Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C(COC)[C:10](OC)=[O:11])C=C(Cl)C=1.S(=O)(=O)(O)O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[O:26][C:27](=[CH2:31])[C:28]([OH:30])=[O:29]>[OH-].[Na+].O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[O:26][CH:27]([CH2:31][O:11][CH3:10])[C:28]([OH:30])=[O:29]
Reactant: COCC(C(=O)OC)c1cc(Cl)cc(Cl)c1
Reactant: C=C(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O

Procedure:
An emulsion of methyl 2-(3,5-dichlorophenyl)-3-methoxypropionate in sodium hydroxide (0.14 g) and water (2 ml) was stirred at ambient temperature for 2 hours when a clear solution was produced. The mixture was acidified with concentrated sulphuric acid (0.34 g), diluted with water then extracted with diethyl ether. The organic phase was separated, extracted with aqueous sodium hydrogen carbonate and the organic phase discarded. The basic aqueous extract was acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract was dried over magnesium sulphate and evaporated under reduced pressure to give a colourless oil, 0.50 g, containing a mixture of the required product and 2-(3,5-dichlorophenoxy)-acrylic acid in the ratio 2:1, which was used in the next Stage without further purification. 2-(3,5-Dichlorophenoxy)-3-methoxypropionic acid was characterised from its NMR spectrum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].N1C=CC=CC=1>C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([O:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:22])[CH:15]=2)=[O:12])=[CH:2]1
Reactant: Cc1cccc(O)c1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1cccc(OC(=O)C(=O)c2c[nH]c3ccccc23)c1
Reaction time: 0.5 h

Procedure:
3-Indolylglyoxylyl chloride (104 g. ) was stirred in diethyl ether (500 ml.) and treated with m-cresol (108 g.) followed by pyridine (79 g.). After stirring for 30 minutes the solid product was collected by filtration, washed with water then with acetonitrile and dried to give m-cresyl 3-indolylglyoxylate as a yellow powder, m.p. 194°-197°. Yield 119 g. (85.5%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14](OC(F)(F)F)=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].BrC1C(O)=C(C=C(C(C)(C)C)C=1)C=O.[F:39][C:40]([F:51])([F:50])C1C=CC(B(O)O)=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:40]([F:51])([F:50])[F:39])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 4-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-:3])=[O:2].[BH4-].[Na+].CC(C)=O.[NH4+].[Cl-]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-:3])=[O:2]
Reactant: CCOC(=O)C(=O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CO
Product: CCOC(=O)C(O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(2,6-dinitrophenyl)-2-oxopropanoate (3.16 g, 11.2 mmol) is dissolved in dry methanol and cooled to 0° C. Sodium borohydride (0.13 g, 3.36 mmol) is added at 0° C. and stirring continued at 0° C. for 30 min. The mixture is warmed to room temperature and stirred for another 15 min. Acetone (10 ml) is added and subsequently of saturated aq. NH4Cl (5 ml) is added. The solvent is evaporated in vacuo, the remainder is dissolved in ethyl acetate and water, the organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product is purified with column chromatography on silica gel (eluent: cyclohexane/ethyl acetate, 1:1). Yield: 1.43 g (44%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH:9]([CH2:10][C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:8]1>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH:9]([OH:7])[CH2:10][C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:17])[F:16])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CC1CO1
Product: OC(CN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 10 h
Yield: 93.2 %

Procedure:
To 8.7 g of morpholine, 27.6 g of 1,2-epoxy-4,4,5,5,6,6,7,7,7-nonafluoroheptane was added dropwise. The mixture was then stirred at 80° C. for 10 hours. The reaction mixture was directly purified by silica gel column chromatography, obtaining 33.8 g of 1-morpholino-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptanol (yield 93%).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[Br-].[CH:15]1([Zn+])[CH2:17][CH2:16]1.C(OCC)(=O)C.O>C1COCC1.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>[CH:15]1([C:2]2[C:11]([F:12])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]3)=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: Cc1ccc2ccc(Br)c(F)c2n1
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2ccc(C3CC3)c(F)c2n1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A solution of 7-bromo-8-fluoro-2-methylquinoline (0.15 g, 0.63 mmol), Pd(PPh3)4 (0.072 g, 0.063 mmol) and 0.5 M cyclopropylzinc(II) bromide (2.50 ml, 1.25 mmol) in THF was stirred at reflux for 12 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1) to give 7-cyclopropyl-8-fluoro-2-methylquinoline (0.10 g, 80.3%) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18]O)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:52][N:53](C(C)C)[CH:54](C)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][N:53]([CH3:54])[CH3:52])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of Intermediate 186c (293 mg, 0.44 mmol) and DIPEA (304 μL, 1.76 mmol) in DCM (10 mL) was added methanesulfonyl chloride (103 μL, 1.33 mmol). The reaction mixture was stirred at RT for 1 hour. The mixture was concentrated in vacuo. The residue was taken up in THF (2 mL) and dimethylamine solution in THF (2M, 3.3 mL) was added. The reaction mixture was heated at 60° C. in a sealed tube for 72 h. The reaction mixture was cooled to RT and concentrated in vacuo. The product was purified by HPLC using a gemini C18 column and using a gradient of 20-35%+0.1% Formic acid over 10 minutes. The combined fractions were evaporated under reduced pressure and crystallised by MeCN/Et2O to afford the title compound as a white solid (90 mg, 30%). LCMS (Method 3): Rt 3.01 min, m/z 706 [MH+]. 1H NMR (300 MHz, d6-DMSO): 0.91 (3H, d, J=6.7 Hz), 1.23 (9H, s), 1.46-1.54 (2H, m), 1.63-1.72 (2H, m), 1.75-1.76 (2H, m), 2.00-2.18 (2H, m), 2.43 (6H, s), 2.66 (2H, t, J=5.8 Hz), 2.85-2.95 (2H, m), 3.12-3.20 (4H, m), 4.10 (2H, t, J=5.4 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (2H, m), 7.06-7.14 (2H, m), 7.19 (1H, dd, J=10.0 Hz), 7.25-7.32 (3H, m), 7.33-7.42 (2H, m), 7.58 (1H, d, J=10.6 Hz), 7.63 (1H, d, J=1.8 Hz), 8.17 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][C:22](=[O:24])[CH3:23])[CH:3]=1.[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][CH:22]([OH:24])[CH3:23])[CH:3]=1
Reactant: CC(=O)COc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)COc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2

Procedure:
The product from Example 75 is treated with sodium borohydride in absolute ethanol at reflux to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)=[O:24])[CH:22]=1)[O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1.O>[OH:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)=[O:24])[CH:22]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3cc[nH]n3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
A solution of ethyl 4-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[(1H-pyrazol-3-ylamino)carbonyl]phenoxy}benzoate (175 mg, 0.4 mmol) in THF (5 mL) and water (1 mL) was treated with 1N sodium hydroxide solution (3 mL) and the reaction stirred at RT for 16 hours. On completion, the solvent was removed in vacuo and 1N citric acid added until pH 3-4. The white precipitate was collected by filtration and dried in vacuo to give the desired product as a white solid (138 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]3OCC[O:19]3)[C:15]([F:23])=[CH:14][N:13]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:24].Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=[O:19])[C:15]([F:23])=[CH:14][N:13]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:24]
Reactant: CC[C@@H](Nc1cc(C2OCCO2)c(F)cn1)c1ccc(Cl)c(C)c1
Agent: Br
Solvent: C1CCOC1
Product: CC[C@@H](Nc1cc(C=O)c(F)cn1)c1ccc(Cl)c(C)c1
Temperature: 70 °C

Procedure:
INT 45 (500 mg, 1.43 mmol) was dissolved in THF (20 mL) and HBr (33% in AcOH, 15 eq) was added. The resulting mixture was stirred at 70° C. until completion of the reaction. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (cyclohexane/EtOAc) to give INT 46.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1.[Cl-].[NH4+]>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(Cl)Cl.C(OCC)C>[F:37][C:38]1[CH:45]=[CH:44][C:41]([C:42](=[O:43])[CH:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC(=O)OC(C)(C)C)c2cccc3cccnc23)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(F)cc1)c1cccc2cccnc12
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
5.5 g (13 mmol) of tert-butyl [quinolin-8-yl(toluene-4-sulfonyl)methyl]carbamate, 336 mg (1.3 mmol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, 27 ml (200 mmol) of triethylamine and 3.9 g (13 mmol) of 4-fluorobenzaldehyde were mixed in 115 ml of methylene chloride at room temperature and then heated at 35° C. for 3 h. After reaction of the aldehyde was complete, 50 ml of saturated ammonium chloride solution were added, and the reaction mixture was stirred for 10 minutes. After removal of the aqueous phase, the organic phase was washed with 0.5 M sodium hydroxide solution and saturated sodium chloride solution. Drying of the organic phase over magnesium sulfate and concentration resulted in a semisolid residue which was stirred with 50 ml of diethyl ether. Filtration of the solid residue by suction resulted in 3.2 g of tert-butyl [2-(4-fluorophenyl)-2-oxo-1-quinolin-8-ylethyl]carbamate.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]([OH:37])[CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:38])[CH:10]=1)C1C=CC=CC=1.[H][H]>CN(C=O)C.[Pd]>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH:21]([OH:37])[CH2:20][O:19][C:15]3[CH:14]=[C:13]4[C:18]([C:9]([OH:8])=[CH:10][C:11](=[O:38])[O:12]4)=[CH:17][CH:16]=3)[CH2:24][CH2:25]2)=[CH:35][CH:34]=1
Reactant: [H][H]
Reactant: O=c1cc(OCc2ccccc2)c2ccc(OCC(O)CN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1cc(O)c2ccc(OCC(O)CN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Yield: 61.8 %

Procedure:
A solution of 1-[3-(4-benzyloxycoumarin-7-yloxy)-2-hydroxypropyl]-4-(4-chlorobenzyl)piperazine (7 g) in dry DMF (80 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst till one equivalent of hydrogen was absorbed. Filtration and evaporation of the solvent in vacuo afforded an oily product which crystallized from ethanol/petrol to give 3.60 g (63%) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][NH2:13]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:12][NH2:13]
Reactant: NN
Reactant: Oc1ccc2ccccc2c1
Product: NNc1ccc2ccccc2c1
Temperature: 85 °C
Reaction time: 100 h

Procedure:
57.6 g (0.4 mol) of 2-naphthol and 200 ml of hydrazine (4 mol) are introduced into a 500 ml autoclave. The mixture is stirred at 85° C. at a pressure of 60 bar for approximately 100 hours. The reaction medium is subsequently extracted with dichloromethane. The organic phase is washed with 10% sodium hydroxide, then with water and finally with brine; it is dried over magnesium sulphate. After filtration and evaporation under vacuum, 50.6 g (80%) of product are obtained, the melting point of which is 124° C. (alcohol/water).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[C:21]3[O:20][C:19]([F:23])([F:22])[O:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[F:23][C:19]1([F:22])[O:18][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:6]3[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1](=[O:3])[CH:2]=[CH:26][N:27]([CH3:29])[CH3:28])=[N:5]3)[C:21]=2[O:20]1
Reactant: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)C=CN(C)C)c1=O
Yield: 74 %

Procedure:
A solution of 3-acetyl-1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxypyridazin-4(1H)-one (2.3 g, 7.1 mmol) in N,N-dimethylformamide dimethyl acetal (75 mL) was refluxed for 3 h. The mixture was concentrated under reduced pressure. The brown crystals were washed with AcOEt/hexane (1/1) to give the title compound (2.0 g, 74% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.94 (3H, s), 5.78 (1H, d, J=11.7 Hz), 7.10 (1H, dd, J=8.3, 1.1 Hz), 7.23 (1H, t, J=8.3 Hz), 7.63 (1H, d, J=8.7 Hz), 7.79 (1H, brs), 8.03 (1H, s).
Reaction SMILES: [CH3:1][CH:2](C[AlH]CC(C)C)[CH3:3].[Cl:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]CC)=O)[CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][CH:22]([OH:24])[CH:2]([CH3:3])[CH3:1])[CH2:19][CH2:20]1
Reactant: CCOC(=O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)C(O)CC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
DIBAL-H (6.9 ml, 10.35 mmol, 1.5 M in toluene) was added to a solution of ethyl [1-(3,4-dichlorobenzyl)piperidin-4-yl]acetate (1.9 g, 5.8 mmol) in dry toluene (60 ml) at −60° C. under nitrogen atmosphere. The reaction mixture was stirred at dry ice bath temperature for 0.5 h, quenched with saturated sodium bisulfite solution and then allowed to warm to room temperature. The aqueous layer was separated and basified with 2N sodium hydroxide to pH between 8-9 and the product was extracted with diethyl ether. The combined ether layers were washed with brine and dried over sodium sulfate. After concentration, the residue was dissolved in dry tetrahydrofuran (30 ml) and cooled to 0° C. Isopropyl magnesium chloride (2.0 M, 5.8 ml) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature. After 0.5 h, the reaction mixture was quenched with water and extracted with diethyl ether. The ether layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel column with 25% acetone, 25% dichloromethane in hexanes to give 1(RS)-[1-(3,4-dichlorobenzyl)piperidin-4-ylmethyl]-2-methylpropanol (0.75 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:13]2[O:15][CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A mixture of 4-nitrophenol (0.6 mole, 82.3 grams), epichlorohydrin (1.8 mole, 167 g.) and piperidene (3 ml.) is stirred at 100° C. for 17 hours. The solution is evaporated and to the residue is added sodium hydroxide (2 mole) in 500 ml. of water. After 24 hours of stirring, the solution is extracted with chloroform. After washing with dilute sodium hydroxide, the dried chloroform solution is evaporated yielding 3-(4-nitrophenyloxy)-1,2-epoxypropane. A solution of the epoxide (1.0 g.) in 50% aqueous acetic acid (15 ml.) is heated at 90° C. for five hours and then evaporated and chromatographed on silica acid plates (chloroform-methanol 9:1). The band with an Rf of about 0.5 is eluted and crystallized from chloroform and ethyl acetate to yield 1,2-dihydroxy-3-(4-nitrophenyloxy)-propane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-nitrobenzotrifluoride (2 g) and 1-methylpiperazine (2 mL) were dissolved in methanol (5 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic solutions were evaporated to give 2-(4-methylpiperazino)-5-nitrobenzotrifluoride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Si:22]([NH:9][CH:8]([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(N)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(N[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic 4-fluoro-α-methylbenzenemethanamine (2.95 g, 21.2 mmol) and triethylamine (4.3 mL, 30.9 mmol) in acetonitrile (75 mL) in a flame-dried flask under nitrogen was added dropwise t-butylchlorodiphenylsilane (5.5 mL, 21.1 mmol). The mixture was stirred at room temperature overnight and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in ether and washed sequentially with H2O, saturated NaHCO3 solution and brine. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave a clear oil which was distilled under high vacuum. The major fraction consisting of the pure title compound (3.8 g, 47%) distilled from 123° to 143° C. at 0.15 mm Hg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.