Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24]>O.O1CCOCC1>[CH:38]1[C:39]2[CH:27]([CH2:26][O:25][C:23]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:14]([OH:16])=[O:15])=[O:24])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a stirred mixture of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.0 g, 4.34 mmol) and Na2CO3 (0.90 g, 10.80 mmol) in water (10 mL) was added solution of FMOC-Cl (1.23 g, 4.77 mmol) in 1,4-dioxane (10 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h then diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1N aqueous HCl (10 mL) to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (0.87 g) as an off-white solid. The crude product was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH3:16]O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:16])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 5-chloro-2-thiophenecarboxylic acid (10 g, 61.5 mmol) in methanol (200 ml) was added sulfuric acid (0.983 ml, 18.45 mmol). The resulting solution stirred at 50° C. overnight. H2O (50 mL) was added and the reaction was cooled to 0° C. in an ice-bath. The pH was adjusted to ˜12 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 5-chloro-2-thiophenecarboxylate (7.2 g, 40.8 mmol, 66.3% yield): LCMS (ES) m/z 178 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]([O:13][CH3:14])=[O:12].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]([O:13][CH3:14])=[O:12]
Reactant: Oc1ccc(F)cc1Br
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1Br
Reaction time: 2 h
Yield: 91.8 %

Procedure:
First, 93 g (0.49 mol) of 2-bromo-4-fluorophenol was suspended in 200 ml of water, into which 55 g (0.59 mol) of methyl chloroformate and a solution of 21.5 g (0.51 mol) of sodium hydroxide in 60 ml of water were poured together at 10° C. or lower, and the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were collected by filtration, washed with water, and dried in a vacuum oven, which afforded 111.6 g (0.45 mol) of methyl 2-bromo-4-fluorophenoxyformate.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[SH:19].CO>C1(C)C=CC=CC=1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[SH:19].[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[S:19][C:12]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(I)cc1
Agent: COc1ccc(N)c(S)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2nc(-c3ccc(I)cc3)sc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
2-Amino-5-methoxythiophenol was prepared as set forth in C. A. Mathis, Y. Wang, D. P. Holt, G-F. Huang, M. L. Debnath and W. E. Klunk, “Synthesis and Evaluation of 11C-Labeled 6-Substituted 2-Arylbenzothiazoles as Amyloid Imaging Agents.” J. Med. Chem., 46, pp 2740-2754 (2003). 4-Iodobenzyl chloride (5.0 g, 18.8 mmol) was added to a hot solution of 2-amino-5-methoxythiophenol (2.32 g, 15.0 mmol) in toluene (75 mL) and the reaction mixture was stirred at 100° C. for 1 h. Methanol (1 mL) was then added to destroy the excess 4-iodobenzoyl chloride. The hot toluene solution was then passed through a pad of silica gel (˜15 g) in a Buchner funnel. The silica gel was rinsed a few more times with hot toluene. The filtrate upon concentration gave pure 2-(4-iodophenyl)-6-methoxy-1,3-benzothiazole (4) (1.65 g, 40%) as off-white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].ClCCC(OCC)=O>CN(C=O)C>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:2]=[CH:3]2)#[N:11]
Reactant: CCOC(=O)CCBr
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: CCOC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 1H-indazole-5-carbonitrile (D1) (3.88 g, 27.3 mmol) in DMF (85 ml) was added Cs2CO3 (17.8 g, 54.6 mmol) and then ethyl 3-bromopropanoate (3.5 ml), 27 mmol) and ethyl 3-chloropropanoate (3.3 g, 24.2 mmol) were added. The reaction mixture was stirred at 80° C. for 4 hours and then allowed to cool. The solvent was removed in vacuo and the crude material was partitioned between EtOAc and water, the organics were separated, washed with brine, dried and evaporated. The crude was azeotroped with toluene and then purified by flash chromatography (EtOAc/hexane 1:9 to 1:1) to give 3.84 g of a yellow gum. MS data as for previous example.
Reaction SMILES: [C:1]1([C:7]2N[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(N[C@H:23]([C:25](OC1C=C(C2C=CC(Cl)=CC=2)NC=1)=[O:26])C)(C1C=CC(C)=CC=1)(=O)=O>CC(C)=O>[CH2:25]([OH:26])[CH2:23][CH2:9][CH2:10][CH2:11][CH2:7][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Oc2c[nH]c(-c3ccc(Cl)cc3)c2)cc1
Reactant: c1ccc(-c2ccc[nH]2)cc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCO

Procedure:
Test devices were prepared as in Experiment 7.3.3 except that the acetone solution contained, in place of the phenylpyrrole, 1.3 mM 3-(N-tosyl-L-alaninyloxy)-5-(p-chlorophenyl)pyrrole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([OH:15])=O)#[N:2].[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([N:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH3:35])[CH3:16])=[CH:23][CH:22]=1)[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=1)=[O:15])#[N:2]
Reactant: N#Cc1cccc2c1OCCC2C(=O)O
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3c(C#N)cccc32)cc1
Yield: 64.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-cyanochroman-4-carboxylic acid (0.7 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.92 g) as starting materials, 8-cyano-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (1.0 g) was obtained. melting point: 178.8° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCc2cc(-c3ccccc3)no2)CC1
Yield: 53 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-(2-methoxyphenyl)piperazine (19.2 mg, 0.10 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0.15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.5 hr and followed the same processes as in Example 1 to obtain 10 mg (53.0%) of the target compound.
Reaction SMILES: [Na].[CH2:2](O)C.[CH:5]1[C:18]2[CH:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.CI>O>[CH:15]1[C:16]2[CH:17]([C:19]([O:21][CH3:2])=[O:20])[C:18]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CCO
Agent: [Na]
Solvent: CI
Solvent: O
Product: COC(=O)C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sodium ethoxide solution is prepared from 21.75 g (0.95 mol) of sodium and 1500 mL of ethanol. 214 g (0.95 mol) of xanthene-9-carboxylic acid is added batchwise to this solution and the suspension obtained is stirred for 1 hour at ambient temperature. Then the solid is separated off, washed with 1500 mL diethyl ether, and the isolated crystals are suspended in 1500 mL of dimethylformamide and combined with 126.73 mL (2.0 mol) of methyl iodide with stirring. The solution formed is left to stand for 24 hours at ambient temperature, then diluted with water to a total volume of 6 L, crystallized, suction filtered, washed with water, and dried. Yield: 167 g of white crystals (74% of theoretical yield); melting point: 82° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:17])([P:13]([OH:16])(=[O:15])[OH:14])[P:9]([OH:12])(=[O:11])[OH:10])[CH:2]=1.[OH-:18].[Na+:19]>O>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:9]([O-:11])([OH:12])=[O:10])([P:13]([OH:16])([OH:15])=[O:14])[OH:17])[CH:4]=1.[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:9]([O-:11])([OH:12])=[O:10])([P:13]([OH:16])([OH:15])=[O:14])[OH:17])[CH:4]=1.[OH2:18].[OH2:10].[OH2:10].[OH2:10].[OH2:10].[Na+:19].[Na+:19]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 25 °C
Yield: 194.1 %

Procedure:
To 60 ml of purified water, 10.0 g of 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid (risedronic acid) and 1.41 g of sodium hydroxide were added and dissolved at an elevated temperature of 65° C. After the dissolution, the resulting solution was cooled to 25° C. over 3 hours for crystallization. The obtained crystals were filtered and vacuum dried to obtain 8.0 g of risedronate sodium hemipentahydrate (64.7% of theoretical yield). (LOD by TGA=13.2%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[C:6]([O:9]CC2C=CC=CC=2)[C:7]=1[F:8]>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:17]([CH3:23])([CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[C:6]([OH:9])[C:7]=1[F:8]
Reactant: CCOC(=O)C(C)(C)c1cc(F)c(F)c(OCc2ccccc2)c1
Solvent: CCO
Product: CCOC(=O)C(C)(C)c1cc(O)c(F)c(F)c1
Reaction time: 8 h
Yield: 117.2 %

Procedure:
A solution of ethyl 2-{3,4-difluoro-5-[(phenylmethyl)oxy]phenyl}-2-methylpropanoate (111 mg, 0.332 mmoles) in EtOH (2 mL) was degassed and flushed with N2. To the solution was added Pd/C (10% by weight) and a H2 balloon was attached. After overnight under H2, the solution was filtered through celite and concentrated to afford 95 mg of crude product purified by Biotage.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Cl.[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:28])=[C:18]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19]=2[F:21])[C:14](=[O:29])[C:13]([C:30]([OH:32])=[O:31])=[CH:12]1)[CH3:10].C(I)C>CN(C=O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:28])=[C:18]([N:22]3[CH2:23][CH2:24][N:25]([CH2:1][CH3:2])[CH2:26][CH2:27]3)[C:19]=2[F:21])[C:14](=[O:29])[C:13]([C:30]([OH:32])=[O:31])=[CH:12]1)[CH3:10]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
Triethylamine (0.2 g), 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (0.3 g), ethyl iodide (0.19 g), and DMF (5 ml) were mixed, heated with stirring at 90° C. for 3 hours, and the solvent was evaporated. The residue was dissolved in 2N sodium hydroxide solution. The alkaline solution was neutralized with aqueous acetic acid and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-7-(4-ethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g), mp 236°-239° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC(S(N)=O)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH2:70][CH2:71][CH2:72][S:73]([OH:76])(=[O:75])=[O:74]>O.CN(C)C=O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:70][CH2:71][CH2:72][S:73]([OH:76])(=[O:75])=[O:74])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: NCCS(=O)(=O)O
Agent: CC(C)(C)S(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)CC(Nc1ccc(C(=O)NCCS(=O)(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
A 5 mL vial equipped with magnetic stirrer was charged with 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinic acid (0.200 g, 0.467 mmol) as prepared in Example 1.1 using racemic 2-methylpropane-2-sulfinamide in Step B, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (266.0 mg, 0.700 mmol), N-methylmorpholine (236.1 mg, 2.334 mmol), N,N-dimethylformamide (2.4 mL). The mixture was purged with nitrogen, heated to 30° C. and stirred for 30 minutes. Then 2-aminoethanesulfonic acid (58.4 mg, 0.467 mmol) was added. The mixture was stirred at 30° C. for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×20 mL) and dried over sodium sulfate, filtered and concentrated. Purification by prep-HPLC provided (+/−)-2-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido) ethanesulfonic acid (89.6 mg, 35.8%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.41 (s, 1H), 8.29 (m, 1H), 8.25-8.19 (m, 1H), 7.88 (d, 2H), 7.78-7.70 (m, 4H), 7.54 (d, 2H), 7.13 (d, 1H), 5.05-4.92 (m, 1H), 3.76 (t, 2H), 3.06 (t, 2H), 1.88-1.82 (m, 1H), 1.72-1.62 (m, 2H), 1.07 (d, 3H), 1.04 (d, 3H) ppm. MS (M+1): 536.2.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15](Cl)Cl>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:6]2[CH2:15][C@H:7]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: ClCCl
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
To a mixture of ethyl 4-bromocinnamate and Pd(OAc)2 (0.05 eq) in methylene chloride (1M) at 0° C. was added dropwise a solution of CH2N2 in ether until the reaction was completed by NMR analysis. The mixture was filtered through a plug of silica gel and concentrated to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([CH3:31])[CH:33]=2)[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: Cc1cccc(C(=O)O)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 3-methylbenzoic acid were coupled to give the title compound as a white foam (82 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][CH2:2][CH2:3][C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NCCc1cccs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(NCCc1cccs1)c1ccc(Cl)cc1

Procedure:
Prepared from 2-(2-aminoethyl)-thiophene and 4-chlorobenzenesulphonic acid chloride analogously to Example 1a.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:5]([N:7]([CH3:24])[C@H:8]([C:21]([OH:23])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Cl.[CH3:30][O:31][C:32](=[O:45])[C@H:33]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH2:34].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:30][O:31][C:32](=[O:45])[C@H:33]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH:34][C:21](=[O:23])[C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[N:7]([C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[CH3:24]
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@@H](Cc2ccc(-c3ccno3)cc2)C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1

Procedure:
At 0° C., N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine (445 mg) is stirred in N,N-dimethylformamide (24 ml) together with (L)-tryptophane methyl ester hydrochloride (400 mg), hydroxybenztriazol (330 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.32 ml) for 1 hour and at ambient temperature over night. After extraction with ethyl acetate and 10% aqueous citric acid the organic phase is washed with 4% aqueous sodium bicarbonate, and with brine, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate 2:1) gives the product as a mixture of diastereoisomers. Separation by medium pressure chromatography on a silica gel column, using ether/dichloromethane (1:1) as solvent gives both [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-tryptophane methyl ester. NMR (CDCl3, 400 MHz) δ [ppm] 8.60 (s), 8.30 (m), 7.70 (m), 7.55 (m), 7.30 (m), 7.10 (m), 6.90 (m), 6.50 (m), 5.85 (s), 5,43 (m), 4.90 (m), 4.33 (m), 3.75 (s), 3.70 (s), 3.35 (m), 3.15 (m), 2.85 (s), 2.57 (s), 2.35 (s), 2.20 (s), 1.93 (s), 1.85 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:12]([O-])=O)[C:4]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H][H]>[C].[Pd].C(O)C>[NH2:12][C:5]1[C:4]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCCCCOc1c(OC)ccc(C(=O)O)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1N
Yield: 94.7 %

Procedure:
4-Methoxy-2-nitro-3-pentyloxybenzoic acid (26.8 g, 94.6 mmol) and ethanol (350 ml) were mixed, and 10% palladium-carbon catalyst (2.6 g) was added to this solution. The reaction miture was stirred at room temperature for 7.5 hours in a hydrogen gas stream (3 kgf/cm2) and filtered. The filtrate was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give 2-amino-4-methoxy-3-pentyloxybenzoic acid (22.7 g, 95%) as gray crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([Cl:3])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC(=O)Cl)cc1OC
Reaction time: 2 h

Procedure:
Over a period of two hours, thionyl chloride (600 ml) is added dropwise, with stirring, to a suspension of 3,4-dimethoxy-phenylacetic acid (549.4 g) in methylene chloride (600 ml). After the development of gas has ended (16 hours) the mixture is refluxed for a further hour. After the highly volatile components have been removed the residue is distilled in vacuo. Yield: 486 g. Bp: 134°-136° C./1.95 mbar.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH2:12]([O:14][CH2:15][C:16]([OH:18])=O)[CH3:13].Br.[NH2:20][C:21]1[S:22][C:23]([Br:26])=[CH:24][N:25]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:26][C:23]1[S:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][O:14][CH2:12][CH3:13])=[N:25][CH:24]=1
Reactant: CCOCC(=O)O
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCC(=O)Nc1ncc(Br)s1
Reaction time: 1 h
Yield: 70.2 %

Procedure:
EDCI (0.53 g, 2.78 mmol) was added to a solution of ethoxyacetic acid (0.29 g, 2.78 mmol) in CH2Cl2 (5 ml) under ice-cooling. After stirring for 1 h, a solution of 2-amino-5-bromothiazole hydrobromide (0.60 g, 2.31 mmol) and diisopropylethylamine (0.40 ml, 2.34 mmol) in CH2Cl2 (5 ml) was added dropwise, and the entire mixture was kept at 0° C. for 1 h, then at room temperature overnight. The solution was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was further washed with water, 5% citric acid, water, saturated sodium bicarbonate, and water. Drying over sodium sulfate and evaporation gave a solid which was triturated with isopropyl ether to give the title compound as a beige solid (0.43 g; 70%)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[CH3:16][N:17]([CH3:20])[C:18]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[NH:19]
Reactant: CN(C)C#N
Reactant: Cc1cccc(N)c1-c1ccccc1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(NC(=N)N(C)C)c1-c1ccccc1

Procedure:
A mixture of 2-amino-6-methylbiphenyl hydrochloride (2.98 g), N,N-dimethylcyanamide (1.46 g) and m-cresol (25 ml) was heated at 90°-95° C. for 6 hours to give N,N-dimethyl-N'-(6-methyl-2-biphenylyl)guanidine (m.p. 181°-182° C.) which was recrystallised from hexane.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:15][NH2:16]>ClCCl.C(O)C>[CH3:15][NH:16][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH:3]=1
Reactant: CN
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: CNCc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
10 g of 4-Biphenylcarbaldehyde and 40 ml of 33% ethanolic methylamine are stirred overnight at room temperature with a 4 Å molecular sieve. The mixture is filtered and concentrated under vacuum. The residue is treated in 60 ml of ethanol with 2 g of sodium borohydride and stirred for 3 hours. The solvent is removed under vacuum, the residue partitioned between ether and water and the organic phase dried and concentrated. The pure base is obtained as an oil following chromatography on silica gel with dichloromethane/ethanol=9/1 as eluant.