Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29](B5OC(C)(C)C(C)(C)O5)[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[CH3:7][N:5]1[CH:6]=[C:2]([C:29]2[N:23]3[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:8]5[CH2:13][CH2:12][O:11][CH2:10][CH2:9]5)=[CH:15][CH:16]=4)=[N:22]3)=[CH:27][CH:28]=2)[N:3]=[CH:4]1
Reactant: CC1(C)OB(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)OC1(C)C
Reactant: Cn1cnc(Br)c1
Product: Cn1cnc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)c1

Procedure:
[7-(1-Methyl-1H-imidazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 4-bromo-1-methyl-1H-imidazole and (4-morpholin-4-yl-phenyl)-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine in an analogous manner to Example 1042b. Product isolated as a yellow foam (7 mg, 7%). LCMS (m/e) 376 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.64 (s, 1H), 7.92 (d, 1H, J=1.2 Hz), 7.55 (d, 2H, J=8.9 Hz), 5.52 (s, 1H), 7.27 (d, 1H, J=4.8 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.82 (d, 1H, J=4.8 Hz), 6.59 (bs, 1H), 3.93-3.87 (m, 4H), 3.76 (s, 3H), 3.18-3.13 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[N+:24]([O-])([OH:26])=[O:25].[K+].[Br-]>C(O)(=O)C>[OH:1][C:2]1[CH:3]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[C:4]2[S:10][CH:9]([N+:24]([O-:26])=[O:25])[CH2:8][C:5]=2[O:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(NC1c2sccc2OCC1O)c1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(NC1C(O)=COC2=C1SC([N+](=O)[O-])C2)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared as described in Example 9 starting with 5,6-dihydro-6-hydroxy-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran (1.5 g, 4.04 mmol) and 90% nitric acid (2.5 mL) in acetic acid (20 mL) to give a yellow solid, 0.165 g (10%): mp 219°-220° C.; IR (KBr): 3310, 1661, 1538 and 1504 cm-1, MS: m/z 417 (MS+) 1H NMR (DMSO-d6): δ 1.26 (s, 3H), 1.45 (s, 3H), 3.92 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 4.98 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.99 (d, 1H, exchanges with D2O), 7.74 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H) and 9.30 (d, 1H, exchanges with D2O).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1COCC1>[C:14]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3.0 M solution of phenylmagnesium bromide in ether (49.7 mL, 149 mmol) was added THF (300 mL). To this solution cooled to 0° C. cyclopentanone (13.23 mL, 149 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, then at reflux for 2 h. Ice (20 g) was added, followed by 6 N HCl, until the precipitate dissolved. The product was extracted with ether. The combined etherial layers were washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give cyclopentenylbenzene (21.49 g, 149 mmol, 100% yield) as a colorless oil. LC-MS (M+H)+=145.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.48 (2H, d, J=7.3 Hz), 7.35 (2H, t, J=7.8 Hz), 7.22-7.27 (1H, m), 6.22 (1H, t, J=2.1 Hz), 2.70-2.80 (2H, m), 2.52-2.64 (2H, m), 2.01-2.12 (2H, m).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[C:7]([NH:20][C:21](=[O:30])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=O.[C:31](=[S:34])([NH2:33])[CH3:32]>CCO>[F:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[C:21]([NH:20][C:7]1[S:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:5]([C:3]2[N:33]=[C:31]([CH3:32])[S:34][CH:2]=2)[N:6]=1)=[O:30]
Reactant: O=C(CBr)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
To the solution of Compound 85 (51 mg, 0.1 mmol) in 5 mL of EtOH was added ethanethioamide (0.2 mmol) at room temperature. The resulting solution was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was treated with saturated solution of NaHCO3 and extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated. Column chromatography on silica gel (eluted with ethyl acetate) gave Compound 86 (41 mg, 86%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[F:12].O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[C:3]([F:12])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)c(F)c1N
Yield: 84.7 %

Procedure:
To a solution of 140 (34 g, 0.144 mol) and EtOH (510 mL) was added SnCl2.2H2O (130.1 g, 0.576 mol) and the resulting mixture was heated to reflux for 4 h. After the completion of the reaction, the solvent was removed in vacuo. The residue was taken up in water and made slightly basic with 10% NaHCO3. The resulting solid was filtered and washed well with EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 25 g (84%) of 4-bromo-3-fluoro-benzene-1,2-diamine (142) as yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=c1nc(-c2cccc(Cl)c2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3-chloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (2.44 g, 8.88 mmol) and phosphoroxychloride (25 mL) according to the general procedure I. Obtained as a white solid (1.62 g, 62%). MS (EI) 292.0 [(M)+]; mp 89.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[CH:4]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:3]=1.[H-].[Na+].I[CH3:28]>CN(C)C=O>[CH3:28][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:2]([CH3:1])=[N:3][CH:4]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:5]1=[O:13]
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A solution of 1,3-dihydro-5-methyl-3(R,S)[-(benzyloxycarbonyl )-amino]-2H- 1,4-benzodiazepin-2-one (2 g, 6.2 mmol) in dimethylformamide (20 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.26 g of a 57% dispersion in mineral oil, 6.2 mmol) in one portion, at -10° C. After 30 min, iodomethane (0.39 ml, 6.2 mmol) was added and the resulting mixture stirred at room temperature for 3 h. The solvent was then evaporated and the crude residue partitioned between water (20 ml) and dichloromethane (3×20 ml). The combined organic phase was washed with brine (20 ml), dried (MgSO4) and evaporated. The residue was triturated with ether to afford the title compound (1.05 g, 50%) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 2.52 (3H, s), 3.42 (3H, s), 5.0-5.25 (3H, m), 6.65 (1H, d, J=8 Hz), 7.2-7.7 (9H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC#CCOc1cc(NCc2ccccc2)ncn1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
In 8 ml of ethanol were added 1 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 1.17 g of benzylamine, followed by heating under reflux for 6 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. A saturated aqueous ammonium chloride solution was poured onto the residue, which was extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 1.58 g of 6-(2-butynyloxy)-4-benzylaminopyrimidine (the present compound (133)).
Reaction SMILES: [N:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30](O)=[O:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30]([N:4]1[CH2:3][CH2:2][N:1]([N:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3=[O:13])[CH2:6][CH2:5]1)=[O:31])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1CCCCN1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCN(N2CCCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.8 %

Procedure:
1-(piperazin-1-yl)piperidin-2-one (0.44 g) obtained in Example 8b), (2S)-3-[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.76 g), HOBt (0.37 g) and triethylamine (0.34 mL) were dissolved in DMF (10 mL), WSC (0.46 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was washed with an aqueous sodium bicarbonate solution and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1), and recrystallized form ethyl acetate to obtain the title compound (0.32 g, 28%) as a colorless powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[O:18][C:13]([O:19][CH2:20][CH3:21])=[CH:14][CH:15]([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=CC(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 197.3 %

Procedure:
A 2 liter flask was equipped with a mechanical stirrer, addition funnel, reflux condenser, nitrogen inlet and thermometer. The flask was dried with external heat and then charged with 563 milliliters of dry tetrahydrofuran, 75.9 grams (0.75 mol) of diisopropylamine and cooled to 0° C. Over a 30 minute period 523 milliliters of 1.6 M n-butyl lithium (0.94 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 15 minutes, then cooled to -76° C. in a dry ice-acetone bath and 97.65 grams (0.75 mol) of ethyl isovalerate was added dropwise over about 30 minutes. When this addition was complete, the reaction mixture was stirred for 15 minutes at -76° C., then 205 milliliters (2.20 mol) of chlorotrimethylsilane was added dropwise. When this addition was complete, the dry ice-acetone bath was removed and the reaction mixture allowed to come to room temperature. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue which was triturated with ether and filtered. The filtrate was concentrated under vacuum to give a residue and the residue was vacuum distilled through a vigreux column to give 136.44 grams (1.48 mol) of 1-trimethylsilyloxy-1-ethoxy-3-methylbutene having a boiling point of 78°-88° C. at 30 millimeters pressure.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1C)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=O)[C:2]1[CH:7]=CC=[CH:4][CH:3]=1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:20]>>[CH2:3](/[C:2](=[CH:1]\[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)/[CH:7]=[O:20])[CH3:4]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(C(=O)c2ccccc2)[nH]c2ccccc12
Product: CC/C(C=O)=C\c1cc2ccccc2[nH]1
Temperature: 150 °C
Yield: 39.4 %

Procedure:
Ethyl (2E)-3-[2-(3-methylindolyl)]-3-phenyl-2-propenoate. A mixture of 2-benzoyl-3-methylindole (J. Org. Chem., 37, 3622 (1972)) (0.6 g, 2.55 mmol) and (carbethoxymethylene) triphenylphosphorane (2.1 g, 6 mmol) was heated at 150° C. in a sealed tube for 40 h. After cooling, the residue was chromatographed over silica gel (EtOAc/hexane 2:8) obtaining 0.2 g (25.7%) of the crude title compound as a solid, m.p.=125-130° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].Cl.[CH2:23]([NH:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:26]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:24][CH3:25])=[O:12]
Reactant: CCCNC(C)C
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
Triethylamine (27.89 mL, 200 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-propyl-N-iso-propylamine hydrochloride (- 92 mmol) in toluene (100 mL). The reaction was stirred overnight at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed with brine, dried (MgSO4), and concentrated to afford 2.50 g of the title compound as a waxy amber solid, an 80% yield.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:25][C:21]1[C:20]([I:26])=[CH:19][C:18]([C:10]2[C:8]3[C:9]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]=3[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)=[CH:23][C:22]=1[I:24]
Reactant: Oc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
4-(Benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diiodo-phenol (0.543 g, 0.94 mmol), methyl bromoacetate (0.181 mL, 1.88 mmol), potassium carbonate (0.141 g, 1.03 mmol) and N,N-dimethylformamide (5.4 mL) were combined and stirred at ambient temperature for 1 h. The reaction mixture was added to water and filtered. The solid was washed with water and dried in vacuo to provide the (4-benzo [b]naphtho[2,3-d]thiophen-11-yl-2,6-diiodo-phenoxy)-acetic acid methyl ester as a white solid (0.537 g, 88%): mp 203-205 ° C. Aqueous potassium hydroxide (0.5 N, 2.54 mL, 1.28 mmol) was added to a stirred solution of this methyl ester (0.55 g, 0.85 mmol) in THF (5.0 mL) at ambient temperature. After 1 h the solution was concentrated, diluted with water (75 mL) and acidified with 10% aqueous HCl. The solid was filtered and washed with water to provide the title compounds as a white solid (0.428 g, 80%): mp 250-252° C.: NMR (DMSO-d6); δ8.66 (s, 1 H), 8.07 (d, J=8 Hz, 1 H), 8.01 (d, J=8 Hz, 1 H), 7.93 (s, 2 H), 7.61 (ddd, J=8, 7, 1 Hz, 1 H), 7.54-7.48 (m, 2 H), 7.47 (ddd, J=8, 7, 1 Hz, 1 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.71 (d, J=8 Hz, 1 H), 4.69 (s, 2 H); MS (EI): 636 (100%, MI); Anal. Calc. for C24H14I2O3S: C, 45.31, H, 2.22, N, 0.00. Found: C, 44.95, H, 1.99, N, 0.23.
Reaction SMILES: Cl.Cl.[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][N:20]([C:36](=[O:38])[CH3:37])[C@@H:19]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N2CCN[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](CN3CCCC3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
A solution of (S)-1-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-(pyrrolidin-1-ylmethyl)piperazine, dihydrochloride (Example 40, Compound 128) (108 mg, 0.25 mmol) in CH2Cl2 (5 mL) at 0-5 C was treated with triethylamine (105 uL, 0.75 mmol) followed by acetic anhydride (51 uL, 0.50 mmol). The reaction mixture was allowed to warm to room temperature and stir 16 h. After this time the reaction mixture was treated with a saturated aqueous solution of NaHCO3 (2 mL). The organic portion was then dried over MgSO4, filtered, and evaporated to afford quenched with evaporated and the residue purified by silica gel flash chromatography with 100% EtOAc then 10% MeOH/EtOAc as eluant to afford product as an oil (65 mg, 65%). LC/MS (Method B) 2.22 min, [M+1]+ 402. Potency class C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH3:27])=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].O>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[C:2]2[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)=[CH:22][C:21]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CNc1ccc(F)c(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(F)c(NC(=O)OC(C)(C)C)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloro-5-nitropyrimidin-4-yl thiocyanate (2.73 g, 12.6 mmol) and sodium hydrogen carbonate (2.76 g, 32.9 mmol) in tetrahydrofuran (80 mL) was added a solution of tert-butyl [2-fluoro-5-(methylamino)phenyl]carbamate (2.63 g, 11.0 mmol) produced above in tetrahydrofuran (20 mL), and the mixture was stirred for 1.5 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {2-fluoro-5-[methyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1.[C:18]([CH2:21][N:22]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27][CH2:26][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:24][CH2:23]1)([OH:20])=[O:19].[OH-].[K+]>O1CCOCC1.O>[OH:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1)[CH2:17][N:31]1[CH2:32][CH2:33][N:22]([CH2:21][C:18]([OH:20])=[O:19])[CH2:23][CH2:24][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:26][CH2:27][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29][CH2:30]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: OCCCCCc1ccc(OCC2CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(CCCCCO)cc2)CCN(CC(=O)O)CC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
12.3 g (51.97 mmol) of 2,3-epoxy-1-[4-(5-hydroxypentyl)-phenoxy]-propane and 10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) are dissolved in a mixture of 50 ml of dioxane and 80 ml of water, and the pH is brought to pH 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 40° C. It is evaporated to dryness, the residue is taken up with 200 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 3 with 5N hydrochloric acid and evaporated to dryness. The residue is concentrated by evaporation in a vacuum and boiled out (extracted) with 200 ml of methanol/50 ml of methylene chloride. It is cooled in an ice bath and filtered off from precipitated potassium chloride. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 50 ml of water/20 ml of ethanol and then added to a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water. After concentration by evaporation in a vacuum, 8.92 g (53% of theory) of the title compound is obtained as strongly hygroscopic, vitreous solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.O>CN(C=O)C>[O:25]1[CH2:26][CH2:27][O:28][CH:24]1[CH2:23][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: BrCC1OCCO1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CC3OCCO3)c(=O)c2c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.5 g, 1.72 mmol) in DMF (10 mL) was added potassium carbonate (1.2 g, 8.6 mmol) and 2-(bromomethyl)-1,3-dioxolane (0.62 mL, 6.03 mmol). The reaction mixture was heated at 140° C. and stirred for 5 h. The mixture was cooled to rt, water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-(1,3-dioxolan-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.32 g, 64%). LC-MS: (FA) ES+ 290.