Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N+](C)(C)C)[N:4]=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])([O-:18])=[O:17].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[N:4]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C[N+](C)(C)c1nc(N)nc2nc[nH]c12
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1nc(Oc2ccccc2[N+](=O)[O-])c2[nH]cnc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(2-Aminopurin-6-yl)trimethylammonium chloride (see Example 1, Step 1; 2.08 g, 9.10 mmol) and o-nitrophenol (2.45 g, 17.63 mmol) were suspended in dry dimethylsulfoxide (25 ml) and triethylamine (5.5 ml) was added. This mixture was stirred at 75° under a refux condenser under N2 for 51/2 hours, then left at room temperature overnight. The reaction mixture was poured into ice-lN HCl (300 ml) and the mixture was extracted with ethyl ether (3×300 ml). The aqueous layer was neutralized by careful addition of solid NaHCO3 and then was extracted with ethyl acetate (3×300 ml). The organic phase was dried over MgSO4, l filtered and evaporated to dryness to give a yellow solid. This material was dissolved in hot ethyl acetate purified by chromatography on silica gel, using ethanol-ethyl acetate (1:9) followed by ethanol-ethyl acetate (15:85) as developing solvents. Chromatographically and spectroscopically pure material was obtained in essentially quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][C:10](=[C:12]1C(=O)O[C:15](C)([CH3:19])[O:14][C:13]1=[O:21])[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[CH2:15]([O:14][C:13](=[O:21])[CH2:12][C:10](=[O:11])[CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:22])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCC(O)=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Yield: 108 %

Procedure:
A stirred solution of [3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidene)-3-hydroxy-propyl]-carbamic acid tert-butyl ester (18.75 g, 50 mmol) in absolute ethanol (112 ml) was heated overnight at 70° C. The mixture was concentrated under reduced pressure to give 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (14 g, 98%) as a yellow oil which was used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:35]4[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(Br)cc3)nc(=O)c1-2
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: O
Solvent: CCO
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(-c4ccc(OC)cc4)cc3)nc(=O)c1-2
Yield: 59.3 %

Procedure:
To a stirred mixture of 100 mg (0.2 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-bromobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 38 mg (0.25 mmol) of 4-methoxyphenylboronic acid in 10 mL of toluene, 0.5 mL of EtOH, and 2 mL of 2 M Na2CO3 was added to 5 mg of Pd(Ph3P)4. The mixture was heated to reflux overnight, poured into water, and extracted with CHCl3. The organic extract was dried (MgSO4), filtered through celite, chromatographed (elution with 5% MeOH/CH2Cl2), and recrystallized to afford 64 mg (59%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(4-methoxyphenyl)benzyl) pyrazolo[3,4-d]pyrimidin-4-one as a pale brown powder, mp 275-277° C., Mass spec.: 537 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:16]([O-:18])=[O:17])[C:9]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: CN(C)CCCN
Solvent: Cc1ccccc1
Product: CN(C)CCCNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 13.5 h
Yield: 87.9 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (5.125 g) was added to 2,3-dichloronitrobenzene (3.841 g) and stirred for 13.5 hours at 125° C. The reaction mixture, with toluene added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (4.881 g) was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=1:0-50:1), thereby yielding the entitled compound (4.53 g) as reddish orange oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@H:17](O)[CH2:18][C@@H:19]([OH:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:21][C@@H:19]([CH3:20])[CH2:18][C@H:17]([CH3:16])[O:14]2)[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)C[C@H](C)O
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C[C@@H]1CN(Cc2ccccc2)CCC12O[C@@H](C)C[C@H](C)O2

Procedure:
To a solution of 1-benzyl-3-methylpiperidin-4-one (Acros, 62.09 g, 305.4 mmol) and (2S,4S)-pentane-2,4-diol (TCI-US, 34.06 g, 327.0 mmol) in benzene (800 mL) was added p-toluenesulfonic acid mono hydrate (69.72 g, 404.9 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux. The reaction mixture was cooled after 16 hours of reflux, concentrated to a total volume of about 500 mL and transferred to an Erlenmeyer flask with ethyl acetate. A sodium bicarbonate solution (500 mL) added with stirring and the mixture was further neutralized with solid Na2CO3 (35 g). The layers were partitioned, the organic phase washed with sodium bicarbonate, dried (Na2SO4) and concentrated to yield approximately 95 g of crude material. The residue was purified in 15 g batches by silica gel chromatography (Analogix SF-65-600 g; 35 micron silica; elution with 10% ethyl acetate-hexane) at 50 mL/min to provide 42.33 g of the first eluting isomer, (2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane. 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.19 (m, 5H), 4.07-3.86 (m, 2H), 3.40 (ABq, 2H, JAB=13.5 Hz, δνAB=23.3 Hz), 2.41-2.20 (m, 4H), 1.90-1.76 (m, 2H), 1.59-1.47 (m, 3H), 1.12 (d, 3H, J=6.4 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.90 (d, 3H, J=7.1 Hz); MS (DCI/NH3) m/e 290 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[I:32][CH2:33][O:34][C:35](=[O:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>ClCCl>[I-:32].[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N+:13]([CH2:33][O:34][C:35](=[O:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CCCCCCCCCCCC(=O)OCI
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[N+]1(CCCCOc2ccc3ccc(=O)[nH]c3c2)CCN(c2cccc3sccc23)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (0.85 g) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added iodomethyldodecanoate (1 g) synthesized in the same manner as in Reference Example 19, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, ether was added and the mixture was left standing. The obtained crystals were collected by filtration to give 4-(benzo[b]thiophen-4-yl)-1-(dodecanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)piperazin-1-ium iodide (1.07 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:31])([F:30])[F:29])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:22])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.95 (M+H+); retention time=1.05 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)cc1OC

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 3,4-dimethoxyphenyl boronic acid (182 mg, 1.0 mmol) to afford after chromatographic purification the title compound (92 mg, 42%). 1H NMR (CDCl3, 300 MHz) δ 7.15 (s, 1H), 7.11 (s, 1H), 7.01-7.04 (m, 2H), 6.89 (d, 1H, J=8.0 Hz), 4.02-4.10 (m, 1H), 3.92 (d, 6H, J=8.1 Hz), 3.64-3.78 (m, 1H), 2.82-3.52 (m, 8H), 1.82-1.90 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 437 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[O:14])=[O:7]
Reactant: NCc1ccncc1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2ccncc2)c1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (68 mg, 0.2 mmol), 4-aminomethyl pyridine (0.024 ml, 0.24 mmol) in DMF 3.0 mL was added EDC (57.5 mg, 0.3 mmol), HOBt (40.6 mg, 0.3 mmol) and DIPEA (0.052 ml, 0.3 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-pyridine-4-ylmethyl-benzamide as a white solid (60.6 mg, 70% yield).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:18]1([CH3:26])[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=1>C1COCC1>[C:1]1([C:7]2([CH:24]([C:20]3[CH:19]=[C:18]([CH3:26])[CH:23]=[CH:22][CH:21]=3)[OH:25])[S:8][CH2:9][CH2:10][CH2:11][S:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(C=O)c1
Reactant: c1ccc(C2SCCCS2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(O)C2(c3ccccc3)SCCCS2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
2-Phenyl-[1,3]dithiane (JYC-II-051-A) (10.0 g, 50.9 mmol) in 100 mL of anhydrous THF w a s cooled down to −78° C. nBuLi (22.4 mL of 2.5 M solution in hexanes, 56 mmol) was added dropwise and the mixture was stirred at −78° C. for 1 h. A solution of m-tolualdehyde (6.12 g, 50.9 mmol) in anhydrous THF was added to the mixture dropwise via a cannula at −78° C. under N2 counterflow. The reaction was then warmed up to room temperature and stirred at room temperature overnight. The mixture was quenched with a saturated NH4Cl aqueous solution. The organic phase was washed with H2O and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give brown oil. The product was purified by column chromatography (silica gel, hexanes:dichloromethane=1:2 (v/v)) to give light yellow oil (12.35 g, 76.6%). 1H NMR (300 MHz, CDCl3, δ): 7.66-7.70 (m, 2H), 7.25-7.33 (m, 3H), 6.98-7.02 (m, 2H), 6.64-6.68 (m, 1H), 6.56 (s, 1H), 4.94 (s, 1H), 2.86 (br s, 1H), 2.58-2.76 (m, 4H), 2.16 (s, 3H), 1.86-1.95 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, δ): 136.90, 136.74, 135.67, 130.14, 128.43, 128.06, 127.41, 126.86, 126.20, 124.80, 80.39, 65.90, 26.85, 26.62, 24.42, 21.04. HRMS-EI (m/z): [M]+ calcd for C18H20OS2, 316.09556; found, 316.09640.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[N:11]2)[CH:5]=1.S(Cl)([Cl:22])(=O)=O>C(Cl)Cl>[Cl:22][C:5]1[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]#[N:17])[CH:12]=[N:11]2)=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c(C#N)cnn1-c1cc(OC(F)F)n(C)n1
Solvent: ClCCl
Product: Cc1c(C#N)cnn1-c1nn(C)c(OC(F)F)c1Cl
Reaction time: 1 h

Procedure:
0.57 g (2.25 mmol) 1-(5-Difluoromethoxy-1-methyl-3-pyrazolyl)-5-methyl-4-pyrazolecarbonitrile was dissolved in 30 ml methylene chloride and at room temperature was treated with 0.30 g (2.25 mmol) sulfuryl chloride. The mixture was stirred for one hour and then concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][N:11]([CH3:24])[C:12]1(C#N)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1.[Cl-].[NH4+].[Cl:27][Si](C)(C)C>C1COCC1.O>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]([C:12]2([N:11]([CH3:24])[CH3:10])[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(F)c2)CCC2(CC1)OCCO2
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
0.5 M 3-fluorophenylmagnesium bromide solution in THF (3, 750 ml, 375 mmol) was added to a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (19.8 g, 94 mmol) in THF (100 ml) in the course of 15 min, under argon and while cooling with ice, and the mixture was then stirred at room temperature for 16 h. For working up of the reaction mixture, saturated ammonium chloride solution (150 ml) and water (60 ml) was added, while cooling with ice, and the mixture was extracted with diethyl ether (3×100 ml). The organic phase was extracted by shaking with water (50 ml) and saturated NaCl solution (50 ml) and the extract was concentrated. A brown oil (26.5 g) remained which, apart from the phenyl compound 4, still contained the ketal 2. The crude product was dissolved in ethyl methyl ketone (156 ml), and ClSiMe3 (17.8 ml, 141 mmol) was added, while cooling with ice. After a reaction time of 6 h, it was possible to isolate the hydrochloride in a yield of 55% (16.3 g) as a white solid with a melting point of 275-278° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[PH2:11]([OH:13])=[O:12]>>[OH:10][C:8]([P:11]([OH:13])[OH:12])([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:9]
Reactant: O=[PH2]O
Reactant: CC(=O)c1ccc(C)cc1
Product: Cc1ccc(C(C)(O)P(O)O)cc1
Temperature: 0 °C

Procedure:
A mixture of p-methylacetophenone (2.68 g. 0.02M) and hypophosphorous acid (90%, 1.45 g. 0.02M) is heated on a steam bath for 12 hours. The reaction mixture is poured into ice-water and the organic material is extracted with ethyl acetate. Evaporation and co-evaporation with toluene gives a white solid which is crystallised from chloroform/hexane. There is obtained 1-hydroxy-1-p-tolylethylphosphonous acid, m.p. 115° C.
Reaction SMILES: [CH3:1][N:2]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[N:3]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl.[CH:35]1([NH2:38])[CH2:37][CH2:36]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH:35]1([NH:38][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][N:3]([C:4]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:5])[N:2]([CH3:1])[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[CH:16][CH:17]=2)[CH2:37][CH2:36]1
Reactant: NC1CC1
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)NC2CC2)cc1)C(=O)OCc1ccccc1

Procedure:
16.5 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)methyl]-benzoyl chloride were added to 100 ml. of absolute benzene and treated with 3.1 g. of cyclopropylamine hydrochloride. 7.5 g. of triethylamine and 50 ml. of benzene were then dropped into the reaction mixture at 20°-30° with stirring. The reaction mixture was worked up as in Example 3, yielding 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoic acid cyclopropylamide, the carbobenzoxy groups of which were then removed by treatment with hydrogen bromide/glacial acetic acid. The product, 4-[(2-methyl-hydrazino)-methyl]-benzoic acid cyclopropylamide hydrobromide, melted at 180°-182°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1cc(F)cc(F)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-1-(3,5-difluoro-phenyl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (EI): m/z=429 ([M]+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[Br:38]C1C=C(Cl)C=CC=1C1NC2C=CC=CC=2N=1.BrCC1CCCCC1>>[Br:38][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=2[N:9]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)c(Br)c1
Agent: BrCC1CCCCC1
Product: Clc1ccc(-c2nc3ccccc3n2CC2CCCCC2)c(Br)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-4-chloro-phenyl)-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Colorless solid (95%). MS (Turbo Spray): m/z=404.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].COC1C=C(C=C(OC)C=1OC)C=O.C[Si]([C:36]1[NH:41][C:40](=[O:42])[N:39]([Si](C)(C)C)[C:38](=[O:47])[C:37]=1[F:48])(C)C.FC1C(=O)NC(=O)NC=1>ClCCl.C(O)CO>[OH:14][CH2:15][CH2:16][O:17][CH:13]([N:41]1[CH:36]=[C:37]([F:48])[C:38](=[O:47])[NH:39][C:40]1=[O:42])[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C2OCCO2)cc(OC)c1OC
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Agent: COc1cc(C=O)cc(OC)c1OC
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: ClCCl
Solvent: OCCO
Product: COc1cc(C(OCCO)n2cc(F)c(=O)[nH]c2=O)cc(OC)c1OC

Procedure:
2-(3,4,5-Trimethoxyphenyl)-1,3-dioxolan (20.3 g) prepared from 3,4,5-trimethoxybenzaldehyde and ethylene glycol was dissolved in dichloromethane (50 ml). To the solution bis(trimethylsilyl)-5-fluorouracil prepared from 5-fluorouracil (10 g) was added and treated as in Example 10 to give 7.2 g of crystalline 1-[α-(2-hydroxyethoxy)-3,4,5-trimethoxybenzyl]-5-fluorouracil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[C:9]([O:13][C:14](=[O:28])[NH:15][C@@H:16]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17]O)([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:9]([O:13][C:14](=[O:28])[NH:15][C@@H:16]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(C)(C)O[SiH2]C(C)(C)C
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(Br)c1)C(C)(C)O[SiH2]C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A 100 mL RBF was charged with 3-bromo-5-hydroxypyridine (1.20 g, 6.87 mmol), (R)-[1-(tert-butyl-dimethyl-silanyloxymethyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (2.1 g, 6.87 mmol) and Ph3P (2.34 g, 8.93 mmol), and was purged with nitrogen. THF (30 mL) was added at 0° C. After stirring at 0° C. for 10 min, DEAD (1.41 mL, 8.93 mmol) was added via syringe. The reaction mixture was stirred at 0° C. for 0.5 h and at rt for 2 h. The reaction mixture was concentrated and the residue was separated by flash chromatography (5-25% EtOAc in hexane) to provide the desired product (3.14 g, 99%). MS (DCI) m/z 461, 463 (M+1)+.