Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:13]([C:21]#[N:22])=[CH:12][N:11]=2)C=CC=CC=1.C(C1C=CC(NC([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][C:44]([CH:46]([O:49]C)OC)=[N:45][C:36]2=3)=O)=NC=1)#N.[CH3:51][N:52]([CH:54]=[O:55])[CH3:53]>>[C:21]([C:13]1[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:15][C:10]([NH:9][C:8]([N:35]2[C:36]3[C:37](=[CH:42][C:43]([CH2:51][N:52]4[CH2:53][CH2:53][N:52]([CH3:54])[CH2:51][C:54]4=[O:55])=[C:44]([CH:46]=[O:49])[N:45]=3)[CH2:38][CH2:39][C@@H:41]2[CH3:40])=[O:23])=[N:11][CH:12]=1)#[N:22]
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2
Product: COCCOc1cc(NC(=O)N2c3nc(C=O)c(CN4CCN(C)CC4=O)cc3CC[C@@H]2C)ncc1C#N

Procedure:
From intermediates 108 and 268, coupled and deprotected in an analogous manner to intermediate 236, but using DMF instead of THF, and Example 201. The title compound was obtained as a light yellow-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH3:12][N:13](C(=O)C(F)(F)F)[CH2:14][CH2:15][CH:16](OC(=O)C(F)(F)F)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][NH:13][CH3:12])=[CH:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2occc2c1
Reactant: CN(CCC(OC(=O)C(F)(F)F)c1ccccc1)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1cc2cc(OC)ccc2o1
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
5-methoxybenzofuran (0.48 g) and trifluoro-acetic acid 3-[methyl-(2,2,2-trifluoro-acetyl)-amino]-1-phenyl-propyl ester (0.48 g) were mixed and heated in a sealed tube at 110° C. for 90 minutes. Upon cooling, the reaction mixture was taken up in methanol and treated with excess 1N sodium hydroxide solution, sufficient to form a strongly basic solution. After stirring for 20 minutes, the reaction mixture was concentrated at reduced pressure to remove the bulk of the methanol. The resulting mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was evaporated to dryness. Purification by column chromatography (silica gel, dichloromethane (130):methanol (10):ammonium hydroxide (1)) followed by preparative tlc afforded [3-(5-Methoxy-benzofuran-2-yl)-3-phenyl-propyl]-methyl-amine (M+H=296) as the major component.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].[P:13]([O:18]C)([O:16][CH3:17])[O:14][CH3:15]>C(#N)C>[CH2:11]([O:10][C:8]([N:1]1[CH:6]=[CH:5][CH:4]([P:13]([O:16][CH3:17])(=[O:18])[O:14][CH3:15])[CH:3]=[CH:2]1)=[O:9])[CH3:12]
Reactant: COP(OC)OC
Reactant: CCOC(=O)Cl
Reactant: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)N1C=CC(P(=O)(OC)OC)C=C1
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of pyridine (316 g, 4.0 mol) in acetonitrile (4.0 L) was cooled to 0° C. and ethyl chloroformate (434 g, 4.0 mol) was added over about 1.25 hours while keeping the temperature less than 5° C. The resulting yellow suspension was stirred at −5° C. to 0° C. for 1.5 hours. It was then cooled to −25° C. and trimethyl phosphite (496.3 g, 4.0 mol) was added over 1 hour, keeping the temperature less than −20° C. It was allowed to warm to ambient temperature overnight. The solvent was removed under reduced pressure at t<70° C. and the resulting oil was dissolved in dichloromethane (2.8 L) and washed with water (2 L) 5% HCl (2 L), 2% K2CO3 solution (1 L), and finally water (2 L) to pH neutrality. The solution was then concentrated under reduced pressure to a yellow oil (645 g, 62%) which by capillary GC was a 1:1 mixture of dimethyl N-ethoxycarbonyl-1,4-dihydropyridine-4-phosphonate and dimethyl N-ethoxycarbonyl-1,2-dihydropyridine-2-phosphonate. This material was used directly for the hydrogenation below, since attempted distillation leads to decomposition.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CC1NN=NN=1.C(N(CC)[P:28]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)C.C1C=C(Cl)C=C(C(OO)=[O:55])C=1>C1COCC1.C(Cl)Cl>[CH2:38]([O:37][P:28]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:55])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)COCCOCCO
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)COCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
A mixture of tert-butyl 3-(2-(2-hydroxyethoxy)ethoxy)-2,2-dimethylpropanoate (49) (6.87 g, 26.2 mmol), 5-methyl-1H-tetrazole (4.40 g, 52.4 mmol), and dibenzyl diethylphosphoramidite (12.47 g, 39.3 mmol) in THF (66 mL) was allowed to stir at RT for 1.5 h. The solution was cooled to 0° C. and m-CPBA (10.85 g, 47.1 mmol) was slowly added, the mixture was allowed to stir at RT for 16 h. The reaction was diluted with DCM (200 mL) and washed with sat. NaHCO3 (aq.) (4×100 mL), the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (220 g, 0-40% EtOAc in isohexane) to afford tert-butyl 3-(2-(2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)ethoxy)-2,2-dimethylpropanoate (50) (12.2 g, 89%) as a colourless oil: m/z 545 (M+Na)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.35-7.31 (m, 10H), 5.09-5.00 (m, 4H), 4.13-4.09 (m, 2H), 3.65-3.63 (m, 2H), 3.59-3.52 (m, 4H), 3.39 (s, 2H), 1.41 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:36]C)[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:23]#[C:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=3)[CH:6]=[CH:5][C:4]1=2)C.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:3]1([CH3:36])[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:23]#[C:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:34][CH:35]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(F)(F)F)cc2)=CCC3(CC)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(C(F)(F)F)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-diethyl-8-(4-trifluoromethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 9) 70.0 mg (0.148 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.1 Hz), 7.61-7.47 (6H, m), 6.97 (2H, s), 6.16 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.6 Hz), 1.30 (6H, s).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:21]([N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH:27]=[C:26]([NH:28][C:2]2[N:20]=[C:5]3[C:6]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: FC(F)(F)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CCn1cc(N)cn1
Product: CCn1cc(Nc2nc3c(-c4ccc(C(F)(F)F)cc4)cccn3n2)cn1

Procedure:
2-Chloro-8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4-triazolo[1,5-a]pyridine (1.23 g, 5.29 mmol) and (4-trifluoromethyl-phenyl)boronic acid (1.23 g, 6.50 mmol) in a manner analogous to Example 2c. Product was isolated as a white solid (0.95 g, 62%). MP=163-165° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.65 (d, J=6.77 Hz, 1H), 8.12 (d, J=8.09 Hz, 2H), 7.80 (d, J=8.17 Hz, 2H), 7.77 (d, J=8.40 Hz, 1H), 7.22 (t, J=7.12 Hz, 1H). MS=298 (MH)+. 215b) (1-Ethyl-1H-pyrazol-4-yl)-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.100 g, 0.31 mmol) and 1-ethyl-1H-pyrazol-4-ylamine (0.046 g, 0.41 mmol) in a manner analogous to Example 2d. Product was isolated as a tan solid (52 mg, 44%). MP=162-164° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.77 (d, J=6.36 Hz, 1H), 8.38 (d, J=7.76 Hz, 2H), 7.85-7.97 (m, 3H), 7.81 (s, 1H), 7.47 (s, 1H), 7.11 (t, J=6.80 Hz, 1H), 4.10 (q, J=7.12 Hz, 2H), 1.36 (t, J=6.92 Hz, 3H). MS=373 (MH)+.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:13]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[N:12][N:11]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CCCCCC.CO.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:27][C:22]([C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:10]([CH2:9][OH:8])=[N:11][N:12]=2)=[CH:23][CH:24]=1
Reactant: Fc1ccccc1-n1c(COCc2ccccc2)nnc1-c1ccc(-c2ccccc2)cc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CO
Product: OCc1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
3-Benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole (6.00 g) was dissolved in chloroform (200 ml), followed by dropwise addition of 1 mol/liter boron trichloride-hexane solution (30 ml) at −44° C. and stirred at the same temperature for 30 minutes and at ambient temperature for one hour. To the reaction solution were added methanol (5 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml), followed by concentration under reduced pressure. To the resulting residue were added tetrahydrofuran (100 ml), aqueous 2 mol/liter sodium hydroxide solution (100 ml) and tetrabutylammoniumhydrogensulfate (0.10 g), and stirred at ambient temperature for 12 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=96/4) and recrystallized from a mixture solution of n-hexane-ethyl acetate-ethanol, to afford the entitled compound as white crystal (2.09 g, 44%). The physico-chemical values are as follows.
Reaction SMILES: [F:1][C:2]([F:16])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.C(N(CC)CC)C.[Cl-].[C:31]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])(=[O:37])/[CH:32]=[CH:33]\[C:34]([O-])=[O:35]>C(Cl)(Cl)Cl>[C:31]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])(=[O:37])/[CH:32]=[CH:33]\[C:34]([O:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:6]([F:14])([F:15])[C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[O:35]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC(CC)COC(=O)/C=C\C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
3,3,4,4,5,5,6,6,6-Nonafluorohexanol (515 g, 1.95 mol), pyridine (169 g, 2.13 mol) and triethylamine (394 mL, 3.89 mol) were dissolved in chloroform (1000 mL) and added dropwise with 2-ethylhexyl maleate chloride (530 g, 2.14 mol), while the internal temperature was kept at 20° C. or lower on an ice bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour and then added with chloroform. The organic phase was washed with water and a saturated sodium chloride aqueous solution. Then, the organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (508 g, yield: 50%), which was colorless and transparent.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(OCC)=O.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([OH:24])[CH3:23]>>[CH2:12]([N:9]1[CH2:8][CH2:7][N:6]([CH2:1][CH2:23][CH2:22][OH:24])[CH2:11][CH2:10]1)[CH:13]=[CH2:14]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCO
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCN1CCN(CCCO)CC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
32 g of 1-carbethoxy-piperazine and 24.5 g of allyl bromide are dissolved in 70 ml of ethanol. 25 g of calcined potassium carbonate are added to the solution and the mixture is stirred under reflux for 30 hours. The reaction mixture is cooled to 0° C, the solids are filtered off, and the filtrate is evaporated under reduced pressure. The residue is admixed with 55 ml of concentrated hydrochloric acid, the mixture is boiled for 24 hours and then it is evaporated. The residue is triturated with 30 ml of ethanol and the solid is filtered off. The obtained 27 g of solid 1-allyl-piperazine dihydrochloride are dissolved in 80 ml of water, the aqueous solution is rendered alkaline (pH = 8) with 20% aqueous sodium hydroxide solution, and the alkaline mixture is extracted with 3×80 ml of ethyl ether. The etheral extracts are combined, dried over sodium sulfate, filtered, and the ether is evaporated. The resulting 15.5 g of 1-allyl-piperazine are dissolved in 100 ml of ethanol, 12.3 g of trimethylene chlorohydrine and 18 g of calcined potassium carbonate are added to the solution, and the mixture is stirred and refluxed for 30 hours. The reaction mixture is cooled to 0° C, the solids are filtered off, and the filtrate is evaporated. The obtained residue is purified by distillation. In this way 15 g (45%) of 3-(4-allyl-piperazin-1-yl)-1-hydroxy-propane are obtained; b.p.: 98°-100° C/8 mm Hg; nD20 : 1.4935.
Reaction SMILES: O1CCOCC1.N[C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11](NC2C=CC(O)=CC=2)=[CH:10][C:9]=1C#N.FN1N=C(F)C=C(N2CCCC2)N1.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C>[CH:15]1[C:14]2[C:13](=[O:23])[C:12]3[C:21](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:20](=[O:22])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cc(Nc2ccc(O)cc2)c2c(c1N)C(=O)c1ccccc1C2=O
Agent: FC1=NN(F)NC(N2CCCC2)=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 80 °C
Yield: 235.6 %

Procedure:
To dioxane (100 ml), 1-amino-2-cyano-4-(4-hydroxyanilino)anthraquinone (3.55 g), 2,4-difluoro-6-(1-pyrrolidinyl)triazine (1.9 g), triethylamine (1.1 g) and anhydrous potassium carbonate (1.4 g) were added, and the mixture was heated at 80° C. for 1 hour to effect condensation. The reaction liquor was treated as in Example 6 to produce 4.9 g of an anthraquinone dye of the following formula in a yield of 94%. ##STR46## The dye had a λ max (acetone) of 630 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Br[CH2:32][CH2:33]Cl.[F:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:35][C@@H:36]1[CH2:40][CH2:39][N:38]([CH2:32][CH2:33][N:20]2[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]4)/[S:22][C:21]2=[O:23])[CH2:37]1
Reactant: F[C@@H]1CCNC1
Reactant: ClCCBr
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CC[C@@H](F)C5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-{2-[(3R)-3-Fluoropyrrolidin-1-yl]ethyl}-5-[(1-{[4-(methyloxy)-2-(trifluoro-methyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8), 1-bromo-2-chloroethane and (3R)-3-fluoropyrrolidine following General Procedure G.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@:7]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:8][CH2:9][CH3:10])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C@:7]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCC[C@](OCCN=[N+]=[N-])(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@](OCCN)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-1-(2-azidoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (790 mg, 1.81 mmol) in the mixture of THF/H2O (20:1, 10.5 mL) was added PPh3 (1.9 g, 7.25 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure to the residue, which was purified by column chromatography on silica gel to afford (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (410 mg, 55%). 1HNMR (CDCl3, 400 MHz) δ 7.31 (s, 1H), 7.24 (m, 2H), 7.15 (m, 1H), 4.31-3.52 (m, 3H), 3.27 (m, 2H), 2.93 (m, 1H), 2.41-2.22 (m, 3H), 2.15-1.95 (m, 3H), 1.85 (m, 4H), 1.57 (m, 1H), 1.44 (s, 9H), 1.38-1.10 (m, 2H), 0.95 (t, 31).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:12]1(=[O:21])[N:11]([CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1ccncc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 3.1 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 13.97 g (55 mmol) of N-(2-bromoethyl)phthalimide in 80 ml of DMF, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added. The mixture was stirred at room temperature for 32 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.41 g of the desired compound (yield: 3.1%, colorless crystal).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:11])[CH2:6]2.[Cl:12][C:13]1[C:14]([O:24][CH3:25])=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH:21]=1)[C:18](Cl)=[O:19]>ClCCl>[ClH:12].[CH3:11][N:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:13]([Cl:12])[C:14]([O:24][CH3:25])=[CH:15][C:16]=2[O:22][CH3:23])[CH2:6]1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1Cl
Reactant: CN1Cc2cccc(N)c2C1
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CN(C)C3)cc1Cl
Product: Cl
Yield: 19.1 %

Procedure:
A solution of freshly prepared 4-amino-2,3-dihydro-2-methyl-1H-isoindole (400 mg, 3.0 mmol) in dry ethyl acethate (40 ml) under argon was treated dropwise with a solution of 5-chloro-2,4-dimethoxybenzoyl chloride (700 mg, 3.0 mmol) in a mixture of ethyl acethate (10 ml) and dichloromethane (10 ml). The reaction was stirred at room temperature for 6h and then concentrated in vacuo. The residue was triturated with diethyl ether/ethyl acethate and then crystallised twice from methanol/diethyl ether to give the title compound as a pale grey solid (0.11 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:36]([C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)[N:37]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
1.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 0.5 ml of triethylamine and 0.7 g of 4-nitrophenylhydrazine hydrochloride are boiled under reflux for 1 h in 10 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-nitrophenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 180-183° C.
Reaction SMILES: C([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=O.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].[C:31](=O)([O-:33])[O-:32].[K+].[K+]>CN(C)C=O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][CH:4]([CH2:5][CH2:6]2)[CH2:9][CH:8]3[C:31]([O:33][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:32])[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: O=C([O-])[O-]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: OCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(CC1)CC2C(=O)OCCCCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg), 5-bromo-1-pentanol (18.7 μL), potassium carbonate (23.5 mg), and N,N-dimethylformamide (1.5 mL) were mixed together. The mixture was stirred at room temperature for 4 hours. The insoluble materials in the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant: chloroform:methanol=10:1) to give (2S,4S)-4-fluoro-1-[[N-(5-hydroxypentyloxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (32.4 mg).