Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][NH:12][C:13]([NH:15][C:16]#[N:17])=[NH:14].Cl>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][C:16]([NH:15][C:13]([NH:12][CH3:11])=[NH:14])=[NH:17]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CNC(=N)NC#N
Agent: Cl
Solvent: CCCCO
Product: CNC(=N)NC(=N)Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
To 20 g (0.1 mole) of 2,4,6-trichloroaniline and 12.6 g (0.1 mole) of 1-methyl-3-cyanoguanidine in 10 ml (0.1 mole) of concentrated hydrochloric acid is added 125 ml of n-butanol. The reaction mixture is refluxed for 17 hours, cooled and the alcohol evaporated off. The residue is extracted with ether after making it alkaline with 40% sodium hydroxide. The ether extract is dried over potassium carbonate and evaporated. The residue is dissolved in methanol, the pH adjusted to about 7, charcoal filtered and evaporated. The residue is triturated with ether and the solid that forms is recrystallized from water to obtain 1-(2,4,6-trichlorophenyl)-5-methylbiguanide hydrochloride.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[CH3:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].Cl>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]([OH:18])([CH:15]([CH3:19])[CH3:14])[CH3:17])=[CH:8][CH:9]=1
Reactant: CC(=O)C(C)C
Reactant: Ic1ccc(I)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (37.0 mL of a 2.5 M solution in hexanes, 92.8 mmol) was added to a stirred solution of 1,4-diiodobenzene (30.0 g, 90.9 mmol) in THF (200 mL) at −78° C. After approximately 20 min, 3-methyl-2-butanone (10.2 mL, 95.5 mmol) was added, and the resulting mixture was allowed to stir at −78° C. for about 1 h. The reaction mixture was poured into aqueous 1N HCl and extracted twice with diethyl ether. The combined organic extracts were washed water, brine, dried (magnesium sulfate) and concentrated in vacuo to afford the title compound i-3a. m/z (ES) 273 (M-OH)+. 1HNMR (500 MHz, CDCl3): δ 7.67 (d, 2H, J=8.5 Hz), 7.20 (d, 2H, J=8.7 Hz), 2.00 (m, 1H, J=6.7 Hz), 1.52 (s, 3H), 0.92 (d, 3H, J=6.7 Hz), 0.81 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:30])[C:24]=2[CH:23]=[CH:22]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:30][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[CH:22][NH:21]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Nc1cccc2[nH]ccc12
Solvent: ClCCl
Product: O=C(Nc1cccc2[nH]ccc12)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 110 mg; 0.40 mmol) in DCM was treated with polymer-supported Mukaiyama reagent (1.1 g) followed by 1H-indol-4-amine (Aldrich, 58.2 mg; 0.44 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (120 mg, 77%).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:18]1([C:24]23[CH2:31][CH2:30][C:27]([CH2:32][OH:33])([CH2:28][CH2:29]2)[CH2:26][CH2:25]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:33][CH2:32][C:27]23[CH2:26][CH2:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)([CH2:29][CH2:28]2)[CH2:31][CH2:30]3)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC12CCC(c3ccccc3)(CC1)CC2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4)(CC2)CC3)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Pyridine (4 mL), then a solution of toluene-4-sulfonyl chloride (7.4 g, 38.81 mmol) in dry DCM (30 mL), were added to a stirred solution of (4-phenylbicyclo[2.2.2]oct-1-yl)methanol (7.0 g, 32.36 mmol) in DCM (70 mL), maintaining 0-5° C. throughout. The reaction mixture was stirred at 0° C. overnight, refluxed for 2 h then cooled to 35° C. Further pyridine (2 mL) and a solution of toluene-4-sulfonyl chloride (3.9 g) in DCM (10 mL) were added and the mixture stirred at reflux for 2 h. As some starting material remained, a catalytic amount of 4-dimethylaminopyridine was added and the mixture stirred under reflux overnight. The mixture was cooled, diluted with DCM (200 mL) then washed with water (100 mL), hydrochloric acid (2M; 150 mL), water (50 mL), sat. aq. NaHCO3 (100 mL), water (50 mL) and brine (50 mL). After drying (MgSO4) the solution was concentrated to give crude product which was purified by silica column chromatography (silica 40-63 micron) eluting with hexane:ethyl acetate (19:1 to 4:1) to afford the title compound as a pale yellow solid (10.7 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4-chloro-3-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH3CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13]>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13]
Reactant: CCC(=O)c1ccccc1
Reactant: Cc1cc(C)c(N)c(C)c1
Product: CCC(=Nc1c(C)cc(C)cc1C)c1ccccc1
Temperature: 200 °C

Procedure:
2,4,6-Trimethylaniline (11.5 mL, 82 mmol, Aldrich) was mixed with propiophenone (10 mL, 74.5 mmol, Aldrich) and TSOH (1.4 g, 7.3 mmol, Aldrich). The resulting mixture was heated for 2 h at 200° C. under a weak stream of Ar to remove formed H2O. After cooling to RT the reaction mixture was poured into hexanes (100 mL), filtered, and the precipitate washed with additional hexanes (2×100 mL) followed by the evaporation of the filtrate. The residue was filtered through a 9×4.1 cm plug of silica gel in hexanes/ether 10/1 (300 mL collected). After evaporation of the solvent the unreacted starting materials were distilled off under vacuum (45–50° C./53 Pa). The residue was crystallized from methanol at −30° C. Product was isolated as large orange-yellow crystals, 4.8 g, (25.6%). 1H NMR (CDCl3) 8.00–7.94 (m, 2H); 7.51–7.45 (m, 3H); 6.89 (s, 2H); 2.50 (q, 2H; J=7.7 Hz); 2.31 (s, 3H); 2.04 (s, 6H); 0.98 (t, 3H; J=7.7 Hz). 13C NMR (CDCl3): 170.8, 146.4, 138.2, 131.9, 130.3, 128.7, 128.6, 127.7, 125.6, 23.9, 20.9, 18.2, 11.6. Anal. Calcd for C18H21N: C, 86.00; H, 8.42; N, 5.57. Found: C, 85.79; H, 8.41; N, 5.56.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].C(=O)([O-])O.[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)CCCNC(=O)c1ccccc1
Yield: 90.1 %

Procedure:
Into 300 ml of distilled water, were suspended 50 g of 3-aminopropyldimethylamine and 62 g of sodium hydrogencarbonate. To the suspension, while cooling in ice and stirring vigorously, was added dropwise 105 g (1.5 equivalents) of benzoyl chloride. After 6 hours of reaction at room temperature, the reaction mixture was acidified to pH 4 with concentrated hydrochloric acid and extracted with ethyl ether to remove the excess benzoyl chloride. The aqueous layer was adjusted to pH 12 with 5N aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over sodium sulfate and stripped of the solvent by distillation under reduced pressure to give 91 g of 3-benzamidopropyldimethylamine. To this residue, was added a solution of 118 g (1 equivalent) of N-3-bromopropylphthalimide in 300 ml of tetrahydrofuran. After stirring at room temperature for 18 hours, the precipitated colorless crystals were collected by filtration, washed with tetrahydrofuran and dried to yield 188 g (90% yield) of colorless crystals of the quaternary ammonium salt. This salt was dissolved in 1,000 mg of 6N hydrochloric acid and heated at 110° C. for 8 hours to effect hydrolysis. After cooling, the precipitated phthalic and benzoic acids were removed by filtration and the filtrate was evaporated to dryness under reduced pressure to remove the excess hydrochloric acid. The residue was dissolved in distilled water and passed through a column of an ion exchange resin Dowex®-1 (Cl-type, 600 ml in volume). The effluent was evaporated to dryness under reduced pressure to yield 96 g (90% yield) of bis(3-aminopropyl)dimethylammonium trihydrochloride. This compound was too hygroscopic to determine its melting point. The PMR spectrum measured in heavy water showed the following δ values: 2.1-2.8 ppm, 4H (m), 2.4 ppm, 6H (s), 3.1-3.9 ppm, 8H (m) (wherein, the letters in parentheses indicate the signal types: m: multiplet, s: singlet). These values were in compliance with the assigned structure. The IR absorption maxima (in wave number, cm-1), as measured in KBr-tablet, were: 3425, 2975, 2625, 2000, 1600, 1480, 1470, 1350, 1320, 1300, 1230, 1200, 1160, 1140, 1060, 1040, 1000, 930, 840, and 760.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1)[CH3:2].[CH3:16][NH2:17]>C1COCC1.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH:17][CH3:16])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC)c1

Procedure:
3-Methylamino-4-nitro-benzoic acid ethyl ester (2.8 g) was prepared by following General Procedure A starting from 3-fluoro-4-nitro-benzoic acid ethyl ester (3 g) and 2 M methylamine in THF (15 mL) in DMF (15 mL).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cccc(F)c1
Agent: N
Product: Fc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.43-7.51 (m, J=8.5, 8.5, 2.6, 1.0 Hz, 1 H), 7.61-7.72 (m, 2 H), 7.98 (ddd, J=9.1, 2.6, 1.4 Hz, 1 H), 8.08 (ddd, J=8.0, 1.3, 1.0 Hz, 1 H), 8.56 (dt, J=8.0, 1.9 Hz, 1 H), 8.74 (dd, J=5.2, 1.6 Hz, 1 H), 9.30 (dd, J=2.0, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:34][CH2:35][C:36](Br)=[O:37]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:36](=[O:37])[CH2:35][Br:34])[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: O=C(Br)CBr
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a cold (ice bath) stirred solution of racemic 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-piperidine (4.25 g, 12.54 mmol, described in Example 7b), diisopropyl ethylamine (4.37 mL, 25.08 mmol) in methylene chloride (75 mL) was added bromoacetyl bromide (1.36 mL, 15.68 mmol). After stirring the resulting mixture for 1 h at 0° C., the cooling bath was removed and the reaction was allowed to reach ambient temperature and stirred for an additional 18 h. The reaction mixture was treated with saturated sodium bicarbonate (2×150 mL) and brine (100 mL), dried (sodium sulfate), filtered, and concentrated to give the title compound as a brown foamy glass (5.74 g, quant.)
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Reactant: CSc1ccc(B(O)O)cc1
Product: COC(=O)c1ccc2occ(-c3ccc(SC)cc3)c2c1
Yield: 92 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and 4-(methylthio)phenylboronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 92%) was obtained as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH2:29])=[S:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]2[S:28][CH:2]=[C:3]([CH2:4][O:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[N:29]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C(CBr)COc1ccc2c(c1)CCC(=O)N2
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: O=C1CCc2cc(OCc3csc(Nc4ccc(Cl)c(Cl)c4)n3)ccc2N1
Yield: 23.6 %

Procedure:
To a stirred solution of 6-(3-bromo-2-oxopropoxy)-3,4-dihydroquinolin-2(1H)-one (0.15 g, 0.503 mmol) in ethanol (3 mL) was added 1-(3,4-dichlorophenyl)thiourea (0.133 g, 0.604 mmol). The reaction mixture was refluxed for 12 h, then concentrated and purified by preparative HPLC to afford a white solid (0.05 g, 24%). 1H NMR 400 MHz, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.85 (t, J=8.00 Hz, 2H), 4.99 (s, 2H), 6.80 (d, J=8.80 Hz, 1H), 6.87 (q, J=2.80 Hz, 1H), 6.92 (d, J=2.40 Hz, 1H), 6.98 (s, 1H), 7.48-7.49 (m, 2H), 8.06 (d, J=2.00 Hz, 1H), 9.92 (s, 1H), 10.56 (s, 1H). LCMS: RT 1.99 min; LCMS (ES-API), m/z 420. LCMS: RT 1.99 min; LCMS (ES-API), m/z 420.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].CO.[OH-].[K+]>O>[CH2:1]([C:5]1[O:6][C:7]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC(=O)OCC)c(-c2ccco2)o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(CC(=O)O)c(-c2ccco2)o1
Yield: 83.4 %

Procedure:
4.0 g of ethyl 2-[2-n-butyl-5-(2-furyl)-4-oxazolyl]acetate, 50 ml of methanol, 5 ml of water and 4.75 g of potassium hydroxide are treated in the same manner as described in Example 16. 3.0 g of 2-[2-n-butyl-5-(2-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 83.3%
Reaction SMILES: [CH2:1]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C>[Br:27][C:16]1[S:17][CH:18]=[CH:19][C:15]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccsc1Br
Reaction time: 8 h

Procedure:
3-Tetradecylthiophene (5.6 g, 20 mmol) was dissolved in 30 mL of dry DMF. NBS (3.56 g, 20 mmol) was dissolved in 20 mL of DMF. At room temperature, the NBS solution was add to the 3-tetradecylthiophene solution dropwise. The reaction mixture was stirred in dark overnight. The reaction mixture was then poured onto ice, and then extracted with tert-butyl methyl ether (50 mL×3). The organic layer was collected and washed with half-brine (5×100 mL). After the organic layer was dried by MgSO4, the solvent was removed by rotary evaporation. The organic solution thus formed was dried by vacuum pump to give 2-bromo-3-tetradecylthiophene as a colorless oil. The product was used as is in the next step without further purification.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 4-(3-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 4 & 5, Part C). The mixture was heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 90% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=1
Reactant: COCCOc1cc(C(=O)OC)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCOc1cc(C(=O)O)ccn1
Temperature: 80 °C
Yield: 87.1 %

Procedure:
Methyl 2-(2-methoxyethoxy)pyridine-4-carboxylate (562 mg, 2.66 mmol), dioxane (6 mL) and NaOH (7.1 mL of 1M, 7.1 mmol) were combined and the mixture was heated at 80° C. for 50 min. The solvent was evaporated under reduced pressure and the residue was dissolved in water before it was washed with EtOAc (3×). The aqueous layer was acidified with 1N HCl and was washed with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to yield 2-(2-methoxyethoxy)pyridine-4-carboxylic acid (457 mg, 87%) as a white solid. ESI-MS m/z calc. 197.2. found 198.3 (M+1)+; Retention time: 0.66 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.64 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.39 (d, J=5.2 Hz, 1H), 7.18 (s, 1H), 4.51-4.27 (m, 2H), 3.78-3.54 (m, 2H), 3.30 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:36][C:37]([O:39]OCC1C=CC=CC=1)=[O:38])([CH3:35])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([OH:33])=O)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:8]1=[O:34])=[O:5].[CH3:48][O:49][C:50]1[CH:57]=[CH:56][C:53]([CH2:54][NH2:55])=[CH:52][CH:51]=1>>[CH3:48][O:49][C:50]1[CH:57]=[CH:56][C:53]([CH2:54][NH:55][C:31]([C:26]2[C:25]([C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:9]4[C:10]5[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=5[CH2:12][CH2:13][C@@H:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([NH:36][C:37]([O:39][CH2:12][C:11]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:10]=5)=[O:38])([CH3:35])[CH3:1])[C:8]4=[O:34])=[CH:24][CH:23]=3)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:33])=[CH:52][CH:51]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)O)cc2)C1=O)NC(=O)OOCc1ccccc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2ccccc2-c2ccc(CN3C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc4ccccc4)CCc4ccccc43)cc2)cc1

Procedure:
The title compound was prepared from 4'-[[2,3,4,5-tetrahydro-3(R)-[[3-methyl-1-oxo-3-[[(benzyloxyoxy)carbonyl]amino]butyl]amino]-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylic acid (Example 72, Step B) and 4-methoxybenzylamine by the procedure described in Example 74, Step A. 1H NMR (200 MHz,CD3OD): 1.40 (s,6H), 2.00 (m,1H), 2.31 (m,1H), 2.50-2.75 (m,4H), 3.82 (s,3H), 4.27 (s,2H), 4.43 (dd;7,11 Hz;1H), 4.95 (d,15 Hz,1H), 5.05 (d,12 Hz,1H), 5.15 (d,12 Hz,1H), 5.37 (d,15 Hz,1H), 6.87 (m,3H), 7.03 (d,8 Hz,2H), 7.20-7.57 (m,19H). FAB-MS: calculated for C45H46N4O6 738; found 740.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][NH:15][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)=CCOc1ccc(SCCN)cc1
Product: CCOC(=O)NCCSc1ccc(OCC=C(C)C)cc1

Procedure:
In the same manner, 2-[4-(3-methyl-2-butenoxy)phenylthio]ethylamine is reacted with ethyl chloroformate to yield ethyl N-{2-[4-(3-methyl-2-butenoxy)phenylthio]ethyl}carbamate (compound 77, Table A).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10])=[O:28]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1ccccc1-c1cccs1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1cccs1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Thiophen-2-yl-benzoic acid. LC-MS (basic): tR=1.33 min; [M+H]+=463.1.