Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[C:22]([F:25])([F:24])[F:23])[N:3]=1.O.[NH2:27][NH2:28]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]3[C:11]([C:12]([NH2:13])=[N:27][NH:28]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[C:22]([F:25])([F:24])[F:23])[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCCC3C(F)(F)F)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC2C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
4-{2-Amino-6-[2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (60 mg, 0.17 mmol) was disolved in ethanol (1.5 mL) with stirring in a 5 mL microwave vessel. Hydrazine monohydrate (0.207 mL, 4.27 mmol) was added, and the mixture was capped and heated at 100° C. in an oil bath overnight. HPLC showed complete conversion. The hot mixture was filtered through a 0.2 um filter disc, rinsing with ethanol (1 mL). Water (˜3 mL) was added to the filtrate with stirring, and the mixture was heated to evaporate most of the ethanol to a volume of ˜4 mL. The mixture was allowed to cool with stirring to room temperature, at which time some product had precipitated as a gum. Stirring was continued for approximately one hour and the precipitate became a free flowing white solid, which was filtered, washed with water and dried to afford the title compound (42 mg) as an off-white solid. LC-MS (ES) m/z=364 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.98-2.08 (m, 2H), 2.08-2.23 (m, 2H), 3.49-3.60 (m, 1H), 3.60-3.72 (m, 1H), 5.06-5.17 (m, 1H), 5.39 (s, 2H), 6.22 (s, 2H), 6.52 (s, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](I)[C:6]([F:10])=[CH:5][C:4]=1[CH3:11].[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:11])=[CH:5][C:6]([F:10])=[C:7]([B:17]([OH:20])[OH:18])[CH:8]=1
Reactant: COc1cc(I)c(F)cc1C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(F)cc1C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To 122D (750 mg, 2.8 mmol) in THF (10 mL) was added n-BuLi (1.6M in hexane, 2.3 mL) at −78° C. After stirring for 10 min, trimethyl borate (0.63 mL) was introduced. The mixture was stirred from −78° C. to rt for 3 h before it was quenched by 1N HCl and extracted with ethyl acetate. The organic extracts were washed with saturated Na2S2O3, brine and dried over MgSO4. Evaporation of the solvent gave product 122E (356 mg, 69% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.18 (s, 3H) 3.80 (s, 3H) 6.80-6.86 (m, 2H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[N:20]1([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: O=C(O)c1ccccc1-n1cccn1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-n1cccn1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-pyrazol-1-yl-benzoic acid. LC-MS (basic): tR=1.19 min; [M+H]+=447.1.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([F:33])[C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([F:33])[C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: Cc1ccc(Cl)c(B(O)O)c1F
Product: Cc1ccc(Cl)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1F
Yield: 2.4 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-6-fluoro-5-methylphenylboronic acid (available from Combi-Blocks Inc.; 94 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-6′-fluoro-5′-methyl-biphenyl-2-carboxylic acid (3 mg, 2%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.48-8.56 (m, 1H), 8.26-8.37 (m, 2H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.27-7.39 (m, 2H), 2.54 (s, 8H).
Reaction SMILES: C1CCC(N=C=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)CC1.[CH:16]1[CH:17]=CC2N(O)N=N[C:20]=2[CH:21]=1>CO>[CH3:17][CH2:16][CH2:21][CH2:20][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:10][NH2:9]
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Product: CCCCCCCCCCN

Procedure:
Equation 2 shows the synthetic steps involved in the construction of the required N-[p methyl-aminobenzoyl]-glutamyl-γ-4-fluoroglutamic acid (12). The free acid 7 was obtained by treatment with Dowex 50WX8 in 60% EtOH/H2O. Coupling of the α, γ-carboxyl protected D,L-erythro, threo-4-fluoroglutamate ester to 8 was accomplished using DCC/HOBt giving the pipeptide 9 in 90% yield, hydrogenation of 9 in MeOH using 10% Pd on carbon catalyst gave the free amine 10 in quantitative yield.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[C:12]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2N(CC3C=CC=CC=3)N=CC=2CC1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:18]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=2)=[N:13]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(C#N)cc3)nn(Cc3ccccc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2cnn(Cc3ccccc3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 43, Step C, 0.30 g) in 9 mL of 1,4-dioxane was added 0.20 g of K3PO4, 0.10 g of 4-cyanophenylboronic acid, and 0.05 g of PdCl2dppf. The mixture was heated at reflux for 72 h. The mixture was filtered through diatomaceous earth and concentrated in vacuo to give 0.33 g of an orange solid. Chromatography on SiO2 (5 to 30% EtOAc/hexanes) afforded 0.21 g of a 7:1 mixture of 1-benzyl-3-(4-cyano-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and a side product, 1-benzyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The mixture of compounds (0.21 g) was dissolved in 7 mL CH2Cl2 and 7 mL of TFA was added. The mixture was stirred at RT for 1 h and concentrated in vacuo. The crude product was dissolved in CH2Cl2 and treated with Dowex® 550A resin. After stirring for 2 h, the mixture was filtered and concentrated in vacuo. Chromatography using a C18 reverse phase column afforded 0.14 g of the title compound as its TFA salt. MS (ESI): exact mass calculated for C21H20N4, 328.17; found, m/z 329.1 [M+H]+, 351.1 [M+Na]+. 1H NMR (500 MHz, CD3OD): 7.83-7.81 (m, 2H), 7.76-7.74 (m, 2H), 7.36-7.28 (m, 3H), 7.19-7.17 (m, 2H), 5.46 (s, 2H), 3.39-3.37 (m, 4H), 3.15-3.09 (m, 4H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([N:12]3[C:16]([C:17]4[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=4)=[CH:15][CH:14]=[C:13]3[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.O>[N:31]1([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[N:12]([C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)=[CH:11][N:10]=4)[C:13]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(Br)cc2)n1-c1ccc(-n2ccnc2)cn1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(-n2ccnc2)cn1
Yield: 20.6 %

Procedure:
To a mixture of ethyl 3-(1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-5-(4-bromophenyl)-1H-pyrrol-2-yl)propanoate (29A) (200 mg, 0.43 mmol) and imidazole (35 mg, 0.516 mmol) in DMSO (5 mL) was added L-proline (19.8 mg, 0.172 mmol), CuI (16.4 mg, 0.086 mmol) and K2CO3 (119 mg, 0.86 mmol). The resultant mixture was heated at 150° C. for 5 h under microwave irradiation, poured into water and extracted with EA for 5 times. The combined organic layers were washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (DCM:MeOH=20:1) to afford ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(5-(1H-imidazol-1-yl)pyridin-2-yl)-1H-pyrrol-2-yl)propanoate as a brown oil (40 mg, 21%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([NH:7][C:8]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[C:11]=1[O:20][CH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:9])([CH3:6])[CH3:5].Cl>CO.[OH-].[Na+]>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:20][C:11]1[C:12]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=2[S:14][C:10]=1[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:31])=[O:2])=[O:9]
Reactant: COC(=O)C(C)(C)NC(=O)c1sc2ccc(F)cc2c1OCc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NC(=O)c1sc2ccc(F)cc2c1OCc1nc2ccccc2s1)C(=O)O
Yield: 59.8 %

Procedure:
138 mg 2-{[3-(Benzothiazol-2-ylmethoxy)-5-fluoro-benzo[b]thiophene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 2 ml methanol and 1 ml 1M aqueous sodium hydroxide solution was refluxed for 0.5 h. The reaction was acidified with 2 M hydrochloric acid, and the precipitated product was collected by filtration, dissolved in ethyl acetate, dried over sodium sulphate adding also active charcoal, filtrated, concentrated in vacuo, and the resulting crude product was crystallized from diethyl-ether to yield 0.08 g 2-{[3-(Benzothiazol-2-ylmethoxy)-5-fluoro-benzo[b]thiophene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:25])([C:20]([S:22][CH2:23][F:24])=[O:21])[C@:18]2([CH3:26])[C@H:4]([C@H:5]3[C@:15]([F:28])([C@@H:16]([OH:27])[CH2:17]2)[C@:14]2([CH3:29])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:30])[CH2:6]3)[CH2:3]1>C(O)CCC>[CH3:8][CH2:9][C:10]([O:25][C@@:19]1([C:20]([S:22][CH2:23][F:24])=[O:21])[C@@:18]2([CH3:26])[CH2:17][C@H:16]([OH:27])[C@:15]3([F:28])[C@:14]4([CH3:29])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]4)=[O:11])[C@@H:7]([F:30])[CH2:6][C@H:5]3[C@@H:4]2[CH2:3][C@H:2]1[CH3:1])=[O:11]
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)SCF
Solvent: CCCCO
Product: CCC(=O)O[C@]1(C(=O)SCF)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C

Procedure:
The crude fluticasone obtained as above is dissolved in 68 ml 1-butanol at 117–120° C. to get a clear solution (which may be optionally charcoalized and filtered hot), and then gradually cooled to ambient temperature for crystallization. The crystallized product is filtered. washed with 1-butanol (4 ml). Dried at 55–60° C. to obtain pure fluticasone propionate (Yield 3.0 g, purity 99.24%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)[CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
A solution of acryloyl chloride (20 μL, 0.25 mmol) was added dropwise to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 150, 180 mg, 0.42 mmol) and triethylamine (73 lilt, 0.53 mmol) in THF (3 mL) at −5° C. over a period of 1 minute under an atmosphere of N2. The resulting mixture was stirred at 0° C. for 0.25 h. The reaction was judged to be incomplete so further acryloyl chloride (10 μL, 0.125 mmol) was added dropwise and the mixture was stirred at 0° C. for a further 15 minutes. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH2Cl2 (5 mL) plus a few drops of CH3OH. This solution was washed with sat. NaHCO3 (2 mL), dried (MgSO4) and filtered through a 1 g silica pad, eluting with 4:1 CH2Cl2—CH3OH. Eluent that contained desired product was concentrated in vacuo. Purification by FCC, eluting with 5-20% CH3OH in CH2Cl2 gave the title compound (31 mg, 14%) as a cream crystalline solid; 1H NMR: 2.33 (3H, s), 2.40 (2H, s), 2.57 (2H, d), 3.03 (2H, s), 3.89 (3H, s), 5.70 (2H, m), 6.17 (1H, m), 6.46 (1H, m), 6.88 (1H, s), 7.09 (1H, t), 7.32 (1H, d), 7.47 (1H, t), 8.12 (1H, s), 8.21 (1H, s), 8.39 (1H, d), 8.51 (1H, d), 8.81 (2H, m), 9.36 (1H, s); m/z: ES+ MH+ 482.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([F:36])[CH:24]=3)[CH:16]=2)=[C:9]([CH3:37])[C:8]=1[CH3:38])[CH3:2].[OH-].[Na+].[ClH:41].Cl.C(OCC)(=O)C>CO.O1CCCC1.C(OCC)(=O)C>[ClH:41].[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:38])=[C:9]([CH3:37])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([F:36])[CH:24]=3)[CH:16]=2)=[C:11]([CH3:14])[C:12]=1[CH3:13])[CH3:2]
Reactant: CCOCCOc1c(C)c(C)c(-c2cccc(CNc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOCCOc1c(C)c(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of ethyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,3′,5′,6′-tetramethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoate (0.40 g, 0.77 mmol) in a mixture of methanol (4.0 mL) and tetrahydrofuran (8.0 mL) was added 1 N aqueous sodium hydroxide solution (1.53 mL, 1.53 mmol), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) to give a colorless oil. The obtained oil was dissolved in ethyl acetate, and 4 N hydrogen chloride/ethyl acetate solution was added. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to give the title compound (0.28 g, yield 70%) as colorless crystals.
Reaction SMILES: Cl.[NH:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][NH:11][C:12]=3[CH:13]=[C:5]2[CH2:4][CH2:3]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[N:11]1[C:12]2=[CH:13][C:5]3[CH:4]=[CH:3][NH:2][C:6]=3[CH:7]=[C:8]2[CH2:9][CH2:10]1
Reactant: c1cc2cc3c(cc2[nH]1)CCN3
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4cc5[nH]ccc5cc43)c2cc1OC
Yield: 67 %

Procedure:
Utilizing a procedure analogous to that described in Example 24 (with conversion to its HCl salt using a procedure analogous to that described in Example 2), this product was prepared in 67% yield from 1,2,3,5-tetrahydro-pyrrolo[2,3-f]indole (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 245°-252° C.; LC-MS: 347 (MH+); RP18-HPLC RT: 3.67 min)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[Cl-].[NH4+].C(OCC)(=O)C.CCCCCC>O1CCCC1>[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([CH:18]=[CH:17][C:13]=1[C:14](=[O:15])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:21]#[N:22]
Reactant: N#Cc1ccc(C(=O)Cl)c(CCl)c1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-fluoro phenylmagnesium bromide (3.76 g) in tetrahydrofuran (15 ml) was added to a cooled solution of 2-chloromethyl-4-cyano-benzoyl chloride (3.95 g) in tetrahydrofuran (10 ml) so that the temperature did not raise above 0° C. The mixture was warmed slowly to room temperature and stirred over night. Saturated ammonium chloride solution (60 ml) was added and stirring continued for 0.5 hours. The phases were separated and the aqueous phase was extracted with diethylether (30 ml). The combined organic phases were dried over sodium sulfate, filtered and dried in vacuo to give a brown solid. Flash chromatography (ethyl acetate/n-hexane=1/10) provided the product as colourless solid. Yield 2.95 g, 58%. 1H NMR (CDCl3, 400 MHz): 4.71 (2H, s), 7.16-7.21 (2H, m), 7.46 (1H, d, J=7.9 Hz), 7.71 (1H, dd, J=1.5, 7.9 Hz), 7.81-7.86 (2H, m), 7.89 (1H, d, J=1.5 Hz). 13C NMR (CDCl3, 100 MHz): 42.3, 115.0, 116.4, 116.6, 117.9, 129.6, 132.95, 132.98, 133.4, 133.5, 134.3, 138.7, 142.4, 165.5, 168.1, 194.5.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][C:28]([NH2:30])=[O:29]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])[O:29][CH:15]=2)[CH:9]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: O=C(O)COc1ccc(Br)cc1-c1coc(Cc2ccc(F)cc2Cl)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(2-chloro-4-fluorophenyl)acetamide according to GP5 and GP3: LC/MS (an 10p8) Rt 2.75 min, m/z 440 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:17][C:18]1([CH3:34])[O:23][CH:22]([C:24]([NH:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:25])[C:21]([CH3:33])([CH3:32])[CH2:20][O:19]1>>[CH3:17][C:18]1([CH3:34])[O:23][CH:22]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:30])=[O:25])[C:21]([CH3:33])([CH3:32])[CH2:20][O:19]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCCCC(=O)NCCCO
Product: CCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 98.1 %

Procedure:
N-(3-Hydroxypropyl)decanamide (2.29 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 4.61 g of the title compound (yield: 98%)
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(C)CCCCCCCCCCCCCCCO
Reactant: O=C(O)c1cccnc1
Product: CC(C)CCCCCCCCCCCCCCCOC(=O)c1cccnc1

Procedure:
Isooctadecyl nicotinate was prepared using the method of Example 7 from nicotinic acid and a commercial product, isooctadecyl alcohol, obtained from Farbwerke Hoechst AG. The product had an estimated purity 94.5%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(CC(=O)C)(=O)C.Br[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:21](=[O:22])[O:20][CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>[Cu](Br)Br.O.CN(C=O)C>[O:7]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:21](=[O:22])[O:20][CH2:19]2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C1OCc2cc(Br)ccc21
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCc2cc(Oc3ccccc3)ccc21
Yield: 72 %

Procedure:
A reactor was charged with DMF (68 Kg), and stirring was initiated. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromophthalide (85 Kg), copper bromide (9 Kg), and potassium carbonate (77 Kg). The mixture was heated above 85° C. and maintained until reaction completion and then cooled. Water was added. Solid was filtered and washed with water. Solid was dissolved in dichloromethane, and washed with aqueous HCl and then with water. Solvent was removed under pressure and methanol was added. The mixture was stirred and filtered. Solid was washed with methanol and dried in an oven giving 5-phenoxyphthalide (Yield: 72%, HPLC: 99.6%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:10][CH:8]1[CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]2[S:13][CH:12]=[CH:11][C:7]1=2
Reactant: Fc1ccccc1Br
Reactant: CCN1CCc2sccc2C(O)C1
Product: CCN1CCc2sccc2C(Oc2ccccc2Br)C1

Procedure:
The same method as in Example 1 was conducted using 6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 45) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C=C.C(F)(F)=C(Cl)F.C(OOC(C)(C)C)(=O)C(C)(C)C.C(OOC(C)(CCC(OOC(C)(C)C)(C)C)C)(C)(C)C.[Br:41][C:42]([C:45]([CH2:48][CH2:49]Br)([Cl:47])[F:46])([F:44])[F:43]>FC(F)(F)CC(F)(F)C>[Br:41][C:42]([C:45]([CH:48]=[CH2:49])([Cl:47])[F:46])([F:44])[F:43]
Reactant: FC(F)(Br)C(F)(Cl)CCBr
Agent: C=C
Agent: CC(C)(C)OOC(=O)C(C)(C)C
Agent: CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Product: C=CC(F)(Cl)C(F)(F)Br

Procedure:
A supply of BCTFB was obtained by reacting ethylene with dibrominated CTFE in 1,1,1,3,3-pentafluorobutane at 120° C. for 4 hours using a mixture of tert-butyl peroxypivalate (TBPPi, 3 mol %) and 2,5-bis(tert-butylperoxy)-2,5-dimethylhexane (Trigonox 101, 4.5 mol %) as radical initiators, with the resulting structure being Br—CF2—CFCl—CH2—CH2—Br after distillation under vacuum. This was dehydrochlorinated with KOH in refluxing methanol for 15 hours, forming Br—CF2—CFCl—CH═CH2 (BCTFB). Successful radical copolymerization of CTFE (96 mol % in the feed) with BCTFB initiated by TBPPi (2 mol % with respect to both monomers) was carried out at 74° C. in a 100 mL autoclave. The 19F NMR spectrum of the obtained polymer is shown in FIG. 7.