Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([OH:38])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.[C:45](Cl)(=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:38][C:45](=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of benzyl 3-(N-FMOC-L-valyloxy)-2-hydroxypropionate (4.6 g 8.89 mmole) and pyridine (1.41 g, 17.8 mmole) in 80 ml dichloromethane was added dropwise a solution of stearoylchloride (3.64 g, 12 mmole) in 20 ml dichloromethane and the mixture was stirred overnight at room temperature. 100 ml of 5% sodium hydrogencarbonate solution was added and the mixture stirred for 30 minutes. The organic phase was seperated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel chromatography. Yield: 6.1 g=87%
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH3:20][O:21][CH2:22][C:23]([O:25][C:26]1[C:27]([F:42])=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:29]([CH3:35])=[C:30]([C:33]#[N:34])[C:31]=1[NH2:32])=O>C(OCC)(=O)C>[F:42][C:27]1[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH3:35])[C:30]([C:33]#[N:34])=[C:31]2[C:26]=1[O:25][C:23]([CH2:22][O:21][CH3:20])=[N:32]2
Reactant: COCC(=O)Oc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
p-Toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) was added to a toluene (30 ml) solution of 4-amino-5-cyano-2-fluoro-6-methylbiphenyl-3-yl methoxyacetate (I-58) (214 mg, 0.68 mmol), followed by stirring for 3 hours and a half with heating under reflux. After cooling to room temperature, the reaction liquid was diluted with ethyl acetate, washed with saturated sodium bicarbonate water and saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (4:1) was concentrated under reduced pressure to obtain the entitled compound (160 mg, 79%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)[C:2]#[CH:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:34]=[CH:35][C:36]([C:3]#[C:2][CH2:1][N:4]3[CH:8]=[CH:7][CH:6]=[N:5]3)=[CH:37][CH:38]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCn1cccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCn3cccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-Propargylpyrazol (500 mg, 4.7 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (680 mg, 1.24 mmol; example 15) in a mixture of tetrahydrofuran (10 mL) and triethylamine (10 mL) The solution was cooled, tetrakis(triphenylphosphine)palladium (118 mg, 0.1 mmol) and copper(I) iodide (38 mg, 0.2 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, diluted with benzene (100 mL) and the resulting mixture was washed with water (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene-chloroform/ether 2:1) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[H-].[Na+].[CH3:22]I.O>CS(C)=O>[CH3:22][N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[C:3]([N:2]([CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4]
Reactant: CI
Reactant: CN(C(=O)c1nc2ccccc2[nH]1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C(=O)c1nc2ccccc2n1C)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
N-Methyl-N-(2-pyridyl)benzimidazole-2-carboxamide (1.0 g) prepared in Example 5 was suspended in dry DMSO (20 ml), sodium hydride (0.16 g) was added in an argon atmosphere and stirred at room temperature for 1 hr. Methyl iodide (0.62 g) was added and stirred at room temperature for 2 hrs. The mixture was poured into water and extracted with chloroform. The chloroform layer was dried over anhydrous Na2SO4, and the solvent was distilled off to obtain the residue. Purification of the residue by column chromatography on silica gel gave the title compound (0.99 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH2:9][OH:10].I[CH3:12]>O1CCCC1>[CH3:12][O:10][CH2:9][C:5]1[S:6][CH:7]=[CH:8][C:4]=1[CH3:3]
Reactant: Cc1ccsc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1sccc1C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
Sodium hydride (2.2 g ˜60%, 55.2 mmol, 1.2 equiv.) was suspended in dry tetrahydrofuran under an inert atmosphere. At 5° C. a solution of (3-methyl-thiophen-2-yl)-methanol (5.16 g, 46 mmol) in dry tetrahydrofuran was added dropwise. The mixture was stirred at room temp. for 1 hour, then iodomethane (7.8 g, 55.2 mmol, 1.2 equiv.) was added dropwise. The mixture was stirred overnight at room temp. and then quenched with diluted acid and extracted with diethyl ether. The combined organic extracts were washed with brine, dried over magnesiumsulfat dihydrate, filtered and evaporated to give 5.7 g of the title compound as a light green oil. GC-MS (EI) M=142.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9]4=[C:10]([CH2:21][C:7]=1[C:8]=24)[CH:11]=[CH:12][CH:13]=3)=[O:4].[N:22]1([C:28](=[O:30])[CH3:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:28]([N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:17]3[NH:16][C:15](=[O:20])[C:14]4[C:9]5=[C:10]([CH2:21][C:7]=2[C:8]=35)[CH:11]=[CH:12][CH:13]=4)=[O:4])[CH2:24][CH2:23]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3cccc4c3c2c1C4
Product: CC(=O)N1CCN(CC(=O)Nc2ccc3[nH]c(=O)c4cccc5c4c3c2C5)CC1
Yield: 58 %

Procedure:
Prepared from the reaction of 2-chloro-N-(5-oxo-5,9-dihydro-4H-cyclopenta[lmn]phenanthridin-1-yl)-acetamide 8 and 1-piperazin-1-yl-ethanone (0.1 mL) according to General Procedure B. White solid in 58% yield, mp155–157° C. 1H-NMR (300 MHz, DMSO-d6) □ 11.44(s, 1H); 9.85(s, 1H); 7.93(d, 2H); 7.61(m, 2H); 7.13(d, 1H, J=8.2 Hz); 4.25(s, 2H); 3.56(s, 4H); 3.24(s, 2H); 2.57(s, 2H); 2.54(s, 2H); 2.02(s, 3H). Anal (C22H22N2O3 1.3 H2O) C H N.
Reaction SMILES: [NH2:1][C:2]([CH:8]([OH:27])[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:6][OH:7])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]([CH:8]([OH:27])[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:3][OH:4])[CH2:6][OH:7]
Reactant: CCCCCCC(=O)CCCCCCC=CCCC(O)C(N)(CO)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC(O)CCCCCCC=CCCC(O)C(N)(CO)CO
Yield: 26.2 %

Procedure:
According to the method of Example 274, 35.0 mg of 2-amino-3-hydroxy-2-(1-hydroxy-12-oxo-4-octadecenyl)propionic acid and 14.4 mg of lithium aluminum hydride were reacted in 2.0 ml of dry tetrahydrofuran to give 8.9 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Cl)cc1

Procedure:
Example 115 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.94–7.81 (br, 1H), 7.53–7.40 (br, 1H), 7.39–7.15 (m, 6H), 6.82 (d, 1H, J=7.2 Hz), 6.68–6.49 (br, 1H), 3.33–3.19 (m, 2H), 3.19–3.06 (m, 2H), 2.63–2.39 (m, 3H), 2.31–2.09 (m, 2H), 1.89–1.62 (m, 7H), 1.54 (s, 6H), 1.13–0.98 (m, 2H), 0.90–0.72 (m, 2H); ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:28]([NH:35][CH2:36][C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:31]([O:30][C:28]([NH:35][CH2:36][C:37]([O:1][C@H:2]([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:38])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1C[C@@H](C)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
To a solution of (R)-benzyl 1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (500 mg, 1.36 mmol), Boc-glycine (263 mg, 1.50 mmol), DMAP (17 mg, 0.136 mmol) in dry CH2Cl2 (5 mL) was added EDCI (417 mg, 2.18 mmol). The mixture reaction was stirred for 3 h at rt. TLC analysis showed that the starting material was consumed completely. The organic layer was then washed with water (3 mL×2), aqueous NaH2PO4 (3 mL×2, 2N) and water (3 mL×2). The organic phase was dried over anhydrous Na2SO4, filtrated and concentrated in vacuo to afford the title compound as a thick oil (750 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][C:7]=2[N:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][N:29]=[C:28]([CH3:31])[C:27]=1[Cl:32]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:32][C:27]1[C:28]([CH3:31])=[N:29][S:30][C:26]=1[NH:25][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][C:4]([CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])=[N:8][C:7]=2[CH:9]=1
Reactant: Cc1nsc(N)c1Cl
Reactant: CC(C)(C)Cc1nc2cc(CC(=O)O)ccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)Cc2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
[2-(2,2-Dimethylpropyl)benzoxazol-5-yl]acetic acid [from step 7] (0.800 g, 0.003 mole) was suspended in dichloromethane (10 ml) and N,N-dimethylformamide (one drop) and oxalyl chloride (0.451 g, 0.004 mole) were added sequentially. The mixture was stirred for 2 hour and then the solvent was removed in vacuo. The residue was taken up in xylene (10 ml), 5-amino-4-chloro-3-methylisothiazole [from step 1] (0.829 g, 0.006 mole) was added and then the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was further purified by flash column chromatography on silica gel, eluting with a 2:1 mixture of hexane:ethyl acetate, to give N-(4-chloro-3-methylisothiazol-5-yl)-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.325 g) as a pale orange solid, m.p. 144-145° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:6]=[N:5][CH:4]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:6]=[N:5][CH:4]=1)=[O:1]
Reactant: N#Cc1ccc(-n2cncc2CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc(-n2cncc2C=O)cc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A mixture of 4-(5-(hydroxymethyl)-1H-imidazol-1-yl)benzonitrile (80 mg, 0.40 mmol, 1.00 equiv) and MnO2 (525 mg, 6.04 mmol, 15.04 equiv) in dichloromethane (10 mL) was refluxed for 1 h. The reaction was cooled to room temperature and the solid material was removed by filtration. The filtrate was concentrated under vacuum to give 55 mg (69%) of 4-(5-formyl-1H-imidazol-1-yl)benzonitrile as a white solid. 1H-NMR (300 MHz, CDCl3): δ 9.80 (s, 1H), 8.03 (s, 1H), 7.99-7.80 (m, 3H), 7.56-7.49 (m, 2H) ppm. LCMS (method D, ESI): RT=1.06 min, m/z=198.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12]([NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[CH:22][CH:21]=[C:20]2Cl)=[O:16])[CH3:13].C(OCC)(=O)C>CS(C)=O.O>[CH2:12]([NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[CH:22][CH:21]=[C:20]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Cl:9])[CH:4]=1)=[O:16])[CH3:13]
Reactant: CCNC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
After dissolving 4-amino-3-chlorophenol (379 mg, 2.64 mmol) in dimethylsulfoxide (10 ml), sodium hydride (106 mg, 2.64 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. N6-Ethyl-7-benzyloxy-4-chloro-6-quinolinecarboxamide (720 mg, 2.11 mmol) was added, and the mixture was heated at 100° C. for 2 hours while stirring. Upon cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with ammonia water, water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (870 mg, 1.94 mmol, 92%) as brown crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([NH:27][CH3:28])=O)[CH2:21][CH2:20]2)=O)=[CH:8]1.O.[OH-].[Na+]>O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH2:16][CH2:17][N:19]2[CH2:20][CH2:21][CH:22]([CH2:25][NH:27][CH3:28])[CH2:23][CH2:24]2)=[CH:8]1
Reactant: CNC(=O)C1CCN(C(=O)Cc2coc3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNCC1CCN(CCc2coc3ccccc23)CC1
Temperature: 60 °C

Procedure:
7.6 g of lithium aluminium hydride are added in portions to a solution of 28.7 g of the product obtained in Step C in 1.5 litres of tetrahydrofuran heated at 60°C. After 18 hours at reflux, the reaction mixture is hydrolysed by the addition of 5.24 ml of water, 4.2 ml of 20% sodium hydroxide solution and then 19.2 ml of water. After filtration, drying and concentration under reduced pressure, the expected product is isolated. The hydrochloride thereof recrystallises from methanol.
Reaction SMILES: [P:1]([O-:26])([O:22][CH2:23][CH2:24]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[S:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[P:1]([O-:26])([O:22][CH2:23][CH2:24][C:28]1[S:27][CH:31]=[CH:30][NH+:29]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2]
Reactant: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Reactant: c1cscn1
Product: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCc1[nH+]ccs1
Temperature: 60 °C
Yield: 30.8 %

Procedure:
3,6-Dioxaoctadecyl 2-bromoethyl phosphate (2.5 g) and thiazole (5.0 g) are mixed and heated at 60° C. The excess thiazole is removed under reduced pressure, silver carbonate and methanol are added to the residue, and the mixture is heated under reflux. The insolubles are filtered off, the filtrate is concentrated to dryness, and the residue is purified twice by silica gel column chromatography (developing solvent: methanol; chloroform-methanol-water). There is obtained 0.78 g of the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:6]([O:8]C)=[O:7].C(O)(=O)C>O1CCCC1>[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:25])[CH:18]=2)=[CH:15][CH:16]=1)/[C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)NCCc3ccccc3)c2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CO/C(=C\c1ccc(-c2cccc(N(C)C(=O)NCCc3ccccc3)c2)cc1)C(=O)O
Temperature: 68 °C
Reaction time: 4 h
Yield: 105.6 %

Procedure:
1.7 mL (1.7 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.5 g (1.1 mmol) of methyl (Z)-2-methoxy-3-[3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]acrylate in 10 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 2 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from hot ethyl acetate. 500 mg (71%) of (Z)-2-methoxy-3-[3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white solid with a melting point of 144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][C:17]1[C:18]([CH3:25])=[C:19]([CH:23]=O)[NH:20][C:21]=1[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:23][C:19]1[NH:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][CH2:14][N:13]([CH3:12])[CH3:26])[C:18]=1[CH3:25]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1CCCN(C)C
Yield: 52.7 %

Procedure:
5-Chloro-1,3-dihydroindol-2-one (167 mg, 1.0 mmol) was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 188.7 mg (53%) of 5-chloro-3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=1)[C:17]([OH:19])=O.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>C1COCC1>[Br:13][C:14]1[CH:22]=[C:21]([CH:20]=[C:16]([C:17]([N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])=[O:19])[CH:15]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCCNCCC
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reaction time: 0.5 h

Procedure:
Carbonyl diimidazole (3.0 g, 18 mmol) is added to a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (XIX, PREPARATION 2, 3.9 g, 15 mmol) in THF (30 mL). The mixture is stirred for 0.5 hours. Dipropylamine (AMINE, 4.2 mL, 30 mmol) is added to the mixture, which is then stirred for 24 hours. The solvent is then removed under reduced pressure and the mixture is partitioned between ethyl acetate and water. The organic phase is then washed with saline, dried over anhydrous magnesium sulfate, filtered, and concentrated. Column chromatography (silica gel; ethyl acetate/hexanes, 15/85) gives the title compound, IR (diffuse reflectance) 2968, 2958, 1714, 1637, 1479, 1440, 1422, 1321, 1310, 1288, 1273, 1252, 889, 772 and 718 cm−1; NMR (300 MHz, CDCl3) δ8.21, 7.96, 7.70, 3.95, 3.46, 3.15, 1.69, 1.57, 1.00 and 0.78; MS (ESI+) for C15H20BrNO3 m/z (M+H)+=344.1.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O.CO.[Cl-].[Na+].O.CCOC(C)=O>[CH3:7][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)NC(=O)c1cnccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(NC(=O)c1cnccn1)C(=O)O

Procedure:
A solution of methyl 2-methyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoate (9.8 mmol) and 1 M NaOH in water (19.6 mL) was stirred in methanol for 6 hours. The reaction was diluted with brine and EtOAc and the layers were separated. The aqueous layer was acidified with 1 M HCl in water (28 mL) to an approximate pH˜2. The aqueous was extracted with EtOAc (3×). These three combined extracts were dried (Na2SO4), filtered and concentrated to obtain 1.96 g (96% over two steps) of the title compound. 1H NMR (300 MHz, CD3OD) δ 9.16 (d, J=1.3 Hz, 1H); 8.75 (d, J=2.4 Hz, 1H); 8.65 (dd, J=1.5, 2.4 Hz, 1H); 1.63 (s, 6H). LC/MS: Rt, =1.27 min, ES+210 (Formic Acid Method).