Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.Cl[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C(=O)(O)[O-].[Na+]>O.O1CCCC1.[Cl-].[Na+].O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21](=[O:22])[CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:6]2)=[CH:24][CH:25]=1
Reactant: CC(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C2CCN(CC(=O)c3ccc(F)cc3)CC2)cc1

Procedure:
To a solution of 3.0 g (12.2 mmol) of N-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide in 10 ml of water and 100 ml of tetrahydrofuran was added 2.3 g (13.4 mmol) of 2-chloro-4'-fluoro-acetophenone followed by 2.0 g (24.4 mmol) of sodium bicarbonate. This mixture was heated to reflux for 1.5 hours. The reaction mixture was poured into 500 ml of brine and extracted with chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield a solid which was recrystallized from 2-butanone/cyclohexane. 1-(4-Fluorophenyl)-2-[4-[(4acetamidophenyl)carbonyl]-1-piperidinyl]-ethanone was obtained as an off-white solid having amp of 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)=[O:28])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)NC(=S)CO1
Yield: 72 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (132 mg, 0.47 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS No. 86873-60-1] (92 mg, 0.58 mmol). The compound was obtained as white foam (177 mg, 72%). MS (ISP): m/z=422.1 [(M+H)+] and 424.1 [(M+2+H)+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:46]=[CH:47][N:48]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:45])[C:35]5[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=5)[CH:28]=4)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>C(OCC)C.O>[C:41]([C:38]1[CH:37]=[CH:36][C:35]([C:34]([NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[C:22]4[N:23]([CH:46]=[CH:47][N:48]=4)[CH:24]=3)[CH:28]=2)=[O:45])=[CH:40][CH:39]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(NC(=O)c5ccc(C(C)(C)C)cc5)c4)cn4ccnc34)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc(N5CCNCC5)cc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15) (2.0 mmol), 1M HCl in diethyl ether (20 mL), and dioxane (60 mL) is stirred at room temperature for 16 hr. Water (100 mL) is added and the pH brought to 11 with 1N NaOH. The mixture is extracted with ethyl acetate (3×80 mL), the extracts washed with water (2×70 mL) and brine (1×70 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is slurried with diethyl ether and filtered to give 4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide (16) as a cream solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C@@H:8]([OH:10])[CH3:9].[CH2:12](Br)[CH:13]=[CH2:14].O>CN(C)C=O>[CH3:9][C@H:8]([O:10][CH2:14][CH:13]=[CH2:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:11])[CH3:3]
Reactant: CC(C)CCC[C@H](C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO[C@@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.9 g, 72 mmol) and dimethylformamide (100 mL) were charged to a 250 mL three-necked flask fitted with thermocouple, magnetic stirrer, condenser and dropping funnel. To the reaction mixture was added a solution of (2S)-6-methylheptan-2-ol (3.1 g, 24 mmol) in dimethylformamide (10 mL). This reaction mixture was stirred at room temperature for 1 hr then allyl bromide (8.6 g, 72 mmol) was added dropwise over 10 minutes ensuring the reaction temperature did not rise significantly (41° C. was observed). The reaction mixture was stirred for a further 20 minutes until the reaction was complete. To the reaction mixture was added water (10 mL) and the resultant mixture was extracted with methyltert-butyl ether (2×100 mL). The combined organic phase was dried over magnesium sulphate and the solvent remove in vacuo to yield a yellow oil which was chromatographed over silica gel (hexane/methyltert-butyl ether) to give 3-{[(1S)-1,5-dimethylhexyl]oxy}prop-1-ene as a sl. yellow oil (2.7 g, 15.8 mmol, chemical yield 66%).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[F:11][C:12]1[C:16]([F:17])=[CH:15][NH:14][CH:13]=1.CC([O-])=O.[Na+]>C(Cl)Cl.O>[F:11][C:12]1[C:16]([F:17])=[CH:15][NH:14][C:13]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: Fc1c[nH]cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]cc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (4.3 ml) was cooled in ice-water bath under N2 and POCl3 (5.2 ml) was added dropwise. The mixture was stirred at room temperature for 10 min. The ice-water bath was replaced, and the mixture was diluted with DCM (45 ml). A solution of 3,4-difluoro-1H-pyrrole (Intermediate 18; 4.57 g) in DCM (45 ml) was added dropwise. The mixture was refluxed for 30 min, cooled to room temperature and a solution of NaOAc (23 g) in water (60 ml) was added slowly. The resulting mixture was refluxed for 30 min, organic phase was separated and aqueous phase was extracted with DCM. The combined organic phase was washed with NaHCO3, dried over Na2SO4, and concentrated in vacuo. The crude solid was triturated with DCM (20 ml)/pentane (100 ml), and then cooled to −20° C. to give the title compound as pale brown needles (4.73 g). NMR (CDCl3): 6.87 (m, 1H), 9.6 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]1.[Br:22]N1C(=O)CCC1=O>>[Br:22][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]([CH:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:12][CH2:11]3)[CH2:3][C:4]=2[CH:9]=1
Reactant: O=C(N1CCC(C2Cc3ccccc3O2)CC1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Product: O=C(N1CCC(C2Cc3cc(Br)ccc3O2)CC1)C(F)(F)F
Yield: 61 %

Procedure:
The title compound is prepared from 1-[4-(2,3-dihydro-benzofuran-2-yl)-piperidin-1-yl]-2,2,2-trifluoro-ethanone and N-bromo-succinimide following a procedure analogous to that described for Intermediate 1. Yield: 61% of theory; LC (method 2): tR=1.47 min; Mass spectrum (ESI+): m/z=378 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[S:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([Sn](=O)CCCC)CCC.CI>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:19][O:9][C@@H:8]1[C@H:10]([OH:11])[C@@H:12]([CH2:13][OH:14])[O:15][C@H:7]1[N:6]1[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]1=[S:17]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=S)[nH]c1=O
Reactant: CCCC[Sn](=O)CCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=S
Temperature: 50 °C

Procedure:
To a stirred solution of 5-methyl-2-thiouridine (0.500 g, 1.8 mmol) in DMF (10 ml) is added dibutyltin oxide (0.500 g, 2.0 mmol), tetrabutyl ammonium iodide (0.738 g, 2 mmol), and methyl iodide (1.022 g, 7.2 mmol). The reaction flask is sealed and heated at 50° C. for 16 hours. The mixture is cooled and another portion of methyl iodide is added (1.022 g, 7.2 mmol) and the reaction heated for an additional 16 hours. At the end of this time, the reaction mixture is cooled to room temperature and diluted with methylene chloride and chromatographed using a methylene chloride/methanol gradient. The appropriate fractions are collected and concentrated to give 2'-O-methyl-5-methyl-2-thiouridine.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:12](=[O:14])[CH3:13])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCNc1nc(C)co1
Product: CCCCN(C(C)=O)c1nc(C)co1
Yield: 75.4 %

Procedure:
The procedure of Example 17 was followed using 15.0 g. (0.0974 m) of 2-butylamino-4-methyl oxazole and 25 c.c. of acetic anhydride. B.p. = 58°-60° C/0.1 mm. wt. = 14.4 g. yield = 75.4%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[C:14]([OH:16])=[O:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(F)ccc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: COc1cc(F)ccc1/C=C/C(=O)O
Yield: 95.8 %

Procedure:
A solution of 4-fluoro-2-methoxybenzaldehyde (1.0 g, 6.49 mmol) and malonic acid (1.350 g, 12.98 mmol) in pyridine (10 mL) was refluxed for 16 h. After concentration the residue was taken into water. The solid was filtered, washed with water, then dried to give (E)-3-(4-fluoro-2-methoxyphenyl)acrylic acid (1.22 g, 96% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.03 (d, J=16.1 Hz, 1H), 7.53 (dd, J=8.5, 6.8 Hz, 1H), 6.75-6.65 (m, 2H), 6.52 (d, J=16.1 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)=[C:4]([NH2:23])[N:3]=1.C([O-])(=O)C.[Na+].[Br:29]Br>C(Cl)(Cl)Cl>[Br:29][C:7]1[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[C:9]2[C:5]([N:6]=1)=[C:4]([NH2:23])[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: COC(=O)Cc1cccc(Cn2cnc3c(N)nc(Cl)nc32)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cccc(Cn2c(Br)nc3c(N)nc(Cl)nc32)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
After 2-chloro-9-(3-methoxycarbonylmethylbenzyl)adenine obtained by Reference example 38 (2.00 g, 6.03 mmol) and sodium acetate (2.95 g, 36.0 mmol) were dissolved in chloroform (100 ml), bromine (4.79 g, 30.0 mmol) was added thereto and the mixture was stirred at room temperature for 5 hours. After removing the solvent, the residue was poured into water and extracted with chloroform. The organic layer was washed with saturated sodium hydrogencarbonate, saturated sodium hydrogensulfite and saturated brine in that order, dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (1.78 g, 4.34 mmol, yield: 72%) as a brown solid.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=O)(=O)C.[C:11]([CH:16]1[CH2:24][CH:23]2[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[NH:17]1)([O:13]CC)=[O:12].C(C1CC2C(=CC=CC=2)N1)(OCC)=O>>[SH:4][CH2:5][CH:6]([CH3:10])[C:7]([N:17]1[CH:18]2[CH:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:24][CH:16]1[C:11]([OH:13])=[O:12])=[O:9]
Reactant: CCOC(=O)C1CC2CCCCC2N1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: CCOC(=O)C1Cc2ccccc2N1
Product: CC(CS)C(=O)N1C(C(=O)O)CC2CCCCC21

Procedure:
Using the method described in example 1, beginning with 3-acetylthio 2-(RS) methylpropionic acid and 2-(RS) carbethoxy perhydroindole, prepared by reduction of 2(RS) carbethoxy indoline according to the method described in example 13, the following are obtained successively:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]([O:10][CH3:11])[O:4]1.O.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CC(C)=O.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:11][O:10][CH:5]1[O:4][C@H:3]2[C@H:7]([O:8][C:13]([CH3:18])([CH3:14])[O:1][CH2:2]2)[C@H:6]1[OH:9]
Reactant: COC1O[C@H](CO)[C@H](O)[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COC1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1O
Reaction time: 60 h
Yield: 5030.4 %

Procedure:
Compound 35.2 (120.45 g, 734 mmol) was dissolved in 1.5 L acetone, treated with p-toluene sulfonic acid monohydrate (0.6 g, 3.15 mmol) and CuSO4 (225 g, 1.41 mol). The mixture was stirred for 60 h. The solid was removed by filtration and washed with (3×200 mL) acetone. The filtrate and the washings were combined and neutralized with 2.5 mL concentrated ammonium hydroxide. The solvent was removed by reduced pressure and the residue was dissolved in 750 mL CH2Cl2 and washed with 3'100 mL water. The water extracts were combined and extracted with 3×100 mL CH2Cl2. The CH2Cl2 extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 0-3% MeOH in CH2Cl2 to give compound 35.3 (32.36 g, 21.6% yield).
Reaction SMILES: [CH3:1][O-].[Na+].[CH3:4][O:5][N:6]=[C:7]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:8](=[N:10][OH:11])C.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[CH:29][O:30][CH3:31])[C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[CH3:31][O:30][CH:29]=[C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:17]([O:11][N:10]=[CH:8][C:7](=[N:6][O:5][CH3:4])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:1])[C:25]([O:27][CH3:28])=[O:26]
Reactant: C[O-]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: C=C(C)CC(=NOC)C(C)=NO
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CC(C=NOC(C)c1ccccc1C(=COC)C(=O)OC)=NOC
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
112.2 g of a 30% strength methanolic solution of sodium methoxide were added to 11.5 g of 5-methylhex-5-ene-2,3-dione 3-(O-methyloxime) 2-oxime from Example 4 in 55 ml of DMF, and the mixture was stirred at 23° C. for 30 minutes. 21.3 g of methyl 2-(2-bromomethylphenyl)-3-methoxyacrylate (preparation: see U.S. Pat. No. 5,286,894) in 400 ml of DMF were subsequently added dropwise (temperature increase to up to 35° C.), and the reaction solution was stirred at 23° C. for one hour and then poured into ice-water/n-pentane. The mixture was subsequently stirred for one hour and the product was filtered off with suction, washed with water and a little n-pentane and dried under reduced pressure. Yield: 16.7 g of the title compound as a yellowish solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:15][Br:16]>CC(C)=O>[Br-:16].[CH3:11][O:12][N:13]=[C:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:15][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CON=C(CBr)c1ccc(C)cc1
Reactant: c1ccc2ncccc2c1
Solvent: CC(C)=O
Product: CON=C(C[n+]1cccc2ccccc21)c1ccc(C)cc1
Product: [Br-]
Yield: 11 %

Procedure:
A solution of quinoline and 2-bromo-1-p-tolylethanone O-methyl oxime was stirred refluxed in acetone for 5 days. A precipitate was separated by filtration and rinsed with Et2O to give a light orange solid in 11% yield: mp 285-288° C.; 1H NMR 500 MHz (DMSO-d6) δ 2.19 (s, 3H), 4.06 (s, 3H), 6.46 (s, 2H), 7.08 (d, 2H, J=7.9 Hz), 7.37 (d, 2H, J=8.2 Hz), 8.04 (t, 1H, J=7.3 Hz), 8.17 (m, 1H), 8.22 (d, 1H, J=9.2 Hz), 8.32 (m, 1H), 8.44 (d, 1H, J=7.9 Hz), 9.68 (d, 1H, J=8.2 Hz), 9.28 (d, 1H, J=5.8 Hz); Elem. anal. found: C, 61.17; H, 5.18; N, 7.50% (calcd for C19H19BrN2O: C, 61.47; H, 5.16; N, 7.55%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH2:35][CH2:36][CH3:37]>CS(C)=O.C(OCC)(=O)C>[CH2:34]([N:26]1[C:27]2[C:23](=[CH:22][CH:21]=[CH:20][C:19]=2[C:16]2[N:15]=[C:14]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[C:4]([Cl:3])[CH:5]=3)[O:18][N:17]=2)[C:24]([CH2:28][CH2:29][C:30]([O:32][CH2:5][CH2:4][CH2:9][CH3:8])=[O:31])=[CH:25]1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCI
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCOC(=O)CCc1cn(CCCC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (65 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodobutane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford butyl 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D123) (61 mg). δH (CDCl3, 400 MHz): 0.73 (3H, t), 0.92 (3H, t), 1.03 (2H, m), 1.34 (2H, m), 1.45 (8H, m), 1.59 (2H, m), 2.71 (2H, t), 3.12 (2H, t), 4.08 (2H, t), 4.16 (2H, t), 4.72 (1H, m), 6.94 (1H, s), 7.07 (1H, d), 7.19 (1H, t), 7.53 (1H, dd), 7.76 (1H, dd), 8.08 (1H, dd), 8.25 (1H, d); MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH2:12]([N:14]([CH2:28][CH3:29])[C:15]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:16]=1[C:17](O)=[O:18])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:17]([C:16]1[CH:20]=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=[CH:23][C:15]=1[N:14]([CH2:28][CH3:29])[CH2:12][CH3:13])=[O:18])[CH2:6][CH2:5]2
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2c(c1)CCNC2
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-diethylamino-5-methanesulfonyl-benzoic acid (example 2.6).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:24]([NH2:26])=[O:25])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)[N:8]=1.C1C=C([Cl:33])C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.[NH:47]1[CH2:52][CH2:51][CH2:50][C@@H:49]([O:53][C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:57]=[CH:56][N:55]=2)[CH2:48]1>CN1C(=O)CCC1.CCOC(C)=O>[C:54]1([O:53][C@@H:49]2[CH2:50][CH2:51][CH2:52][N:47]([C:3]3[N:4]=[N:5][C:6]([C:24]([NH2:26])=[O:25])=[C:7]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[O:17])=[CH:12][CH:11]=4)[N:8]=3)[CH2:48]2)[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=[CH:56][N:55]=1.[ClH:33]
Reactant: c1ccc2c(O[C@@H]3CCCNC3)nccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: NC(=O)c1nnc(N2CCC[C@@H](Oc3nccc4ccccc34)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Yield: 617.1 %

Procedure:
To a solution of 3-(methylthio)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (75 mg, 0.20 mmol) in NMP (4 mL) was added mCPBA (77% strength, 140 mg, 0.60 mmol). The mixture was stirred at RT for 30 m to yield a mixture of corresponding sulfone and sulfoxide. To the mixture was then added DIEA (0.28 mL, 1.60 mmol) and Compound 54 (100 mg, 0.40 mmol). The mixture was heated at 90° C. for 90 min. The mixture was cooled, diluted with EtOAc (100 mL), washed with 1N NaOH and brine, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 50 to 100% EtOAc in DCM and further subjected to reverse phase preparative HPLC to afford the title compound (55) as an HCl salt (45 mg). MS found for C29H30N8O4 as (M+H)+ 555.2, (M−H)− 553.3. UV: λ=275 nm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].O>CN(C=O)C.CCOC(C)=O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[Br:7]
Reactant: COC(=O)CBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1Br
Reaction time: 0.05 h
Yield: 96.8 %

Procedure:
Powdered potassium carbonate (3.84 g, 27.8 mmol) is added to a stirred solution of 2-bromophenol (3.20 g, 18.5 mmol) and methyl bromoacetate (3.11 g, 20.3 mmol) in anhydrous DMF (20 mL). The resultant mixture is stirred at ambient temperature under nitrogen for 16 hours. Water (140 mL) and EtOAc (120 mL) are added to the mixture and the two-layered solution is stirred vigorously for 3 minutes. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed oh silica (gradient 2-8% EtOAc in hexane) to give 4.39 g (17.9 mmol, 97% yield) of the title compound. EIMS: m/z 244 (M+, 79Br), 246 (M+, 81Br).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][N:20]([CH3:27])[CH2:21][CH2:22][CH2:23]C(Cl)=O.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:18])[N:8]([C:6](=[O:7])[CH2:23][CH2:22][CH2:21][N:20]([CH3:27])[CH3:19])[CH2:12]1
Reactant: CN(C)CCCC(=O)Cl
Reactant: C1CCNCC1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N2CCCCC2)N(C(=O)CCCN(C)C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4(dimethylamino)butanoyl chloride, and piperidine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=339.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[OH-].[K+].[N+:17]([CH3:20])([O-:19])=[O:18]>C1COCC1.CO>[N+:17]([CH2:20][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:14][CH:13]=1)[OH:12])([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])CC(O)c1ccc(-c2ccccn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a cooled (0° C.) solution consisting of 4-pyridin-2-yl-benzaldehyde (346 mg, 1.9 mmol) in THF (5 mL) and NO2CH3 (0.3 mL) and MeOH (2.5 mL) was added KOH (2.5 M, 1.13 mL). The reaction mixture was stirred at 0° C. for 30 min. and then quenched with a saturated NH4Cl solution. The aqueous mixture was extracted with EtOAC. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (257 mg, 60%).