Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH2:6])[CH3:3].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([NH:13][C:14]([NH:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCN
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)Nc1ccccc1

Procedure:
88 g of dimethylaminoethylamine are dissolved in 500 ml of toluene and then 119 g of phenyl isocyanate are added dropwise in the course of 10 minutes, whereupon the temperature rises to 97° C. The mixture is refluxed for 4 hours. On cooling, the product crystallises and is filtered with suction. The moist product is recrystallised from 1000 ml of ethyl acetate. Yield: 135 g (65.1%); m.p. 141°-142° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].O=[CH:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@H:2]([NH:1][CH2:13][CH2:14][N:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1)[CH2:3]2
Reactant: COC(=O)c1cccc2ccn(CC=O)c12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2ccn(CCN[C@@H]3CN4CCC3CC4)c12
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred suspension of (S)-(−)-3-aminoquinuclidine (1.4 g, 7.0 mmol) in methylene chloride (50 mL) was added sodium hydride (562 mg, 14.0 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise, followed by methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate (1.3 g, 5.9 mmol) from Step B above and the reaction was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 mmol) was then added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.39 g, 66%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 7.79 (dd, J=4.5, 1.0 Hz, 1H), 7.69 (dd, J=4.3 Hz 1H), 7.18 (d, J=1.8 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.57 (d, J=1.8 Hz, 1H), 4.51 (t, J=6.5 Hz, 2H), 3.96 (s, 3H), 3.46 (s, 1H), 3.07-3.03 (m, 1H), 2.90-2.85 (m, 1H), 2.82-2.70 (m, 5H), 2.63-2.60 (m, 1H), 2.29-2.25 (m, 1H), 1.68-1.59 (m, 3H), 1.40-1.39 (m, 1H), 1.25-1.22 (m, 1H); MS (ESI+) m/z 328 (M+H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([C:18]2[S:19][C:20]([S:2]([OH:5])(=[O:4])=[O:3])=[CH:21][CH:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:24])[F:25])=[N:14]1
Reactant: FC(F)(F)c1cc(-c2cccs2)n(-c2ccccc2Cl)n1
Reactant: O=S(=O)(O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Temperature: -78 °C

Procedure:
Chlorosulfonic acid (1.0 mL, 15 mmol) was added dropwise to a cold (−78° C.) solution of 1-(2-chlorophenyl)-5-(thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.0 g, 3.2 mmol) in CH2Cl2 (22 mL) After 75 minutes stirring at −78° C. the cooling bath was removed and the brown solution was allowed to warm to ambient temperature. After 3½ hours stirring at ambient temperature, the reaction mixture was poured onto ice and diluted with CH2Cl2. The milky lower organic phase was separated and dried over Na2SO4. Filtration and concentration under reduced pressure of the organics gave a biphasic mixture that was further pumped down under high vacuum. NMR and GC/MS analysis of this material showed it not to be the product. The aqueous phase from the workup was saturated with Na2SO4 and extracted with EtOAc (3×). These organic extract were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonic acid as a yellow syrup. This crude material was carried on to the sulfonyl chloride formation without purification. MS(ES): 409[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:22])[CH3:21])#[N:19]>O1CCCC1>[C:18]([C:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:10])([F:11])[F:12])=[C:6]([OH:8])[CH:7]=1)=[O:27])([CH3:22])[CH3:21])#[N:19]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(C(F)(F)F)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(O)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a two-layer solution of 5-amino-2-(trifluoromethyl)phenol (1.50 g, 8.46 mmol) in tetrahydrofuran (25 mL)/1N aqueous sodium hydrogen carbonate solution (25 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 4 hr. The aqueous layer was separated, and extracted with ethyl acetate (200 mL). The combined organic layer was washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate/hexane to give the title compound (2.03 g, 69%) as a colorless powder.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[N+:9]([O-])=O)[C:4]([Cl:12])=[CH:3][CH:2]=1.[CH:13]1[CH2:17][CH:16]=[CH:15][CH:14]=1>>[Cl:12][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]1[CH:15]2[CH2:16][CH:17]([CH:13]=[CH:14]2)[CH:8]1[NH2:9]
Reactant: C1=CCC=C1
Reactant: O=[N+]([O-])/C=C/c1ccccc1Cl
Product: NC1C2C=CC(C2)C1c1ccccc1Cl

Procedure:
This material (LC-MS m/z 220 (MH+)) was prepared via the nitro derivative according to the procedure described in Preparation 92 but starting instead with 2-chloro-omega-nitrostyrene and cyclopentadiene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17]O)[N:7]=1)[CH3:2].CS([Cl:24])(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][Cl:24])[N:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1nn(CO)c(=O)c2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nn(CCl)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate (1.31 g) and methanesulfonyl chloride (0.69 g) in methylene chloride (10 ml) containing pyridine (0.8 ml) was stirred at room temperature overnight. Upon evaporation of methylene chloride and purification of the residue by chromatography on silica gel, eluting with a mixture of a chloroform and ethyl acetate (9:1), the title product was obtained (yield: 0.51 g; m.p. 99°-100° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[C:9]1([NH:15][C:16](=[O:30])[NH:17][N:18]=[C:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.C(O)C>[N:2](=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[C:19]1=[N:18][NH:17][C:16]([NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:30])[OH:3]
Reactant: NO
Reactant: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NN=c1c(=O)c2ccccc2c1=NO)Nc1ccccc1

Procedure:
0.01 mol of hydroxylamine hydrochloride and 0.01 mol sodium acetate in solution in 20 ml water were added to a solution of 0.01 mol of 2-(4-phenyl semicarbazono)-indan-1,3-dione in 150 ml ethanol. The reaction mixture was refluxed for 1 hour, then the ethanol was eliminated at reduced pressure. The resulting crystals were dried on suction pump, washed in water, dried and recrystallised from isopropanol.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH2:7][NH2:8])[CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[ClH:16]>CO.C(O)C.[Pd]>[ClH:16].[ClH:16].[OH:1][CH:2]1[CH:6]([CH2:7][NH2:8])[CH2:5][NH:4][CH2:3]1
Reactant: NCC1CN(Cc2ccccc2)CC1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: NCC1CNCC1O
Yield: 70 %

Procedure:
A solution of 2.19 g (10.6 mmol) of 3-hydroxy-4-aminomethyl-1-phenylmethyl pyrrolidine in 60 ml anhydrous methanol and 5.3 ml 5N hydrochloric acid in ethanol was hydrogenized over 1.83 g palladium on carbon for 17 hours. The catalyst was filtered off, the solvent removed to afford 1.39 g (70%) of title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-13.53 (c=0.58, methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:14]([CH2:15][OH:16])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2CC[C@H]1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@H]2C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of D5 (11 g, 45.6 mmol) in THF (350 mL) cooled at 0° C., BH3 1M in THF (90 mL, 90 mmol) was added and the mixture was stirred at room temperature for 2 hours. Methanol (50 mL) was added; this solution was concentrated and co-evaporated twice from methanol to give the title compound. Yield (11 g, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:27](=O)[CH2:28]Br>>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3cc(F)cc(F)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 14 %

Procedure:
4-[4-(3,5-Difluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (38 mg, 14%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3,5-difluorophenacyl bromide (available from SynQuest Laboratories, Inc.) using the procedure described for the preparation of Example 18. 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.50 (m, 2H), 8.03 (d, J=8.1 Hz, 2H), 7.79 (d, J=7.2 Hz, 2H), 7.50-7.68 (m, 2H), 7.21-7.33 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][C:30]=1[F:29]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=566.2 [M−H+]
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1COc2ccc(I)cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1[nH]c1c3cc(I)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-iodo-3(2H)-benzofuranone (0.551 g, 2.12 mmol) [Cagniant, P. et al. Hebd. Seances Acad. Sci., Ser. C, 1976, 282 (21), 993-6] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 0.480 g (58%) of the title compound as a tan solid: mp 169° C.(dec) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])[O:4][N:3]=1.[CH3:12][N:13]=[C:14]=[O:15]>O1CCCC1>[CH3:12][NH:13][C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:11])([CH3:10])[C:8]#[CH:9])[O:4][N:3]=1)=[O:15]
Reactant: CN=C=O
Reactant: C#CC(C)(C)c1cc(N)no1
Solvent: C1CCOC1
Product: C#CC(C)(C)c1cc(NC(=O)NC)no1

Procedure:
A solution of 7.5 g of 3C and 5 ml of methyl isocyanate in 50 ml of tetrahydrofuran was heated at 50°-60° C. for two days. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel, using as eluent a 1:4:20 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane, to give 1-methyl-3-(5-(1,1-dimethyl-2-propyn-1-yl)-1,2-oxazol-3-yl)urea (3D), as a white crystalline solid, m.p.: 99°-100° C.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[OH:16][CH:17]1[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]1[NH2:19].O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([NH:19][C@@H:18]1[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@@H:24]([CH2:26][OH:27])[O:25][CH:17]1[OH:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
55 g of dodecanoyl chloride were dissolved in 170 ml of tetrahydrofuran and added dropwise, with vigorous stirring, to a solution of 54 g of D-glucosamine hydrochloride in 330 ml of aqueous sodium carbonate solution (20%). After completion of the addition of the acid chloride, the mixture was stirred for a further hour, then 500 ml of water were added to the batch and the solid material was filtered off with suction and washed with water. The residue was recrystallised from isopropanol/water 10/1 (v/v) and dried under high vacuum.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][NH:7][C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:28]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:32][C:30]1([CH3:33])[CH2:31][CH:28]([CH:15]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])=[O:34])=[CH:10][CH:11]=2)[CH2:29]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1
Yield: 120.5 %

Procedure:
(+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (Intermediate 27) (36 mg, 0.076 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (1 mL), and 1.0 M sodium hydroxide (2 mL) was added. This was stirred as a solution at room temperature for 45 min before 1 N HCl was added to bring to pH 4.5. This was extracted twice with ethyl acetate and the combined organics dried over MgSO4. The solution was concentrated in vacuo to give (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid (40.8 mg) as a white solid impure with ethyl acetate. MS (M+1): 446.3. HPLC: XBridge C18 150 mm×4.6 mm, 5 μm column, flow rate 1.50 mL/min, linear gradient of 5% acetonitrile/water (0.1% trifluoroacetic acid modifier) to 100% acetonitrile over 11 min, Retention time=7.046 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)#[N:2].S(Cl)([Cl:16])=O>>[C:1]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CCCc1ccc(C(=O)O)cc1
Product: N#CCCc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 17.5 parts of 4-(2-cyanoethyl) benzoic acid and 120 parts of thionyl chloride are refluxed for 15 minutes. The surplus thionyl chloride is then eliminated under reduced pressure and the 4-(2-cyanoethyl) benzoyl chloride is obtained which is liquid at atmospheric temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22](OC)OC)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:35][O:36][NH2:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH:22]=[N:37][O:36][CH3:35])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CON
Reactant: COC(CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)OC
Agent: Cl
Solvent: CCOC(C)=O
Product: CON=CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 69.4 %

Procedure:
In a solution of 152 mg of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2,2-dimethoxyethyl)-2-methyl benzoic acid amide (Compound of the present invention No. 5-083) synthesized similarly to Synthetic Example 5 in 14 ml of methaol-water (6:1) mixed solvent, 38 mg of methoxyamine hydrochloride was added, and stirred under reflux with heat for 8 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, diluted by adding 80 ml of ethyl acetate, washed with water (30 ml×2), and dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethylacetate-hexane (1:1), and 102 mg of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[O:19]=[S:20]1(=[O:34])[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>>[O:34]=[S:20]1(=[O:19])[CH2:21][CH2:22][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:29][CH:28]=2)[CH2:24][CH2:25]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Product: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(-c5cccnc5)n4n3)cc2)CC1

Procedure:
[4-(1,1-Dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was prepared from 2-methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine and 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine in an analogous manner to Example 1049. Product isolated as an orange foam (19 mg, 11%). LCMS (m/e) 435 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.30 (s, 1H), 8.76 (s, 1H), 8.62 (d, 1H, J=3.8 Hz), 8.49-8.42 (m, 1H), 7.59 (d, 2H, J=8.4 Hz), 7.42 (dd, 1H, J=8.0 and 4.8 MHz), 7.29 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=4.8 Hz), 6.95 (s, 1H), 6.88 (d, 1H, J=4.8 Hz), 3.62 (s, 2H), 3.10-3.03 (m, 4H), 3.02-2.96 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C>C(O)C.[Pd]>[C:8]1([C:5]2[N:4]=[C:3]([C:14]([OH:16])=[O:15])[CH:2]=[CH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1nc(-c2ccccc2)ncc1Br
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccnc(-c2ccccc2)n1
Yield: 83.6 %

Procedure:
A solution of 500 mg 5-bromo-2-phenyl-4-pyrimidinecarboxylic acid and 1 mL N,N-diisopropylethylamine in 5 mL of ethanol was hydrogenated at 40 psi of H2 for 16 hr using 200 mg of 10% palladium-on-carbon as catalyst. The catalyst was filtered off and the ethanol removed by evaporation under reduced pressure. The residue was dissolved in water, acidified with 3N hydrochloric acid and the precipitate was collected by filtration. This material was air dried to yield 300 mg of 2-phenyl-4-pyrimidinecarboxylic acid as a white solid which was used in the next step without further purification or characterization. A solution of 150 mg of 2-phenyl-4-pyrimidinecarboxylic acid in 1 mL of thionyl chloride was heated at 70° C. for 1 hr, cooled to room temperature and the excess thionyl chloride removed by evaporation under reduced pressure to yield 145 mg of 2-phenyl-4-pyrimidinecarboxylic acid chloride which was used in the next step without further purification or characterization.