Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[H][H]>C1COCC1.[Pd]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=3)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a hydrogenation reactor, (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate (3B; 25 g, 56 mmol) was dissolved in THF (200 mL), and 15 mL of 4N HCl was added to the reaction mixture. Then, 10% Pd/C (2.5 g) was added to the reaction mixture. Hydrogen was introduced into the reactor until pressure reached 4 MPa. The reaction was stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with THF. The pH of the solution was adjusted to about 7 by adding saturated NaHCO3 (aq) while the solution was on an ice bath. The organic layer was separated, and the aqueous layer was washed with CH2Cl2 (2×15 mL). The combined organic fractions were dried with anhydrous Na2SO4 to give a solution of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-aminophenyl)propanoate 3C. The solution was used directly in step 3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2].CI.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Reactant: CCOC(=O)CBr
Solvent: CI
Product: CCOC(=O)CN1C(=O)CN=C(c2ccccc2)c2cc(OCC)c(OCC)cc21
Yield: 55 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag), and MeI by ethyl bromoacetate, and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 160–162° C. 1H-NMR (CDCl3, 200 MHz): d 1.21 (t, 3H, CH3), 1.36 (t, 3H, CH3), 1.50 (t, 3H, CH3), 3.88–4.26 (m, 7H, 3×OCH2+1H CH2) 4.49 (AB system, ? d=0.17, JAB=17.4, 2H, —NCH2), 4.80 (m, 1H CH2), 6.71 (s, 1H Ar), 6.81 (s, 1H Ar), 7.27–7.69 (m, 5H Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([NH:14][CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(CCCN)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CCCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 53.5 %

Procedure:
A solution of 3-(3,4-dimethoxy-phenyl)-propylamine (12.51 g, 64.06 mmol) and TEA (10 ml, 71.84 mmol) in anhydrous THF (70 ml) was cooled to 0° C. and (3,4-dimethoxy-phenyl)-acetyl chloride (13.75 g, 64.07 mmol) in THF (28 ml) was added dropwise. After stirring at RT for 13 h under nitrogen, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted three times with AcOEt. The organic phase was dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. A subsequent washing of the crude solid with toluene gave the title compound (12.81 g, 34.30 mmol, 53%) as a beige solid.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=O)[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1.C1C=CC=CC=1>ClCCCl>[F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[S:34])[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1ccccn1C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Solvent: c1ccccc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(n1ccccc1=S)=CC(CF)(CF)O2
Yield: 69.5 %

Procedure:
A mixture of 0.13 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran, 83 mg of a Lawesson's reagent, 1 ml of benzene and 1 ml of 1,2-dichloroethane was refluxed for 3 hours and the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2), and then, recrystallized from a mixture of ethyl acetate and hexane to obtain 0.05 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-thioxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having a melting point of 209-210° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](OC)=[O:33])=[CH:16][C:15]=2[C:36]([F:39])([F:38])[F:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[Cl:31][C:28]1[N:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([CH2:32][OH:33])=[C:21]2[NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[C:15]([C:36]([F:39])([F:37])[F:38])[CH:16]=1
Reactant: COC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(Cl)nc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.6 %

Procedure:
Methyl 4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-6-chloro-1,5-naphthyridine-3-carboxylate (0.565 g, 1.0 mmol) was added to ethanol (10 mL), to the system added sodium borohydride (0.228 g, 6 mmol) in batches, stirred at room temperature for 18 h. Ethanol was removed under reduced pressure, added 10 mL of water, and extracted with 80 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 0.568 g of a crude solid product. The solid was directly used in the next step.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][C:31]3[N:32]=[C:33]([CH3:36])[S:34][CH:35]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Cc1nc(CCl)cs1
Product: Cc1nc(Cn2ccc3c(-c4ccc(Cl)cc4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c32)cs1

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 4-(chloromethyl)-2-methylthiazole. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.61-7.74 (m, 1H) 7.33-7.45 (m, 3H) 7.11-7.21 (m, 1H) 7.00-7.08 (m, 1H) 5.93-6.00 (m, 1H) 5.73-5.89 (m, 2H) 3.65 (s, 3H) 2.63 (s, 3H) 0.86 (s, 9H); LCMS (m/z) ES+=500 (M+1).
Reaction SMILES: NS(C1C=C(C=CC=1Cl)C(O[CH2:11][C:12]1[CH:17]=[CH:16][N:15]2[N:18]=[C:19]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:14]2[CH:13]=1)=O)(=O)=O.[NH2:38]N>C(O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:19]2[C:20]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:14]3[CH:13]=[C:12]([CH2:11][NH2:38])[CH:17]=[CH:16][N:15]3[N:18]=2)=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1cc(C(=O)OCc2ccn3nc(-c4ccc(F)cc4)c(-c4ccncc4)c3c2)ccc1Cl
Reactant: NN
Solvent: CCO
Product: NCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Yield: 58.7 %

Procedure:
[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl 3-(aminosulfonyl)-4-chlorobenzoate (Example 17 106 mg, 0.23 mmol) is dissolved in ethanol (10 mL) and hydrazine (64 mg, 2 mmol) added. The solution is refluxed for 6 h and allowed to cool. A precipitate of phthalhydrazide is filtered off and the mother liquor concentrated to dryness. The crude solid is taken up in dilute hydrochloric acid (20 mL), and washed twice with ethyl acetate (15 mL) followed by basification with sodium hydroxide solution. The solution is extracted five times with dichloromethane (20 mL), dried (MgSO4) and concentrated to give a solid (43 mg). Purified by preparative TLC, eluting with ethyl acteate plus 2% methanol, to give the title compound, 23 mg. 1H NMR (d6-DMSO) δ 3.75 (s, 2H), 6.97 (d, J=7.3 Hz, 1H), 7.22 (t, J=8.9 Hz, 2H), 7.28 (d, J=5.9 Hz, 2H), 7.50 (dd, J=5.7, 8.4 Hz, 2H), 7.64 (s, 1H), 8.53 (d, J=5.7 Hz, 2H), 8.68 (d, J=7.2 Hz, 1H); APESI-MS m/z 319 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([Cl:15])=[CH:10][C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=2)[C:11]([Cl:15])=[CH:10][C:9]=1[F:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A mixture of tert-butyl(4-chloro-2-fluoro-5-hydroxyphenyl)carbamate (6.70 g, 25.6 mmol), 2-chloro-5-nitropyridine (4.06 g, 25.6 mmol), potassium carbonate (3.89 g, 28.1 mmol) and N,N-dimethylformamide (70 mL) was stirred at room temperature for 30 min. To the reaction mixture was added aqueous ammonium chloride solution (100 mL), and the mixture was extracted with ethyl acetate (150 mL×3). The organic layers were combined, and washed successively with water (100 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.52 g, 46%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(#N)C>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1ccccc1F
Solvent: CC#N
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccccc1F
Temperature: 82 °C
Yield: 86.4 %

Procedure:
2-Methoxy-5-trifluoromethylphenyl isocyanate (1057.8 g) is dissolved in acetonitrile (4240 ml), then 2-fluoroaniline (540.8 g) is added thereto and the mixture is rinsed in with acetonitrile (50 ml). The resulting clear solution is stirred under reflux (ca. 82° C.) for 4 h, then seeded at ca. 78° C. and stirred for ca. 15 min. The suspension is cooled to 0° C., and the product is filtered off with suction and washed with acetonitrile (950 ml, cooled to 0-5° C.). The product is dried overnight at 45° C. in a vacuum drying oven using entraining nitrogen. A total of 1380.8 g of N-(2-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea are obtained as a solid, corresponding to 86.4% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[C:31][Si](C)(C)C)[CH:27]=[CH:26][C:25]=3[O:36][CH3:37])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:30]#[CH:31])[CH:27]=[CH:26][C:25]=3[O:36][CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(C#C[Si](C)(C)C)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(OC)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-methoxy-5-(2-trimethylsilanyl-ethynyl)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (50 mg, 0.088 mmol) in MeOH (2 ml) was added 2N NaOH dropwise. The reaction was stirred for 30 min and extracted with EtOAc. The combined organic extract was dried and concentrated and was purified by flash chromatography, eluting with CH2Cl2, then EtOAc. Recrystallization gave the title compound as a white solid (13 mg, 13% yield). MS (H+), 491
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
1.52 ml of 4-tert-butylbenzaldehyde (9.1 mmol) and 1.6 g 2-(3-benzyloxy-phenyl)-ethylamine hydrochloride (6.07 mmol) and 838 mg potassium carbonate (6.07 mmol) were suspended in 18 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 344 mg (9.1 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 2 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 2.13 g [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine as a light yellow viscous oil (94%). MS (ISP) 374.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[Li+].CS([Cl:35])(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH2:18][Cl:35])=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ClCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
A mixture of 4-(7-chloroquinolin-2-ylmethoxy)benzyl alcohol (2.80 g, 9.33 mmol), triethylamine (3.12 g, 30.9 mmol), lithium chloride (0.850 g, 20.0 mmol), and 4-(N,N-dimethylamino)pyridine (10 mg) in DMF (40 mL) was cooled to -10° C. Methanesulfonyl chloride (3.40 g, 29.7 mmol) was added dropwise and the resulting mixture was stirred for 15 minutes. The mixture was warmed to room temperature and stirred for an additional 4 hours, then diluted with ethyl acetate. The resulting solution was washed once with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography of the residue (silica gel, ethyl acetate/hexane gradient) provided 1.60 g (54%) of the intermediate.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)[CH3:17])[CH2:11][CH2:10]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>C(#N)C>[Br:24][C:20]1[CH:19]=[C:18]([C@@H:16]([N:12]2[CH2:11][CH2:10][C@:9]([CH2:8][CH2:7][CH2:6][NH:42][S:39]([CH3:38])(=[O:41])=[O:40])([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[O:14][C:13]2=[O:15])[CH3:17])[CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
3-((R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (6.8 mg, 0.013 mmol) was diluted with acetonitrile (2 mL), added K2CO3 (10 mg, excess) and methanesulfonamide (2.5 mg, 2 equiv.). The mixture was stirred overnight at rt. After filtration and concentration, the residue was purified by preparative HPLC to afford N-(3-((R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide (2.5 mg, 37%). LC-MS (3 min) tR=1.87 min, m/z=514, 516 (M+1). 1H NMR (CDCl3) 7.31 (m, 1H), 7.23 (m, 2H), 7.14-7.05 (m, 3H), 7.02 (t, 1H), 6.87 (d, 1H), 5.64 (q, 1H), 4.17 (m, 2H), 2.97 (s, 3H), 2.33-2.11 (m, 3H), 1.52 (d, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]#[N:6])(=[O:3])[CH3:2].[Na].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH2:8]([N:4]([C:5]#[N:6])[C:1](=[O:3])[CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)NC#N
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)N(C#N)Cc1ccccc1

Procedure:
106.1 g (1.0 mol) of sodium acetylcyanamide and 151.9 g (1.0 mol+20% excess) of benzyl chloride are reacted in 500 ml of dimethylformamide at 100°-112° C. for 4 hours and 20 minutes and the mixture is then filtered. The filtrate is evaporated completly in vacuo on a rotary evaporator at 60° C. to give 146.7 g (88.7% of theory) of a brown viscous residue, which is recrystallised from 290 ml of diisopropyl ether. The yield of pure product of melting point 42° C. is 111.0 g (63.7% of theory).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14]O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][N:41]3[C:40](=[O:42])[C:39]4=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]4[C:37]3=[O:47])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: OCCC1CCN(Cc2ccc(F)cc2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of 1-(4-fluorobenzyl)-4-(2-hydroxyethyl)piperidine (10.0 g), triphenylphosphine (13.04 g) and phthalimide (6.65 g) in tetrahydrofuran (100 ml) was added dropwise a solution of diethyl diazenedicarboxylate (7.7 ml) in tetrahydrofuran (50 ml). After stirring overnight at ambient temperature, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, and dried over magnesium sulfate, and evaporated in vacuo. The residue was suspended with hexane--ether (100 ml--100 ml) and the precipitates were removed by filtration. The filtrate was evaporated in vacuo and the residue was recrystallized from hexane to give N-[2-[1-(4-fluorobenzyl)piperidin4-yl]ethyl]phthalimide (9.23 g).
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].CCN(CC)CC.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([NH:35][C:36]([NH:20][C@H:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C=NCc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)NCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.360 g, 1 mmol) and Et3N (0.42 mL, 3 mmol) in 10 mL CH2Cl2 is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.425 g (96% yield) of the desired product which is used without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH3:16])[CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[OH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[OH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]([CH3:16])[CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4])=[O:21]
Reactant: CC(N)C(C)NC(=O)OCc1ccccc1
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC(NC(=O)OCc1ccccc1)C(C)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
To a mixture of benzyl 3-aminobutan-2-ylcarbamate (5.3 g, 23.8 mmol), 2-hydroxybenzoic acid (3.28 g, 23.8 mmol) and imidazole (1.62 g, 23.8 mmol) in EtOAc (180 mL) at 0° C. was slowly added a solution of DCC (4.90 g, 23.8 mmol) in EtOAc (20 mL). The reaction mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with PE-EA (5:1) to afford benzyl 3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g, 40%) as a colorless oil. Mass calculated for C19H22N2O4=342.39. found: [M+H]+=343.2.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)Nc3cccnc3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)Nc3cccnc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(3-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (230 mg), 1 N aqueous sodium hydroxide solution (1.2 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for one hour. After 1 N hydrochloric acid (1.2 ml) was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(3-pyridylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (190 mg, yield: 86%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 131–132° C.