate (1.0 ml, 6.3 mmol) is added dropwise. The reaction mixture is stirred overnight and the solvent is evaporated. The residue is chromatographed on silica gel using ether as eluent to obtain an amber oil. The oil is dissolved in 10 ml ether, cooled to 0° and the precipitated triphenylphosphine oxide is filtered off. The filtrate is evaporated to give crude ethyl 7-cyano-5-(3-pyridyloxy)-heptanoate, IR (CH2Cl2): 2239, 1729, 1576, 1229, 1167, 1120 cm-1.