Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)OC(=O)C2=CC=CC=C12.[C:12](#[N:21])[C:13]1[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:15]#[N:16].[NH3:22]>>[NH:16]=[C:15]1[C:14]2[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[NH:22])[NH:21]1
Reactant: N
Reactant: N#Cc1ccccc1C#N
Agent: O=C1OC(=O)c2ccccc21
Product: N=C1NC(=N)c2ccccc21

Procedure:
In the third exemplary process, phthalic anhydride or phthalonitrile and ammonia are primarily reacted to produce an intermediate product such as 1,3-diimino isoindoline, then the intermediate product is reacted with a metal halide in the presence of solvent having a high boiling point.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:3]([CH:2]=[P:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 20.4 %

Procedure:
A solution of 1-chloroheptan-2-one (33 g.) and triphenylphosphine (60 g.) in chloroform (50 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in methylene chloride (150 ml.), Dry diethyl ether (600 ml.) was added to precipitate 2-oxoheptyltriphenylphosphonium chloride (60 g.), m.p. 165°-168° C. This compound (23 g.) was added portionwise to a solution of sodium carbonate (25 g.) in water (250 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 40°-60° C.). The solid thus obtained was recrystallised from petroleum ether (b.p. 60°-80° C.) to give hexanoylmethylene triphenylphosphorane (17 g.), m.p. 73°-74° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:24])[CH2:16][CH:17]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccccc1OCc1ccccc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(2-benzyloxyphenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(2-benzyloxyphenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:25]=[C:24]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+].Cl>C(O)C.O>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)C(C)C)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.6 %

Procedure:
To a solution of 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-isobutyryl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (191 mg) in ethanol (2 mL) was added 10 M NaOH (566 μL) and the resulting mixture was stirred at room temperature for 5 h. Then the reaction mixture was diluted with water, acidified with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a reverse-phase HPLC to yield 50 mg of the title compound (29% yield). HRMS calcd for C36H42O9 [M+Na]+ 641.2721, observed 641.2720.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[N:17]#N.CCOCC.[C:24]([C@:31](N)([CH2:34][CH3:35])[CH:32]=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:24]([CH:31]([CH2:34][CH3:35])[C@@:32]([NH2:17])([C:5]1[O:1][C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:3][N:4]=1)[OH:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Reactant: N#N
Reactant: c1cncc(-c2nnco2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C(=O)OC(C)(C)C)[C@](N)(O)c1nnc(-c2cccnc2)o1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 3-[1,3,4]oxadiazol-2-yl-pyridine (5 g, 34 mmol) in THF (100 mL) was added HMPA (5 mL) and n-BuLi (1.6 M solution in hexane, 21.25 mL) drop wise under N2 at −78° C. After 1 h, MgBr.Et2O (8.77 g, 34 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 h before being treated with (S)-2-Boc-amino-butyraldehyde (4.22 g, 22.1 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield (S)-2-Boc-amino-1-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (1.5 g).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:27][NH:28][CH3:29]>CO>[CH3:27][N:28]([C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH:7]([CH3:8])[CH2:2]1)[CH3:29]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: CNC
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(N(C)C)CC3C)c(F)c2)C(=O)O1
Yield: 70 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with 40% aqueous solution dimethylamine (1.72 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 70% yield.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[C:11]([S:14][CH2:15][CH2:16][CH2:17]Cl)(=[O:13])[CH3:12].C(=O)([O-])[O-:20].[Na+].[Na+]>>[C:11]([S:14][CH2:15][CH2:16][C:17]([N:6]1[CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4][C@H:5]1[C:8]([OH:10])=[O:9])=[O:20])(=[O:13])[CH3:12]
Reactant: CO[C@@H]1CN[C@H](C(=O)O)C1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)SCCCCl
Agent: [Na+]
Product: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1

Procedure:
Following the procedure of Example 1 (d), cis-4-methoxy-L-proline is treated with a solution of 3-acetylthiopropyl chloride in the presence of sodium carbonate to yield 1-(3-acetylthio-1-oxopropyl)-cis-4-methoxy-L-proline.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH3:30][NH:31][CH3:32]>CN(C)C(=O)C>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CNC
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with dimethyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-[4-(4-dimethylamino-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 465 (MH+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:41]1[S:45][N:44]=[CH:43][N:42]=1)[S:7]([C:10]1[C:39]([F:40])=[CH:38][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3([OH:37])[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[F:40][C:39]1[C:10]([S:7]([NH:6][C:41]2[S:45][N:44]=[CH:43][N:42]=2)(=[O:8])=[O:9])=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3([OH:37])[CH2:27][NH:28][CH2:29]3)[CH3:19])[C:13]=2[CH:38]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(O)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1C1(O)CNC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Reaction time: 0.25 h

Procedure:
In a 1 dram vial, added (R)-tert-butyl 3-(2-(1-(6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-3-hydroxyazetidine-1-carboxylate (32-3, 60 mg, 0.081 mmol) to DCM (647 μl) and TFA (162 μl). After 15 min, diluted with 1 mL MeOH, filtered through Celite, purified by reverse-phase HPLC (20 min run, 5-60% 0.1% TFA/CH3CN:0.1% TFA/H2O) to give 32-4 as a white solid. 1H NMR δ (ppm) (CH3OH-d4): 8.21 (1H, s), 7.83 (1H, d, J=7.64 Hz), 7.71 (1H, d, J=5.61 Hz), 7.54-7.41 (2H, m), 7.27 (1H, d, J=7.61 Hz), 7.00 (1H, d, J=10.04 Hz), 5.52 (1H, dt, J=13.86, 6.77 Hz), 4.42 (2H, dd, J=10.60, 3.89 Hz), 4.14 (2H, dd, J=10.77, 3.87 Hz), 1.95 (3H, d, J=6.97 Hz). HRMS C20H19FN505S2 [M+H] calc: 492.0806, obs: 492.0796.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:15].[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][C:34]=1[CH:35]=O>ClCCl.C(O)(=O)C>[ClH:15].[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH:20][CH2:35][C:34]1[CH:37]=[C:38]([O:41][C:42]([F:43])([F:44])[F:45])[CH:39]=[CH:40][C:33]=1[O:32][CH3:31]
Reactant: COC(=O)CN
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CNCc1cc(OC(F)(F)F)ccc1OC
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Sodium triacetoxyborohydride (5.6 g) was added portionwise to a mixture of glycine methyl ester hydrochloride (1.63 g), N,N-diisopropylethylamine (2.27 ml) and 2-methoxy-5-(trifluoromethoxy)benzaldehyde (3.8 g) in a mixture of dichloromethane (30 ml) and acetic acid (3 drops) at 0° C. and the whole was stirred at 5° C.˜room temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give N-[2-methoxy-5-(trifluoromethoxy)benzyl]glycine methyl ester hydrochloride (2.76 g) as a colorless powder.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([F:23])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[Br:13][C:14]1[C:15]([F:23])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:33]([O:34][CH3:35])[CH3:32])=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1cccc(Br)c1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Carbonyldiimidazole (7.76 g) was added portionwise to commercially available 3-bromo-2-fluorobenzoic acid [161957-56-8] (9.53 g) in dichloromethane (100 mL) over 30 min. The mixture was then heated at reflux for 30 min (until gas evolution ceased). The reaction was then cooled to room temperature and triethylamine (6.37 mL) followed by N,O-dimethylhydroxylamine hydrochloride (4.7 g) were added. The reaction was left to stir at room temperature for 16 h before being washed with 10% citric acid (2×100 mL) and sat. NaHCO3 (2×100 mL), and then dried over sodium sulfate. The solvent was removed by evaporation to yield the product as a brown oil (10.89 g, 95%). NMR (CDCl3): 3.20-3.80 (6H, m, ArCONCH3OCH3), 7.10 (1H, t, Ar), 7.35 (1H, td, Ar), 7.60 (1H, dt, Ar).
Reaction SMILES: [F:1][CH:2]1[C:7]([F:9])(O)[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3]1.Br[CH2:17][CH2:18][O:19][CH3:20].[I-].[K+].C(=O)([O-])[O-:24].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:24][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:9]
Reactant: OC1(F)C=CC(c2ccccc2)=CC1F
Reactant: COCCBr
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccc(F)c(F)c2)cc1
Yield: 23.4 %

Procedure:
A mixture of 3,4-difluoro-1,1′-biphenyl-4-ol (0.50 g, 2.43×10−3 mol) of 1-bromo-2-methoxyethane (0.34 g, 2.43×10−3 mol), potassium iodide (0.04 g, 2.43×10−4 mol), potassium carbonate (1.34 g, 9.72×10−3 mol) and butanone (20 cm3) was then heated overnight under reflux. The mixture was filtered to remove inorganic material and the filtrate evaporated down under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane as the eluent and recrystallisation from hexane to give the pure (GC: 100%) desired product (0.15 g 23%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH2:6][C@H:7]1[CH2:11][N:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:9]([C:16]([NH:18][CH2:19][C@@H:20]([OH:48])[C@@H:21]([NH:29][C:30](=[O:47])[C@H:31]([CH2:43][C:44](=[O:46])[NH2:45])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH2:8]1.C(=O)(O)[O-].[Na+]>O.CN(C)C=O>[C:1]([NH:6][C@H:7]1[CH2:11][N:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[C@H:9]([C:16]([NH:18][CH2:19][C@@H:20]([OH:48])[C@@H:21]([NH:29][C:30](=[O:47])[C@H:31]([CH2:43][C:44](=[O:46])[NH2:45])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)N1C[C@H](N)C[C@H]1C(=O)NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H]1C[C@@H](C(=O)NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)N(C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
15 mg of freshly distilled acetyl chloride were added to a solution, which was cooled to 0° C. and stirred, of 12 mg of 4(R)-amino-N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide hydrochloride and 21 mg of sodium bicarbonate in 0.5 ml of water and 0.25 ml of dimethylformamide. The mixture was stirred vigorously at 0° C. for 5 hours and then left to stand at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane. The combined dichloromethane extracts were evaporated to give a gum which was purified by flash chromatography on silica gel using 20% methanol in dichloromethane for the elution. There were obtained 2 mg of 4(R)-acetylamino-N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a semi-solid; MS: m/e 639 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccccc2)cc1
Yield: 462.5 %

Procedure:
A suspension of (4'-biphenyl)acetic acid (6.4 g) in 60 ml of ethanol is added with 1.1 g of para-toluensulfonic acid, then the reaction mixture is refluxed for 4 hours 30 minutes. The solvent is evaporated off, the residue is dissolved in diethyl ether and the resulting organic phase is washed three times with a saturated aqueous solution of sodium hydrogencarbonate and once with brine. The organic phase is then dried over sodium sulfate and the solvent is evaporated off to give 7.1 g of the product as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)(O)[O-].[K+].CN(C)C=O.CI>C(OCC)(=O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[OH:1]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)cc1O
Temperature: 40 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
Commercially available 2-hydroxy-4-methylbenzoic acid (1.0 g, 7.0 mmol) and potassium bicarbonate (841 mg, 8.4 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (10 ml) and methyl iodide (0.65 ml, 10.5 mmol) were added thereto. The resulting mixture was stirred at 40° C. for 4 hours. The reaction solution was diluted with ethyl acetate (200 ml), and sequentially washed with water (70 ml), with a saturated aqueous sodium bicarbonate solution (70 ml), twice with water (70 ml), and with a saturated aqueous sodium chloride solution (70 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to yield 2-hydroxy-4-methylbenzoic acid methyl ester (1.1 g) as a pale yellow oily material.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C([Li])CCC.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[CH3:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:19][N:18]([CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1([CH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:31])[CH3:17]
Reactant: CNC(=O)c1ccccc1C
Reactant: CN(C)CC1CCc2ccccc2C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1CC1(O)c2ccccc2CCC1CN(C)C
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 40.0 g (0.28 mole) of o-methyl-N-methyl benzamide and 250 ml. of anhydrous tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5°C. Stirring is initiated and 380 ml. of 1.6 m. n-butyllithium (0.616 mole) in hexane is added dropwise in ca. 1 hour maintaining the temperature below 8°C. The resulting red dilithio salt is stirred at 5°C. for 1 additional hour and the reaction flask is then immersed in a dry-ice acetone bath and cooled to an internal temperature of -60°C. To the cold reaction mixture a solution of 56.8 g. (0.28 mole) of 2-(dimethylaminomethyl)-3,4-dihydro-1-(2H)-naphthalenone in 140 ml. of anhydrous tetrahydrofuran is added dropwise in ca. 45 min. maintaining the temperature between -60°C and -50° C. The resulting reaction mixture is stirred at -60°C. for 1 hour, allowed to warm to 0°C in ca 1 hour, and then treated with 200 ml. of saturated aqueous ammonium chloride while maintaining the temperature below 10°C. The resulting two layers are separated and the tetrahydrofuran layer is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with benzene; ethylacetate (1:1) to provide α-(2-dimethylaminomethyl-1,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)-N-methyl-o-toluamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:5][C:6]=1[CH2:7][S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2.O.[C:31]([OH:35])(=[O:34])[CH:32]=O>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[S:5][C:6]=1[CH2:7][S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[C:14](=[CH:32][C:31]([OH:35])=[O:34])[CH2:13][CH2:12]2
Reactant: O=CC(=O)O
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCCC2=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A slurry of 6-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-3,4-dihydro-2H-naphthalen-1-one (2.0 g, 4.6 mmol) in glyoxylic acid monohydrate (2.0 g, 22 mmol), under nitrogen atmosphere, was warmed to 160° C. and stirred for 1 h. The reaction mixture was cooled to room temperature, dissolved in EtOAc (100 mL) and filtered. The filtrate was washed with water (50 mL×3) and brine. The organic phase was dried over magnesium sulfate, concentrated under vacuum, and purified by recrystallization in ethanol to give 1.02 g (45%) of yellow solid. Analyzed for C24H18NO3S2: Calcd: C, 58.89%; H, 3.71%; N, 2.86%; Found: C, 58.715; H, 3.56%; N, 2.77.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:15]1([CH2:21][S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:1]([NH:5][S:22]([CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:24])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a solution of tert-butylamine (2 g, 27.3 mmol) in dichloromethane (90 mL) was added N,N-diisopropylethylamine (5.7 mL, 32.8 mmol), followed by phenylmethanesulfonyl chloride (6.25 g, 32.8 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then diluted with dichloromethane, washed with water and brine, dried with MgSO4, and purified by silica gel column chromatography (0-50% EtOAc in heptane) to give N-tert-butyl-1-phenyl-methanesulfonamide (4.81 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.51-7.44 (m, 2H), 7.41 (dd, J=4.9, 2.0 Hz, 3H), 4.49 (s, 2H), 4.27 (s, 1H), 1.68 (s, 6H); LCMS (m/z) ES+ 228 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:33])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:14]=2[CH:32]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)[C:14]=2[CH:32]=1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(C)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(C)c(C)c1

Procedure:
6-[(5-Amino-1-(3,4-dimethylphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.