Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][Cl:22])([O-:18])=[O:17].Cl>CO.CCOCC>[ClH:22].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
Analogously to Example 1, a crude ether is obtained from 1.74 g. of 4-(1-imidazolylmethyl)-phenol, 300 mg. of sodium hydride suspension, and 1.72 g. of 2-nitrobenzyl chloride. This crude ether is dissolved in methanol and combined with an excess of methanol which contains hydrogen chloride until the mixture shows an acidic reaction. After the solvent has been removed by evaporation under vacuum, the residue is dissolved in methylene chloride and mixed with ether until the onset of crystallization, thus obtaining 925 mg. of [4-(1-imidazolylmethyl)-phenyl]-(2-nitrobenzyl)-ether, hydrochloride, which melts at 156°-158° after another recrystallization from isopropanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:23])[CH2:17][CH2:16]2)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Cl)cc(OC2CCNCC2)c1C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(OC2CCN(C)CC2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of methyl 5-chloro-2-methyl-3-(piperidin-4-yloxy)benzoate, hydrochloride (140 mg, 0.437 mmol) and formaldehyde (195 μl, 2.62 mmol) in methanol (3580 μl) and acetic acid (597 μl) was added portion wise sodium triacetoxyborohydride (278 mg, 1.312 mmol). The reaction was stirred for 18 h at RT, at which time it was concentrated. The residue was dissolved in water, neutralized with saturated sodium bicarbonate solution, and extracted with EtOAc (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to give methyl 5-chloro-2-methyl-3-((1-methylpiperidin-4-yl)oxy)benzoate (0.130 g, 0.437 mmol, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.61-1.73 (m, 2 H) 1.84-1.94 (m, 2 H) 2.18 (s, 3 H) 2.21-2.27 (m, 2 H) 2.28 (s, 3 H) 3.83 (s, 3 H) 4.54 (dt, J=7.14, 3.63 Hz, 1 H) 7.29 (d, J=2.02 Hz, 1 H) 7.32 (d, J=2.02 Hz, 1 H). MS(ES) [M+H]+ 298.1.
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[C:3](=[O:43])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[CH:26]([C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH2:25][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8].[H][H]>[Pd].CO>[CH3:1][C:2]([CH3:45])([CH3:44])[C:3](=[O:43])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[CH:26]([C:27]([OH:29])=[O:28])[CH2:25][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)O

Procedure:
The diester product from part (d) (2.0 g.) is dissolved in 50 ml. of methanol containing 0.5 g. of 5% palladium on carbon catalyst and hydrogenated at 50 psi on a Parr apparatus until cessation of hydrogen uptake (2-4 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is triturated with acetonitrile or purified by flash chromatography to give (+)-4,5-dihydro-1-[[[(2,2-dimethyl-1-oxopropoxy)methoxy] (4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)=[CH:8][C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:14]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:16])[CH:17]=[CH:18][CH:19]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: C1COCCN1
Product: O=C(c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1)N1CCOCC1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with morpholine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone (58 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 23.7 mg of 337. MS (Q1) 527.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([N:29]([CH2:37][CH3:38])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)[CH3:28]>COC(C)(C)C>[Cl:1][C:2]1[C:3]([NH:36][C:33]2[CH:32]=[CH:31][C:30]([N:29]([CH2:37][CH3:38])[CH2:27][CH3:28])=[CH:35][CH:34]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: CCN(CC)c1ccc(N)cc1
Solvent: COC(C)(C)C
Product: CCN(CC)c1ccc(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)cc1
Yield: 56 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.020 g, 0.051 mmol) and N,N-diethyl-1,4-phenylenediamine (0.1 g) were heated to 180° C. for 2 h. The reaction mixture was diluted with tert-butyl methyl ether (5 ml) and extracted with 2M HCl (20 ml). The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was evaporated in vacuo and the residue was dissolved in CH3CN (2 ml) and purified by HPLC-C18, giving the title product (56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])(C)[C:9]#N.CCO.C([O-])([O-])=O.[K+].[K+].OO.CC#[N:26]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:26])([CH3:12])[CH3:9]
Reactant: CC#N
Reactant: CC(C)(C#N)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(N)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-(2-Chlorophenyl)-2-methylpropanenitrile (5.0 g, 0.028 mol) along with 50 mL of EtOH was added into a 250 mL round-bottomed flask. To this was added 50 mL of saturated aqueous K2CO3. This mixture was cooled to 0° C. then 85 mL of 30% aqueous H2O2 was slowly added. The reaction mixture was allowed to warm to room temperature, and then it was stirred at that temperature for 12 h. The mixture was extracted with CH2Cl2 (3×150 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a viscous oil. To this oil was added 40 mL of CH3CN, 40 mL H2O, and 13.2 g (0.031 mol) of PhI(O2CCF3)2. This mixture was stirred at r.t. for 12 h, diluted with 300 mL of H2O, and then stirred for an additional 4 h at room temperature. The aqueous phase was extracted using MTBE (1×200 mL) follow by diethyl ether (2×100 mL). The aqueous layer was basified with 1N NaOH (pH=13) and then extracted with CH2Cl2 (3×100 mL). The organic extracts were dried and concentrated in vacuo to give the desired product as a colorless oil that was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:37][NH2:38]>C(Cl)Cl>[OH:37][NH:38][C:14](=[O:15])[CH2:13][CH:12]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(SC(CC(=O)NO)Cc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (6.02 mmol) of 3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutanoic acid in 50 mL of CH2Cl2 at 25° C. under argon is added 0.2 mL of DMF followed by 6.02 mL (12.03 mmol, 2 eq) of 2 M solution of oxalyl chloride in CH2Cl2. After stirring at 25° C. for 3 hours, the mixture is cooled to 0° C. and 3.7 mL (30.08 mmol, 5 eq) of O-trimethylsilylhydroxylamine is added. This mixture is then stirred at 25° C. for 18 hours. The reaction is partitioned between CH2Cl2 and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The product is purificatied by flash silica gel chromatography to afford N-hydroxy-3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutyramide as a yellow crystalline solid. (1.7 g, 81%): 1H-NMR (300 MHz, DMSO-d6) δ (TMS) 2.2(m, 2H), 2.81 (m, 2H), 3.6(m, 1H), 3.75(s, 6H), 6.89-7 (m, 3H), 7.17-7.35(m, 5H), 8.85(s, 1H), 10.5(s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>ClC(Cl)C>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:12])[CH:4]=1)(=[O:10])=[O:9])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1F
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(NS(=O)(=O)c1ccc(F)c(C)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a vial containing a solution of 4-fluoro-3-methylbenzenesulfonyl chloride (50 mg, 0.24 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (61 mg, 0.24 mmol) in anhydrous dichloroethane (1 mL) was added pyridine (58 μL, 0.719 mmol). The vial was capped and shaken for 18 h. The solvent was removed in vacuo and the residue transferred to a separatory funnel with EtOAc (100 mL) and washed with distilled water (100 mL×2). The organic layer was removed and the combined aqueous washings were extracted with EtOAc (100 mL×2). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered, and evaporated to give a white solid (66 mg). This material was purified by Gilson RP-HPLC (column YMC Combiprep 50×20 mm, gradient 10-100% CH3CN: H2O) to afford a white solid (29 mg, 28%). Mass Spectrum (−ESI): 424 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.[Cl:16]CCl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CC1C/C(=C\C(=O)O)c2cc(F)ccc21
Reactant: ClCCl
Product: CC1C/C(=C\C(=O)Cl)c2cc(F)ccc21

Procedure:
This compound was prepared in an analogous manner to Example 15h with the replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid with (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetic acid (9 g, 43.6 mmol). The product residue was dissolved in dichloromethane and used, without purification, in Example 17, 18, and 19.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])#[N:2].[I-].C[N:15](C)N(C)C>CS(C)=O>[C:1]([C:3]1([NH2:15])[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:4]1[NH2:5])#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Reactant: CN(C)N(C)C
Agent: [I-]
Solvent: CS(C)=O
Product: N#CC1(N)C=CC([N+](=O)[O-])=CC1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To a solution of 2-cyano-5-nitroaniline (435 mg, 2.67 mmol) in dimethylsulfoxide (25 ml) was added tetramethylhydrazine iodide (534 mg, 2.67 mmol) and sodium t-pentoxide (880 mg, 8.01 mmol). The mixture was stirred at room temperature for 12 hrs., the reaction was quenched with 10% HCl. Precipitated solids were filtered and the remaining solution was extracted with ethyl acetate, the solvent was evaporated and chromatography of the resulting solid on silica gel (25%EtOAc/Hexane) gave the desired product (254 mg, 53%). 1H NMR (CD3COCD3): δ7.49 (d, 1H), 7.03 (bs, 2H), 6.80 (d, 1H), 5.78(bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[C:3]([N:28]2[CH2:29][C@@H:30]([F:31])[C@@H:26]([CH2:25][NH:24][CH:21]3[CH2:22][CH2:23]3)[CH2:27]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 49.7 %

Procedure:
Using 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (300 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 8-chloro-1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow solid (218 mg).
Reaction SMILES: [C:1]([C:4]([F:23])=[C:5]1[CH:12]2[CH2:13][C:8]3([O:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)(O)=[O:2].[Br:24][C:25]1[C:26]([S:32]([NH2:35])(=[O:34])=[O:33])=[C:27]([Cl:31])[S:28][C:29]=1[Cl:30]>>[Br:24][C:25]1[C:26]([S:32]([NH:35][C:1](=[O:2])[C:4](=[C:5]2[CH:12]3[CH2:13][C:8]4([O:15][C:16](=[O:22])[CH2:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:9][CH:10]([CH2:14][CH:6]2[CH2:7]4)[CH2:11]3)[F:23])(=[O:33])=[O:34])=[C:27]([Cl:31])[S:28][C:29]=1[Cl:30]
Reactant: CC(C)(C)CC(=O)OC12CC3CC(C1)C(=C(F)C(=O)O)C(C3)C2
Reactant: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Product: CC(C)(C)CC(=O)OC12CC3CC(C1)C(=C(F)C(=O)NS(=O)(=O)c1c(Cl)sc(Cl)c1Br)C(C3)C2

Procedure:
Coupling of 3,3-dimethyl-butyric acid 4-(carboxy-fluoro-methylene)-adamantan-1-yl ester with 4-bromo-2,5-dichloro-thiophene-3-sulfonamide and isolation is performed analogously to the method as described in Example K c. 3,3-Dimethyl-butyric acid 4-[2-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-fluoro-2-oxo-ethylidene]-adamantan-1-yl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:11])[C:3]=1[C:4]([OH:6])=[O:5].CO[C:14](OC)([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[O:6])[O:5][C:14]([CH3:16])([CH3:15])[S:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1c(S)cccc1Cl
Reactant: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)c2c(Cl)cccc2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 g (106 mmol) of 2-chloro-6-mercaptobenzoic acid, 26 ml (212 mmol) of 2,2-dimethoxypropane and 2 g of Amberlyst 15 (strongly acidic ion exchange resin) are refluxed in 1 l of toluene for 3 h. 100 ml are then distilled off in the course of 2 h, a further 10 ml of 2,2-dimethoxypropane are added, boiling is continued for a short time, and the mixture is stirred overnight at room temperature, filtered and concentrated in vacuo. Yield: 22.4 g (92%) of oil, 1H-NMR (CDCl3) δ=1.82 (s); 7.18-7.40 (m).
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:13][CH2:14][OH:15])[C:8](O)=[CH:9][CH:10]=2)[CH:5]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:4]1)=[O:2].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:1]([N:3]1[C:11]2[C:6](=[C:7]3[CH2:13][CH2:14][O:15][C:8]3=[CH:9][CH:10]=2)[CH:5]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:4]1)=[O:2]
Reactant: CCC(=O)NCCC1CN(C=O)c2ccc(O)c(CCO)c21
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)NCCC1CN(C=O)c2ccc3c(c21)CCO3
Reaction time: 0.33 h
Yield: 33.2 %

Procedure:
To a solution of N-[2-[1-formyl-2,3-dihydro-5-hydroxy-4-(2-hydroxyethyl)indol-3-yl]ethyl]propionamide (0.8 g, 2.61 mmol) in pyridine (10 mL) was added methansulfonyl chloride (0.2 mL, 2.61 mmol.) around -10° C. The mixture was stirred for 20 minutes while keeping the temperature -10 to 5° C. To this was added additional methansulfonyl chloride (0.1 mL, 1.3 mmol.) and the mixture was stirred for further 15 minutes at the same temperature. The mixture was diluted with ethyl acetate(10 mL). Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added slowly and the mixture was stirred for 30 minutes at room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 2N-hydrochloric acid and water, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to afford the title compound (yield 0.25 g, 33%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[Br:26][C:27]1[CH:28]=[C:29]([CH:35]=[C:36](I)[CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>C1COCC1.C(O)(C(F)(F)F)=O.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:26][C:27]1[CH:37]=[C:36]([C:25]#[C:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:7]([CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:35]=[C:29]([C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH:28]=1
Reactant: C#CCCCCCc1cccc(OCCCC(=O)O)c1CCC(=O)O
Reactant: CN(C)C(=O)c1cc(Br)cc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Temperature: 70 °C
Yield: 65.8 %

Procedure:
To a solution of 4-[2-(2-carboxy-ethyl)-3-hept-6-ynyl-phenoxy]-butyric acid (900 mg, 2.6 mmol), 3-bromo-5-iodo-N,N-dimethyl-benzamide (1.0 g, 2.8 mmol), CuI (20 mg, 0.11 mmol) in THF (10 mL) and TEA (10 mL) was added bis(triphenylphosphine) palladium(II) dichloride (75 mg, 0.11 mmol). The reaction mixture was heated at 70° C. for 5 h. Then the reaction mixture was cooled to room temperature, a few drops of TFA were added and the resulting mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (Isco™ 120 g) using ethyl acetate as eluting solvent to give the title compound (980 mg, 65%) as an oil.
Reaction SMILES: [O:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[C:6](=[O:10])[NH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]ccc2ccoc12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cc(Br)c2ccoc12
Temperature: 15 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of 6H-furo[2,3-c]pyridin-7-one (1.0 g, 7.4 mmol) in DMF (30 mL) was treated with NBS (1.32 g, 7.4 mmol) in three equal portions at 0° C. After the resulting mixture was stirred at 15° C. for 2 h, it was treated with water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (PE/EtOAc=3:1) to give the title compound (600 mg, 38%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 11.92 (s, 1H), 8.23 (s, J=2.0 Hz, 1H), 7.47 (s, 1H), 6.88 (m, 1H), 6.88 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.OC1C=CC=CC=1>CC(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: Cc1ccc(N=Nc2ccc(O)cc2)cc1
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: Cc1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Reaction time: 20 h

Procedure:
A 2 l three-neck flask equipped with a mechanical stirrer was charged with 42.4 g (0.2 mol) of 4-hydroxy-4′-methylazobenzene synthesized in the same manner as in the Example, 448 g (2 mol) of 1,6-dibromohexane and 212 g (1.5 mol) of potassium carbonate anhydride. To the mixture was added 800 ml of acetone and the resulting mixture was suspended by stirring. The reaction system was heated until acetone was refluxed to react hydroxybenzene with bromoalkane. After the reaction was continued for 20 hours, insoluble salts were separated by filtration and removed. The system was concentrated to a volume of about ⅓ by using a rotary evaporator. When the system was cooled in a freezing chamber, 4-(6-bromohexyloxy)-4′-methylazobenzene was produced as a crystal. After the generated product was subjected to filtration, it was washed with a small amount of cool acetone, cool ether and n-hexane in this order and then dried under reduced pressure to obtain 38.1 g of crude 4-(6-bromohexyloxy)-4′-methylazobenzene (yield: 50.8%). The resulting product was recrystallized from ethanol to obtain 32 g (yield: 42%) of 4-(6-bromohexyloxy)-4′-methylazobenzene. It was found from an analysis using high performance liquid chromatography that the purity of the product was 98.6% or more.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][NH:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29]>CS(C)=O>[CH3:26][N:27]([C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CN[C@@H](C)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL) was added DIEA (244 mg, 1.89 mmol), and (S)—N-methyl-1-phenylethanamine (204 mg, 1.51 mmol) with stirring for 3 h at 85° C. in an oil bath. The reaction was then quenched by the addition of water (50 mL). The product was precipitated via the addition of water and collected by filtration to give (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (323 mg, 76%).