Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][O:15]C(=O)C)=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].O.[OH-].[Li+]>C1COCC1.O>[C:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(=O)OCc1cncn1Cc1ccc(C#N)cc1
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CO)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of the acetate 4 (50.4 g) in 1.5 L of 3:1 THF/water at 0° C. was added lithium hydroxide monohydrate (18.9 g). After one hour, the reaction was concentrated in vacuo, diluted with EtOAc (3 L), and washed with water, sat. aq. NaHCO3 and brine. The solution was then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product (26.2 g) as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:5]1(=[O:23])=[O:22].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.Cl>>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[S:5](=[O:23])(=[O:22])[N:4]([CH2:3][CH2:2][NH:27][CH:24]3[CH2:26][CH2:25]3)[CH2:9][C:8]=2[CH:10]=1
Reactant: NC1CC1
Reactant: O=S1(=O)N(CCBr)Cc2cc(F)ccc2N1c1ccccc1F
Agent: Cl
Product: O=S1(=O)N(CCNC2CC2)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 95 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(2-bromoethyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{2-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]ethyl}cyclopropanamine (0.099 g, 95%) as a white solid:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9]Cl)=[O:7].[C:11]([NH:14][C:15]1[C:16]([I:31])=[C:17]([N:26]([C:28](=[O:30])[CH3:29])[CH3:27])[C:18]([I:25])=[C:19]([C:22]([O-:24])=[O:23])[C:20]=1[I:21])(=[O:13])[CH3:12].[Cs+].[I-].[Na+]>CN(C=O)C>[C:11]([NH:14][C:15]1[C:16]([I:31])=[C:17]([N:26]([C:28](=[O:30])[CH3:29])[CH3:27])[C:18]([I:25])=[C:19]([C:22]([O:24][CH2:9][O:8][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:23])[C:20]=1[I:21])(=[O:13])[CH3:12]
Reactant: O=C(OCCl)c1cccs1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(=O)c2cccs2)c(I)c(N(C)C(C)=O)c1I
Reaction time: 4 h

Procedure:
Chloromethyl 2-thiopbenecarboxylate (0.63 g, 3.6 mmol) (Intermediate 6) in dry DMF (70 ml) is added dropwise at 50° C. to a solution of cesium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (3.00 g, 3.9 mmol) and sodium iodide (28 mg, 0.19 mmol) in dry DMF (45 ml). The precipitate is removed by filtration after stirring for 4 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (50 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[C:35](Cl)(=[O:37])[CH3:36].C(N(C(C)C)C(C)C)C>>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]3[C:27]([NH:29][C:30]3([C:33]#[N:34])[CH2:31][CH2:32]3)=[O:28])=[O:17])[CH2:19][CH2:20]2)[CH2:26][CH2:25]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (38 mg, 75.1 μmol) in methylenehloride (0.75 mL) was added under stirring ethyldiisopropyl amine (19.7 μL, 113 μmol) and acetyl chloride (5.99 μL, 82.6 μmol). The reaction was stirred at room temperature for 5 hours and additional ethyldiisopropyl amine (19.7 μL, 113 μmol) and acetyl chloride (5.99 μL, 82.6 μmol) was added. The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using a gradient from methylenechloride to a mixture of methylenechloride/methanol (v:v 19:1) as solvent to yield the title compound as a white solid (28.8 mg, 70%). MS ISP (m/e): 548.3/550.4 (100/41) [(M+H)]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol [PCT Int. Appl. (2001), WO 01/00603 A1] in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Zn+].NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13][CH3:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccccc1C[Zn+]
Reactant: N#Cc1cc(I)ccc1N
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: COc1ccccc1Cc1ccc(N)c(C#N)c1

Procedure:
From 9 (610 mg, 2.5 mmol) and 2-methoxybenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the same method as 10a; white powder (364 mg, 61%): mp 77.5-78.5° C.; 1H NMR (CDCl3) δ 3.81 (s, 3H, OMe), 3.82 (s, 2H, CH2), 4.25 (br s, 2H, NH2), 6.64 (d, J=8.0 Hz, 1H, H-3), 6.85-6.88 (m, 2H, H-3′ and H-5′), 7.06 (d, J=7.2 Hz, 1H, H-6′), 7.18-7.23 (m, 3H, H-4′, H-4, and H-6).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:24][C:20]1[C:21]([F:23])=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)c(F)cc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2,4,5-trifluoronitrobenzene and dimethyl sulfoxide, ethyl 2-(4,5-difluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15](=[CH2:18])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:16][C:15]([CH3:18])=[CH2:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: C=C(C)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)COc1ccc(C(=O)OC)cc1OC
Temperature: 55 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a stirred solution of methyl 4-hydroxy-3-methoxy-benzoate (2 g, 10.98 mmol), 2-methylprop-2-en-1-ol (871.0 mg, 1.0 mL, 12.1 mmol) and triphenylphosphine (3.17 g, 2.8 mL, 12.1 mmol) in THF (63.28 mL) at 0° C. was added DIAD (2.44 g, 2.34 mL, 12.1 mmol). The ice bath was removed and the reaction was stirred at 55° C. for 16 hours. The reaction mixture was diluted with EtOAc and washed sequentially with NaHCO3 (2×20 mL) and brine (2×20 mL) solutions. The organic layer was separated, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified with silica gel using (0-30%) ethyl acetate-hexanes to yield methyl 3-methoxy-4-(2-methylallyloxy)benzoate (1.94 g, 75%) as a viscous liquid. ESI-MS m/z calc. 236.1. Found 237.1 (M+1)+. Retention time: 1.63 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 5.07 (br s, 1H), 4.97 (br s, 1H), 4.55 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 1.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH2:16][C:17]#[CH:18])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](O)=[O:6].S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH2:16][C:17]#[CH:18])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5]([Cl:21])=[O:6]
Reactant: C#CCOc1cc(C(=O)O)cc(Cl)c1OCC#C
Reactant: O=S(Cl)Cl
Product: C#CCOc1cc(C(=O)Cl)cc(Cl)c1OCC#C

Procedure:
A mixture of 3-chloro-4,5-dipropargyloxybenzoic acid (10.7 g) and thionyl chloride (30 ml) was stirred under reflux for 1 hour. After cooling, the reaction mixture was evaporated under reduced pressure to give 3-chloro-4,5-dipropargyloxybenzoyl chloride in a quantitative yield.
Reaction SMILES: C1C=C([N+]([O-])=O)C([O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])=CC=1.C(=O)(O)[O-].[Na+]>>[O:10]=[CH:11][C@@H:12]([C@H:13]([C@H:14]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:19])[OH:20])[OH:21]
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Temperature: 37 °C
Reaction time: 2 h

Procedure:
To a solution containing 30.12 g (100 mmol) o-nitrophenyl-β-D-galactoside in 1000 ml distilled water buffered at pH 6.8 with 0.5M phosphate buffer and maintained at 37° C. is added 10 mg of monoclonal antibodies prepared according to Example 6. The reaction mixture is gently agitated for 2.0 hours. The monoclonal antibodies are then recovered from the reaction mixture by ultrafiltration. The filtrate is then cooled to 10° C. and treated with 9.2 g (110 mmol) sodium bicarbonate. The D-galactose is recovered by extracting the filtrate with three 100 ml portions of diethyl ether. The ether portions are combined, washed once with 1.0N sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield D-galactose. The aqueous portion is then combined with the sodium bicarbonate wash and acidified to pH 3 by the addition of 5N hydrochloric acid. The acidified aqueous portion is then extracted three times with ether. The etheral extracts are combined, dried over magnesium sulfate, filtered and concentrated at reduced pressure to yield o-nitrophenol. The o-nitrophenol and D-galactose may be further purified by HPLC or by recrystallization.
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]1[C:19]([O:21][CH3:22])=[O:20].[Br:25]N1C(=O)CCC1=O>CN(C=O)C>[Br:25][C:8]1[C:7](=[O:10])[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([C:19]([O:21][CH3:22])=[O:20])[N:4]([CH2:3][CH:2]([OH:1])[CH2:23][OH:24])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)ccn1CC(O)CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)CO
Temperature: 10 °C
Yield: 86.8 %

Procedure:
A reactor was charged with (3.759 kg, 11.27 mol) of methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 7 and 18.8 L of DMF. To this agitated mixture at 18-20° C. was added N-bromosuccinimide (2.220 kg, 12.47 mol) over 20 minutes via a powder funnel. The resultant mixture was stirred at rt for 16 h. At this time less than 1% of starting material was present by HPLC. The mixture was worked up in half batches by cooling to 10° C. and added an ice/water mixture (12 kg ice in 35 kg deionized water) and the mixture was agitated, then filtered. This was repeated for the second half of the batch. The combined filter cake was washed with 14 L of water and dried in a vacuum oven to provide 4.033 kg of methyl 5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 19 (91.6%) as an off-white powder of 99.2% HPLC purity. 1H NMR (300 MHz, Methanol-d4) δ 8.21 (s, 1H), 7.41-7.33 (m, 5H), 5.16 (s, 2H), 4.17 (dd, J=14.3, 2.4 Hz, 1H), 3.90 (dd, J=14.3, 9.0 Hz, 1H), 3.81 (s, 3H), 3.78 (m, 1), 3.52 (dd, J=11.3, 4.8 Hz, 1H), 3.41 (dd, J=11.3, 6.3 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[I:13]N1C(=O)CCC1=O>ClCCCl.O1CCCC1>[I:13][C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)c1cc2ccccn2n1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)c1nn2ccccc2c1I
Yield: 93.9 %

Procedure:
2-Isopropyl-pyrazolo[1,5-a]pyridine (18.42 g, 115 mmol) and N-iodosuccinimide (28.45 g, 126 mmol) were dissolved in a mixture of 1,2-dichloroethane (300 ml) and tetrahydrofuran (300 ml). The mixture was stirred at reflux for 18 hours. The mixture was cooled and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 20% ethyl acetate in hexanes) to give 30.9 g (94%) of 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine. 1H-NMR (250 MHz, CDCl3) δ 8.36 (d, J=7.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 6.67 (t, J=7.6 Hz, 1H), 3.20 (sept, J=7.0 Hz, 1H), 1.37 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][OH:36].[H-].[Na+]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][C:29]([O:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CN(C)CCO
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(OCCN(C)C)nc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (100 mg, 0.21 mmol), prepared using procedures similar to those described above in Example 1, 2-(dimethylamino)ethanol (50 μL, 0.50 mmol) and dry DMF were combined and 60% NaH in oil (80 mg, 2.0 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethoxy)pyridine-3-sulfonamide (23 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, 1H), 8.73 (s, 1H), 8.38 (dd, 1H), 7.40 (dd, 1H), 7.31 (m, 3H), 7.14 (m, 2H), 6.85 (d, 1H), 6.12 (m, 1H), 4.56 (m, 2H), 3.76 (s, 6H), 3.43 (m, 2H), 2.77 (s, 6H). MS (EI) m/z for C25H28N6O5S: 525.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[O-].[Li+].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].O>CN(C)C=O>[Br:1][C:2]1[C:3](/[CH:13]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ncc(Br)c(C)c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Br)c(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) was dissolved in dimethylformamide (300 mL), and lithium methanolate (6.07 mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated to 100° C. To this mixture was added 1,1-dimethoxy-N,N-dimethylmethanamine (64.5 mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95° C. for 16 hours. The reaction mixture was cooled to room temperature and water was added carefully (300 mL, exothermic). The resulting precipitate was collected by vacuum filtration, washed with water, and dried to provide (E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (13.9 g, 45.9 mmol, 76% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C)C=O.C(N(CC)CC)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1OC
Temperature: 0 °C

Procedure:
4.3 g (20 mmol) 1,5-diacetyl-2-indolinone (Ex. II) are stirred overnight together with 4 g of 3,4-dimethoxybenzoic acid, 7.1 g TBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate) and 14 ml triethylamine in 80 ml DMF (dimethylformamide) at ambient temperature. Then the mixture is poured onto 300 ml ice water with 10 ml of conc. hydrochloric acid and the precipitate formed is suction filtered. The residue is washed with a little methanol and then with ether.
Reaction SMILES: C([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:28]([O:27][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)OC)cc2)cc1)C(=O)O
Yield: 97.1 %

Procedure:
(S)-2-Ethoxy-3-(4-[2-{4-(methoxycarbonylamino)phenyl]ethoxy]phenyl)propanoic acid ethyl ester (described in Example 41) (0.52 g; 1.25 mmole) was dissolved in tetrahydrofuran (10 ml) and lithium hydroxide (0.034 g; 1.42 mmole) dissolved in water (2 ml) was added slowly. The reaction mixture was stirred over night, hydrochloric acid (1 M, 1 ml) was added and tetrahydrofuran evaporated. The residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated and 0.47 g (99% yield) (S)-2-ethoxy-3-[4-{2-[4-(methoxycarbonylamino)phenyl)ethoxy]phenyl}propanoic acid was obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:13][CH3:14].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28]O.C(N(CC)C(C)C)(C)C.S(Cl)(Cl)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([C:6]2[O:8][CH2:28][C:27]([CH3:31])([CH3:30])[N:26]=2)=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Reactant: CC(C)(N)CO
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2=NC(C)(C)CO2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
To a solution of 22.6 g (86.6 mmol) of 4-bromo-3,5-dimethoxybenzoic acid (*) in methylene chloride (400 mL) was added 1.5 mL (19.4 mmol) of dimethylformamide. With ice cooling, 13.0 g (102.0 mmol) of oxalyl chloride was added in portions and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, whereby crude crystals of 4-bromo-3,5-dimethoxybenzoyl chloride were obtained. To an ice-cold solution of 8.40 g (94.2 mmol) of 2-amino-2-methylpropanol in methylene chloride (100 mL), 16.6 mL (95.3 mmol) of N,N-diisopropylethylamine and a solution of crude 4-bromo-3,5-dimethoxybenzoyl in methylene chloride (200 mL) were added. After stirring at room temperature for 10 minutes, the reaction mixture was washed successively with water, 8.0 mol/L hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To the residue was added 47.5 mL (651.0 mmol) of thionyl chloride and the mixture was stirred at room temperature for 10 minutes. Ice water and 600 mL (1500 mmol) of a 2.5 mol/L aqueous sodium hydroxide solution were added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from diethyl ether-hexane, whereby 20.9 g of 2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline was obtained as colorless fine needles (mp: 172.5 to 174.5° C., yield: 77%). * Erdtman, H.; Leopold, B. Acta Chem. Scand. 1948, 2, 34-41 (Chem. Abstr. 1949, 43 1037i), incorporated herein by reference.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[CH:15]1([CH2:14][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Product: O=[N+]([O-])c1ccc2c(cnn2CC2CC2)c1

Procedure:
Synthesized as described in Example 4 using 5-nitro-1H-indazole and (bromomethyl)cyclopropane to afford a mixture of regioisomers. The following data are for the title regioisomer: 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J=2.0 Hz, 1H), 8.26 (dd, J=9.3 and 2 Hz, 1H), 8.20 (s, 1H), 7.48 (d, J=9.3 Hz, 1H), 4.31 (d, J=6.8 Hz, 2H), 1.35 (m, 1H), 0.62 (m, 2H), 0.44 (m, 2H); MS (ES) m/z 218 (M+1).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][CH:9]=1)=[O:7])C>O>[CH2:13]([C:11]1[S:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1)[CH3:14]
Reactant: CCOC(=O)c1csc(CC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(C(=O)O)cs1
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Potassium hydroxide (1.02 g, 18.3 mmol) in water (3 mL) was added to a solution of 5-ethyl-thiophene-3-carboxylic acid ethyl ester (6.1 mmol) in IMS (9 mL). The reaction was stirred for 1 hour then partitioned between diethyl ether and water. The aqueous layer was acidified to pH 7 with concentrated hydrochloric acid and extracted with diethyl ether. The organic solution was dried over magnesium sulphate, filtered and the solvent removed to give the title compound (0.78 g). 1H NMR (400 MHz, CHCl3-d): δ 8.0 (s, 1H), 7.2 (s, 1H), 2.8 (q, 2H), 1.3 (t, 3H).