Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([NH:18][CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1.04 mL (1.0 mmol) of cyclohexanone and 1.6 g (1.0 mmol) of N-(2-t-butoxycarbonylaminoeth-1-yl)amine in 24 mL of tetrahydrofuran were added 0.71 mL (1.2 mmol) of acetic acid and 2.97 g (1.4 mmol) of sodium triacetoxyborohydride. The reaction stirred at room temperature for 20 hr then saturated sodium bicarbonate (12 mL) was added and the mixture extracted with ethyl acetate (12 mL). The organic phase was washed with more saturated sodium bicarbonate (12 mL) and brine (12 mL). At this point a crystalline precipitate formed which was filtered off and washed with water and ethyl acetate to leave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cncc(OCc2ccccc2)c1
Yield: 34.7 %

Procedure:
To a suspension of 5-bromo-pyridin-3-ol (1.9 g, 10.9 mmol) in acetonitrile (152 mL) is added bromomethyl-benzene (2.1 g, 12.0 mmol) and potassium carbonate (4.5 g, 32.8 mmol). The resultant mixture is stirred at room temperature for 16 h. The crude product is purified by silica gel column to afford 3-benzyloxy-5-bromo-pyridine (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[NH:9][CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:32][O:31][CH2:29][CH3:30])[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOC(=O)c1c[nH]c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cc(C(=O)OCC)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Temperature: 15 °C
Reaction time: 5 h

Procedure:
A suspension of 6 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 5.16 g of potassium carbonate in 120 cm3 of dimethylformamide is heated at a temperature close to 110° C. for 1 hour. After cooling to about 15° C., 5.44 cm3 of chloromethyl ethyl ether are added and the mixture is stirred for 5 hours at between 15° and 20° C. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at about 60° C. The residue is taken up in 3 times 150 cm3 of trichloromethane. The combined organic extracts are filtered in order to remove the insoluble matter. The filtrate is dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at about 40° C. The residue is recrystallized from 55 cm3 of dimethylformamide. 5.6 g of 8-chloro-3 -ethoxycarbonyl-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a beige solid melting at 261° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:42][O:41][C:38]1[CH:37]=[N:36][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[N:40][CH:39]=1
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Reactant: COc1cnc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(OC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 55.2 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (89 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methoxy-pyrimidine (92 mg) were added and the mixture was heated to 75° C. for 46 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give ethanesulfonic acid [6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (61 mg) as a white powder. LC-MS: tR: 3.87, [M−H]+: 554.02.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: O=C(CO)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:29]2[CH2:34][CH2:33][N:32]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1CC(N2CCNCC2)C1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C4CCC4)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclobutylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.71 (m, 2 H) 1.76-1.90 (m, 2 H) 1.90-2.07 (m, 2 H) 2.37 (br. s., 4 H) 2.42 (s, 3 H) 2.83 (quin, J=7.71 Hz, 1 H) 3.44 (d, J=7.07 Hz, 2 H) 3.64 (br. s., 2 H) 7.63 (dd, J=7.96, 1.64 Hz, 1 H) 7.69 (s, 1 H) 7.84 (d, J=8.08 Hz, 1 H) 8.03 (dd, J=8.59, 2.27 Hz, 1 H) 8.11 (s, 1 H) 8.40 (d, J=8.59 Hz, 1 H) 8.52 (dd, J=2.27, 0.76 Hz, 1 H); ESI-MS m/z [M+H]+ 443.3.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]C)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:21][NH2:22])=[O:18])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(CCC(=O)OC)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(CCC(=O)NN)cc1

Procedure:
To a solution of methyl 3-(4-n-hexyloxyphenyl)propionate (1.18 g) in ethanol (10 ml) was added hydrazine monohydrate (1.08 ml) and the mixture was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure. Water was added and the precipitate was collected by filtration, washed with water and dried under reduced pressure to give 3-(4-n-hexyloxyphenyl)propionohydrazide (0.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH3:16])[C:13](Cl)=O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][N:10]=[C:11]2[CH:12]([CH3:16])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCCc1ccc(Br)cc1
Product: CC(C)C1=NCCc2ccc(Br)cc21

Procedure:
The desired product was prepared from 2-(4-bromophenyl)ethylamine and 2-methylpropanoyl chloride according to the procedure described in J. Org. Chem. 1991, 56, 6034.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br.O>ClCCl>[Br:16][C:9]1[C:2]([CH3:1])=[C:3]([CH:6]=[C:7]([CH3:11])[C:8]=1[CH3:10])[CH:4]=[O:5]
Reactant: BrBr
Reactant: Cc1cc(C)c(C=O)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C=O)c(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a solution of 2,4,5-trimethylbenzaldehyde (21.3 g, 144 mmol) in dichloromethane (200 mL) was added aluminum chloride (48.0 g, 360 mmol) with ice-cooling, and the mixture was warmed to room temperature. Bromine (7.80 mL, 151 mmol) was added dropwised to the reaction solution at room temperature, the mixture was stirred for 4 hours, water was added to the reaction solution, and dichloromethane was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water, a saturated sodium hydrogen carbonate solution, 5% sodium sulfite aqueous solution, water and a saturated brine. The organic layer was dried over anhydrous sodium sulfate and then was concentrated under reduced pressure to obtain 32.5 g (yield 100%) of the title compound. Melting point: 108-110° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[C:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[CH:20]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])C1C=CC=CC=1.FC(F)(F)C(O)=O>O>[C:27]1(=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[CH:20]=2)[C:15]2[CH:14]=[CH:13][C:12]([S:9]([NH2:8])(=[O:10])=[O:11])=[CH:17][CH:16]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1ccc(C(=C2CCCC2)c2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(C(=C2CCCC2)c2ccc(S(N)(=O)=O)cc2)cc1F
Temperature: 60 °C
Yield: 70.2 %

Procedure:
A solution of 6.5 g of N,N-dibenzyl-4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulfonamide, prepared in Example 10, in ml of trifluoroacetic acid is heated for 10 hours at 60° C. The mixture is poured into iced water and extracted with dichloromethane. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel in a dichloromethane/acetone mixture (95/5) to give 3 g of 4-[(cyclopentylidene)(3-fluoro-4-methylphenyl)methyl]benzenesulfonamide in the form of a semicrystalline oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].Br[C:19]1[C:20]([F:30])=[C:21]([CH:24]=[C:25]([F:29])[C:26]=1[O:27][CH3:28])[CH:22]=[O:23]>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:19]3[C:20]([F:30])=[C:21]([CH:24]=[C:25]([F:29])[C:26]=3[O:27][CH3:28])[CH:22]=[O:23])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Reactant: COc1c(F)cc(C=O)c(F)c1Br
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3c(F)c(C=O)cc(F)c3OC)cc21
Yield: 14 %

Procedure:
The intermediate 3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-difluoro-4-methoxy-benzaldehyde was prepared in a similar manner to example 7a using 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example 2b) and 3-bromo-2,5-difluoro-4-methoxy benzaldehyde. 14% yield. 1H NMR (300 MHz; CDCl3): 1.21 (t, J=6.9 Hz, 3 H), 1.32 (s, 3 H), 1.33 (s, 3 H), 2.13 (s, 3 H), 2.53 (s, 2 H), 3.81 (2 s, 3 H), 4.02 (q, J=6.9 Hz, 1 H), 6.81 (s, 1 H), 7.23 (s, 1 H), 7.68 (dd, J1=6.3 Hz, J2=11.7 Hz, 1 H), 10.25 (2 s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>O1CCCC1.[NH4+].[Cl-]>[CH:11]([C@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@H:7]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][C:20]([F:19])([F:30])[F:31])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@H](Cc2ccccc2OC(F)(F)F)C(OC)=N[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (7.2 g, 39.4 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. A solution of n-butyllithium in hexanes (2.5 M, 18.9 mL, 47.2 mmol) was added dropwise, and stirring was continued for 15 minutes. 2-Trifluoromethoxybenzyl bromide (10.0 g, 39.4 mmol) was added, and the resulting mixture was maintained at −78° C. for 30 minutes, then allowed to slowly warm to room temperature. The reaction was then diluted with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (100% hexanes) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([NH:10][O:11][CH3:12])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][O:11][N:10]=[C:8]([Cl:23])[C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[O:5][CH2:4][C:3]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=1[Cl:1]
Reactant: CONC(=O)c1ccccc1OCc1ccc(Cl)cc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON=C(Cl)c1ccccc1OCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
2-(2,4-Dichlorobenzyloxy)-N-methoxybenzamide (10.44 g) was dissolved in dry methylene chloride (100 ml), phosphorus pentachloride (6.66 g) was added under ice-cooling over about 3 minutes to the solution, and the mixture was stirred at 0° C. for 1 hour. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate (150 ml) was added slowly, and the mixture was extracted with methylene chloride (150 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give α-chloro-2-(2,4-dichlorobenzyloxy)benzaldehyde O-methyloxime (9.52 g) as crystals. A part of the crystals was recrystallized from ethyl acetate/n-hexane to give colorless crystals. mp 91°-92° C.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17](=[O:20])(O)[O-].[Na+]>C(O)CCC>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:7][CH2:9][CH2:10][C:17](=[O:20])[C:3]3[CH:16]=[CH:15][C:6]([Cl:1])=[CH:5][CH:4]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C([O-])O
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: O=C(CCCN1CCC(C(=O)c2ccc(Cl)cc2)CC1)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 4-(p-chlorobenzoyl)piperidine hydrochloride (10.5 g.; 0.04 mole), 2-(p-chlorophenyl)-2-(ω-chloropropyl)-1,3-dioxolane (10.5 g.; 0.04 mole) and sodium bicarbonate (13.5 g.; 0.16 mole) of n-butanol was refluxed for twenty hours. The hot mixture was filtered, the filtrate was concentrated at reduced pressure and the residual material was dissolved in a mixture of ethanol and 6N hydrochloric acid. The mixture was stirred 0.5 hour and hydrochloride salt which separated was collected by filtration. The salt was recrystallized from isopropanol-methanol (charcoal) to give 9.2 g. (57%) of the hydrochloride salt which melted at 253°-256° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].Cl[CH2:16][S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCl
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Temperature: -78 °C
Yield: 88.3 %

Procedure:
A mixture of 2-(2-chloroethoxy)-4-fluoro-1-nitro-benzene (1.3 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) in THF, under nitrogen, was stirred at −78° C., treated dropwise with a solution of 1M potassium t-butoxide (18 ml, 18 mmoles) over a 30 min. period, allowed to warm to −40° C., stirred at −40° C. for 5 hours, poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum. The resultant residue was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2.25 g, 5.3 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O-]CC.[Na+].[Na].CI>C(O)C>[C:7]([OH:9])(=[O:8])[C:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:5]1[CH:18]=[CH:19][CH:2]=[CH:3][CH:4]=1)[OH:10]
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CCO
Product: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid is added to freshly prepared sodium ethoxide solution containing 2.17 g (0.095 mol) of sodium and 200 ml of ethanol at 20° C. and stirred for 3 hours. The solution is evaporated to dryness, the residue is dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide is added dropwise at 20° C., and the mixture is stirred for 24 hours. It is worked up and purified analogously to compound 12b. Yield: 21.06 g (80% of theory).
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].[BrH:18]>O.O1CCOCC1.[Cu]Br>[Br:18][C:6]1[CH:8]=[C:2]([F:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Br
Reactant: COc1cc([N+](=O)[O-])c(N)cc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
5-Fluoro-4-methoxy-2-nitroaniline obtained in Reference Example 14 (4.1 g) was dissolved in a mixed solvent of water (20 ml) and 1,4-dioxane (10 ml), 48% hydrobromic acid (12 ml) was added to the solution under refluxing, and then the mixture was refluxed for 15 minutes. The reaction mixture was cooled to 0° C., sodium nitrite was added dropwise thereto, and the mixture was stirred at 0° C. for 15 minutes. The resulting mixture was added dropwise to a solution of copper (I) bromide (3.6 g) in a mixture of water (20 ml) and 48% hydrobromic acid (12 ml) at 0° C. The mixture was stirred at 60° C. for 15 minutes, cooled to room temperature, and further stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (developing solvent:ethyl acetate-hexane=1:8) to obtain the title compound as crystals (5 g, 91%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].C1C=CC(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:32]([CH2:13][C:12]1[N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[C:4]([F:17])[CH:5]=2)[CH:9]=[N:10][CH:11]=1)=[N+:33]=[N-:34]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc(Cn2cncc2CN=[N+]=[N-])cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-cyano-3-fluorobenzyl)-5-(hydroxymethyl)imidazole, as described above in Example 4, Step F, (103 mg, 0.45 mmol) in dry THF (1 mL), at 0° C., under argon, were added DPPA (147 mg, 0.53 mmol) then DBU (75 mg, 0.49 mmol). The mixture was allowed to warm to ambient temperature and then stirred for 3 hrs. The mixture was then partitioned between H2O (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CHCl3-1% MeOH −0.1% NH4OH to CHCl3-5% MeOH −0.5% NH4OH, to yield the titled product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of hexaethylene glycol monobenzyl ether from above (22.3 g) in anhydrous THF (100 ml) was added to a suspension of 50% NaH (3.5 g) in anhydrous THF (100 ml). The suspension was stirred at ambient temperature for 30 min and then a solution of triethylene glycol methyl tosyl ether from above (22.0 g) in THF (100 ml) was added dropwise. The mixture was refluxed under nitrogen overnight, cooled to ambient temperature, quenched with water (500 ml), and extracted with diethyl ether (3×300 ml). The ether extracts were combined, dried (sodium sulfate), and concentrated in vacuo to give nonaethylene glycol benzyl methyl ether as an oil (27 g, 88%), 1H-NMR (CDCl3) δ: 7.31 (m, 5, 5 phenyl CH), 4.54 (s, 2, benzyl CH2), 3.62-3.52 (m, 36, 18 CH2O), 3.35 (s, 3, CH3).