Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[CH3:36])[CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH3:37][N:38]([CH3:45])[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][NH2:42]>>[CH3:37][N:38]([CH3:45])[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][NH:42][C:3]1[N:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[CH3:36])[CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cccc(-c4ccc(F)cc4C)c3)c3ccccc23)n1
Reactant: CN(C)CC(C)(C)CN
Product: Cc1cc(F)ccc1-c1cccc(C(=O)Nc2ccc(Oc3ccnc(NCC(C)(C)CN(C)C)n3)c3ccccc23)c1

Procedure:
Compound is prepared from 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid [4-(2-methylsulfanyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-amide and N,N,2,2-tetramethyl-1,3-propanediamine according to conditions described in general procedure J. (23 mg). 1H NMR (400 MHz, CDCl3) δ 8.01-8.1 (m, 4H), 7.88 (dd, 1H, J=0.8 and 8 Hz), 7.5-7.65 (m, 5H), 7.26-7.33 (m, 2H), 6.98-7.08 (m, 2H), 6.21 (d, 1H, J=6 Hz), 2.3 (s, 3H), 2.0-2.2 (brm, 10H), 0.6-0.9 (brs, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:36][C@H:33]1[CH2:32][CH2:25][CH2:35][O:34]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-bromo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (75%) as a colorless solid: mp 137-141° C.; 1H NMR (300 MHz, DMSO-d6) (diastereomers) δ7.30-7.10 (m, 3H), 6.42-6.37 (m, 1H), 6.32 (s, 1H), 4.88 (d, J=9.63 Hz, 1H), 4.70-4.63 (m, 1H), 4.46 (t, J=8.6 Hz, 2H), 4.18-4.05 (m, 1H), 3.85-3.52 (m, 4H), 2.93 (t, J=8.5 Hz, 2H), 2.01-1.67 (m, 3H), 1.64-1.49 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.5 (2), 162.2, 161.8, 145.7, 130.9, 130.2 (2), 126.6, 119.9 (2), 119.0 (2), 118.9 (2), 118.1, 92.5, 77.5, 76.3, 76.1, 72.5, 67.7 (2), 65.4, 58.7, 44.5, 29.0 (2), 28.7, 25.5; MS (ES+) m/z 443.9 (M+1), 445.9 (M+1).
Reaction SMILES: [CH3:1][C:2](=[CH2:22])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[CH:15][CH:14]=1)=[O:4].S(Cl)(Cl)=O.O[C:28]1[CH:39]=[CH:38][C:31]([CH:32]=[CH:33][C:34]([O:36][CH3:37])=[O:35])=[CH:30][C:29]=1[O:40][CH3:41].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH3:22][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:28]2[CH:39]=[CH:38][C:31](/[CH:32]=[CH:33]/[C:34]([O:36][CH3:37])=[O:35])=[CH:30][C:29]=2[O:40][CH3:41])=[O:18])=[CH:20][CH:21]=1)=[O:4]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)[O-])cc1
Reactant: COC(=O)C=Cc1ccc(O)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OC)cc2OC)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
8.5 g (0.028 mol) of 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoate were treated with 6 ml of thionyl chloride and 3 drops of DMF and the mixture was heated to 90° C. for 2 hours. The excess thionyl chloride was completely removed firstly in a water-jet vacuum and subsequently in a high vacuum. The residual acid chloride was taken up in 20 ml of dichloromethane and slowly added dropwise at 0° C. to a solution of 5.25 g (0.025 mol) of methyl 4-hydroxy-3-methoxy-cinnamate and 4.25 ml of triethylamine in 25 ml of THF. The batch was stirred at room temperature overnight, filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel with dichloromethane/diethyl ether (19:1) and subsequently by recrystallization from ethanol/THF. 6.31 g of 2-methoxy-4-[(E)-2-methoxycarbonyl-vinyl]-phenyl 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoate were isolated as a white powder; m.p. 92-94° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([S:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:19])[C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4]1>CCO>[CH:3]1([S:6][C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:19])[C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(=O)c1ccc(SC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)c1ccc(SC2CC2)cc1
Temperature: 60 °C

Procedure:
2M aqueous NaOH (163 ml) was added to a solution of ethyl (4-cyclopropylsulfanylphenyl)oxoacetate (40.62 g, 162.5 mmol) in EtOH (200 ml) and the stirred mixture heated at 60° C. for 2 h. After cooling, the mixture was concentrated to 150 ml and washed with ether (2×100 ml). Sufficient concentrated HCl was then added to adjust the pH to 1 and the resulting precipitate was extracted into EtOAc (2×300 ml). The combined organic phases were washed with water (3×100 ml), brine (200 ml) and dried (MgSO4). Removal of the solvent afforded the title compound: m/z (ES−)=221.0 [M−H+]−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[OH:34][N:33]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2ccc(C#CCCC(=O)O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(C#CCCC(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 5-{4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-pent-4-ynoic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4.2:1) as a colorless oil, MS (ESI−): m/z=425.1862 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][NH:23][CH2:24][C:25]#[N:26])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1.[CH:28](O)=[O:29].C(OC(=O)C)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([CH2:22][N:23]([CH2:24][C:25]#[N:26])[CH:28]=[O:29])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:27]=1
Reactant: N#CCNCc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: N#CCN(C=O)Cc1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 0.376 g of [[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]amino]acetonitrile in 10 ml of tetrahydrofuran was treated with 0.1 ml of formic acid-acetic acid anhydride and the clear yellow solution which formed after a short time was stirred at room temperature for 45 minutes. After evaporation the residue was taken up in chloroform, washed with 10 percent potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel with toluene/dioxane (9:1). N-[(10-Chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-yl)methyl]-N-(cyanomethyl)formamide formed a yellow resin.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:28])[C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:16]([O:24][CH3:25])=[CH:15][C:14]=2[O:26][CH3:27])=[CH:6][CH:5]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:28])[C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:16]([O:24][CH3:25])=[CH:15][C:14]=2[O:26][CH3:27])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
4-[3-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-1-hydroxy-prop-2-ynyl]-benzoic acid methyl ester (2.0 g, 4.90 mmol) from Ex-1C was dissolved in dichloromethane (60 mL). Pyridinium dichromate (3.70 g, 9.8 mmol) was added and the resulting mixture was stirred at room temperature under nitrogen for 5 h. The reaction was then filtered through a pad of celite and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol, 30:1) gave 1.5 g (75%) of the desired 4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-benzoic acid methyl ester as a yellow solid, m.p. 198–200° C. 1H-NMR (300 MHz, CDCl3) δ 8.38 (d, 2H, J=8.0 Hz), 8.17 (d, 2H, J=8.0 Hz), 0.88 (s, 1H), 7.41 (dd, 1H, J=3.7 and 1.6 Hz), 7.33 (dd, 1H, J=5.2 and 1.6 Hz), 7.09 (dd, 1H, J=5.2 and 3.7 Hz), 6.55 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 4.00 (s, 31H); EIMS m/z 406 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]([C:15]2[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=2)=[O:14])[N:11]=[C:10]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:9]1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[Cl-].[Cl-].[Al+3]>CN(C=O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:10]2[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:12]([C:13]([C:15]3[S:19][C:18]([C:20]4[N:28]=[N:29][NH:30][N:21]=4)=[CH:17][CH:16]=3)=[O:14])[N:11]=2)[CH:23]=1
Reactant: N#Cc1ccc(C(=O)N2N=C(c3cccnc3)CC2c2ccccc2O)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2nn[nH]n2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 5-{[5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}thiophene-2-carbonitrile (0.300 g, 0.60 mmol) in DMF (5 mL) was added sodium azide (0.120 g, 1.80 mmol) and aluminum trichloride (0.240 g, 1.80 mmol). The reaction mixture was allowed to stir at 100° C. overnight and then concentrated. The residue was purified by column chromatography to give 2-(3-pyridin-3-yl-1-{[5-(2H-tetrazol-5-yl)-2-thienyl]carbonyl}-4,5-dihydro-1H-pyrazol-5-yl)phenol (I-226). LCMS: (FA) ES+ 436, ES-434.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[O:16][C:17]3[C:25]([F:26])=[C:24]([CH3:27])[C:23]([F:28])=[C:22]([NH:29]C(=O)C(C)(C)C)[C:18]=3[C:19](=[O:21])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8]C(=O)C(C)(C)C>S(=O)(=O)(O)O>[NH2:29][C:22]1[C:18]2[C:19](=[O:21])[CH:20]=[C:15]([C:4]3[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([Cl:1])[CH:3]=3)[O:16][C:17]=2[C:25]([F:26])=[C:24]([CH3:27])[C:23]=1[F:28]
Reactant: Cc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(Cl)c3)oc2c1F
Agent: O=S(=O)(O)O
Product: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(Cl)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
8.29 g (16.5 mmol) of the above 2-(3-chloro-4-pivaloylaminophenyl)-6,8-difluoro-7-methyl-5-pivaloylamino-4H-1-benzopyran-4-one was dissolved in 60 mL of concentrated sulfuric acid and the solution was stirred at 50° C. for 10 minutes. The reaction solution was poured into ice water and the precipitated crystals were collected by filtration. The crystals were triturated with a 1N aqueous solution of sodium hydroxide and collected by filtration again. The crystals were recrystallized twice from ethyl acetate/n-hexane to give 2.42 g of Compound 103 (yield: 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CC#N
Product: O=C1Cc2cc(F)cc(Br)c2N1
Temperature: 25 °C
Yield: 86943.7 %

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one 12a (1.5 g, 0.01 mmol) was dissolved in 15 mL of acetonitrile under stirring at room temperature, and N-bromosuccinimide (1.8 g, 0.01 mmol) was then added dropwise to the solution. Upon completion of the addition, the reaction mixture was stirred overnight and lots of precipitates were formed. The reaction was completed until TLC showed the disappearance of starting materials, and the reaction mixture was filtered to give 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 12b (2 g, 87%) as a gray solid.
Reaction SMILES: O.NN.Br[C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=2)[CH:27]=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CCc1cccc(Br)c1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cccc(-c2cccc(OCc3ccccc3)c2)c1

Procedure:
21.5 g (77.2 mmol) of sodium metaborate octahydrate, 0.700 g (977 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.1 ml (2 mmol) of hydrazine hydrate and 10.0 g (42.3 mmol) of 3-(3-bromophenyl)propionic acid are initially introduced in 10 ml of tetrahydrofuran and 30 ml of water, and a solution of 10.0 g (43.9 mmol) of 3-benzyloxy-benzeneboronic acid in 30 ml of THF is added. The batch is subsequently heated under reflux overnight, added to water and extracted three times with MTB ether. The combined org. phases are filtered through silica gel with heptane/ethyl acetate (1:1), and the crude product is recrystallised from toluene, giving 3-(3′-benzyloxybiphenyl-3-yl)propionic acid as a colourless solid.
Reaction SMILES: [F:1][C:2]([F:41])([O:26][C:27]1[CH:36]=[C:35]([C:37]([O:39]C)=[O:38])[CH:34]=[CH:33][C:28]=1[C:29]([O:31]C)=[O:30])[CH:3]([F:25])[O:4][C:5]([F:24])([F:23])[C:6]([F:22])([O:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[C:7]([F:10])([F:9])[F:8].[OH-].[K+].Cl>O>[F:1][C:2]([F:41])([O:26][C:27]1[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[CH:34]=[CH:33][C:28]=1[C:29]([OH:31])=[O:30])[CH:3]([F:25])[O:4][C:5]([F:23])([F:24])[C:6]([F:22])([O:11][C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:16])([F:15])[F:17])[C:7]([F:10])([F:9])[F:8]
Reactant: COC(=O)c1ccc(C(=O)OC)c(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Dimethyl 2-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)-propoxy)ethoxy)terephthalate as prepared in Example 11 (2.25 g, 0.035 mol) was added to a solution of water (50 mL) and potassium hydroxide (KOH, 1.96 g) in a reaction flask. The resulting solution in the reaction flask was heated for 5 hours, cooled to room temperature (about 25° C.) and then acidified by adding concentrated HCl to the reaction flask until a pH of ˜1 was achieved, determined by the formation of a precipitate in the reaction flask. The resulting precipitate was filtered and dried under vacuum. Proton NMR of this precipitate showed the desired material, 2-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)terephthalic acid. The precipitate was then crystallized from ethyl acetate (EtOAc, ˜1 part) and hexane (˜4 parts). After filtration and drying under vacuum, the resulting white di-acid, 2-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)terephthalic acid, had a melting point of 236-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:13]([NH:14][NH2:15])=[CH:12][C:10](=[O:11])[N:9]([CH2:16][CH2:17][CH3:18])[C:7]1=[O:8].[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:13]2[NH:14][N:15]=[C:22]([NH:23][CH3:24])[C:12]=2[C:10](=[O:11])[N:9]([CH2:16][CH2:17][CH3:18])[C:7]1=[O:8]
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2cccc(Cl)c2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O

Procedure:
A solution of 1-(3-chlorobenzyl)-6-hydrazino-3-propyluracil (3.0 g, 9.6 mM) and methyl isothiocyanate (2.2 ml, 32 mM) in DMF (30 ml) was heated at 120° C. for 27 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless crystals (1.22 g, 36%), m.p. 263°-265° C.
Reaction SMILES: OS([O-])(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:15](O)[CH3:16])[CH:11]=[CH:12][C:13]=1[CH3:14]>C1(C=CC(O)=CC=1)O>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[CH3:14])[CH:15]=[CH2:16]
Reactant: Cc1ccc(C(C)O)cc1Br
Agent: O=S(=O)([O-])O
Agent: Oc1ccc(O)cc1
Agent: [K+]
Product: C=Cc1ccc(C)c(Br)c1
Yield: 86.3 %

Procedure:
KHSO4 (0.55 g, 34 mmol), hydroquinone (0.142 g, 1.3 mmol), and 1-(3-bromo-4-methyl-phenyl)ethanol (17.2 g, 80 mmol) were added to a 25 mL round-bottom flask equipped with a distillation equipment. Under stirring, the system was vacuumed at 3 mm Hg and heated. A liquid product (13.6 g, 86% yield) was colleted at 102° C. (3 mm Hg). 1H NMR (300 MHz, CDCl3) δ 2.37 (3H, s), 5.23 (1H, d, J=10.9 Hz), 5.69 (1H, d, J=17.6 Hz), 6.60 (1H, dd, J=10.9, 17.6 Hz), 7.16 (1H, d, J=7.8 Hz), 7.21 (1H, d, J=7.8 Hz), 7.57 (1H, s); 13C NMR (75 MHz, CDCl3) δ 22.63, 114.32, 125.04, 125.09, 129.92, 130.76, 135.30, 137.11, 137.22 ppm; IR (neat) 3091 (m), 3063 (m), 3016 (s), 2985 (s), 2964 (m), 1899 (w), 1833 (w), 1701 (w), 1629 (m), 1602 (m), 1554 (s), 1492 (s), 1450 (s), 1380 (s), 1304 (w), 1278 (m), 1205 (m), 1037 (s), 989 (s), 914 (s), 833 (s), 854 (s), 826 (s) cm−1; MS m/z 197(M++1) 171, 169, 117, 115, 91, 89; HRMS calcd.: C9H9Br 195.9888, found: 195.9887.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([Cl:50])[CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)=[C:38]([Cl:50])[CH:37]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(C(O)c2ccccn2)c(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(Cl)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.81 g), (4-amino-2-chlorophenyl)(pyridin-2-yl)methanol (0.4 g) and 1-hydroxybenzotriazole (0.34 g) were dissolved in N,N-dimethylformamide (15 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.66 g), triethylamine (0.71 ml) and 4-dimethylaminopyridine (catalytic amout) under ice-cooling at room temperature, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), and basic silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy) phenyl]-N-[3-chloro-4-[hydroxy(pyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.37 g) as yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:3]=1
Reactant: O=C(c1ccccc1)c1cn(-c2cccc(Br)c2)cn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1ccccc1)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Temperature: 70 °C

Procedure:
A solution of 7 (250 mg, 0.76 mmol), phenylboronic acid (102 mg, 0.84 mmol) and Na2CO3 (244 mg, 2.3 mmol) in DME/H2O 4:1 (10 mL) was thoroughly purged with argon, after which Pd(PPh3)2Cl2 (36 mg; 0.05 mmol) was added and the mixture was heated to 70° C. for 21 h. The solvents were removed in vacuo and the residue was purified by column chromatography (1 to 5% methanol in CH2Cl2 to give 100 mg (41%) pure 8. HRMS (ESI+): m/z=324.3814 [M+H]
Reaction SMILES: [CH3:1][C@@:2]([S:25]([CH3:28])(=[O:27])=[O:26])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Li+].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1>>[CH3:1][C@@:2]([S:25]([CH3:28])(=[O:26])=[O:27])([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([B:16]2[O:20][C:19]([CH3:21])([CH3:22])[C:18]([CH3:23])([CH3:24])[O:17]2)=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Product: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2)OC1(C)C
Yield: 75.6 %

Procedure:
The title compound (7.4 g, 76%) was prepared from ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate (10.5 g, 25.6 mmol) and lithium hydroxide (4.3 g, 102 mmol) by a procedure analogous to that described for (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid as in Preparation 3 step B. LCMS m/z 381.6 (M−1).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][CH2:5][CH:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:7].[OH-].[Na+].Cl>O>[N:8]1([CH:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:13])=[O:2])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CCC(C)N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CCC(=O)O)N1CCCC1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a suspension of 4-pyrrolidin-l-yl-pentanoic acid methyl ester (2.0 g, 10.0 mmol) in water (20 mL), NaOH (0.8 g, 20.0 mmol, 2.0 eq) was added and the mixture was heated at reflux for 10 hours. The reaction was then allowed to cool to room temperature, the pH was adjusted to 3 with HCl 37% and the mixture was concentrated under reduced pressure. The residue was treated with EtOH, the sodium chloride precipitated was filtered off and the solvent was evaporated under reduced pressure, affording 1.7 g of the title compound as white solid (99% yield).