Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:5]([CH2:6][C:7]2[CH:21]=[CH:20][C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=3)=[O:12])=[CH:9][CH:8]=2)=[C:4]([Cl:25])[CH:3]=1.[N:26]([O-])=O.[Na+].Cl[Sn]Cl.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:33](=[N:26][NH:1][C:2]1[CH:23]=[C:22]([Cl:24])[C:5]([CH2:6][C:7]2[CH:21]=[CH:20][C:10]([C:11](=[O:12])[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=3)=[CH:9][CH:8]=2)=[C:4]([Cl:25])[CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=N[O-]
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C(=O)c2ccc(Cc3c(Cl)cc(N)cc3Cl)cc2)cn1
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Cc1ccc(C(=O)c2ccc(Cc3c(Cl)cc(NN=Cc4ccccc4)cc3Cl)cc2)cn1
Yield: 92 %

Procedure:
The title compound was prepared as pale yellow crystals at yield of 92.0%, in a similar manner as in Reference Example 13, by the reaction of 5-[4-(4-amino-2,6-dichlorobenzyl)benzoyl]-2-methylpyridine, NaNO2, SnCl2 and benzaldehyde.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][NH:18][CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(N)C1C=CC=CC=1>O1CCCC1>[CH2:41]([O:40][C:38]([N:18]1[CH2:19][CH2:20][C:15]2[NH:14][C:13]([C:11]3[S:12][C:8]4[C:7]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)=[N:21][C:16]=2[CH2:17]1)=[O:39])[CH3:42]
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNC4)nc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CCOC(=O)N1CCc2[nH]c(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)nc2C1
Reaction time: 4 h
Yield: 25 %

Procedure:
To a suspension of 0.01 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride in 0.8 ml tetrahydrofurane were added at 0–4° C. 0.06 ml N-ethyldiisopropylamine and 0.003 ml ethyl chloroformate in 0.26 ml tetrahydrofurane. The mixture was refluxed over night, additional 0.06 ml N-ethyldiisopropylamine and 0.05 ml ethyl chloroformate were added and heating was continued for 4 hours. 0.015 ml benzylamine were added and the mixture was kept at 80° C. for 1 hour. Silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate. A second chromatography first with ethylacetate/hexane 1:1 and then with ethylacetate/methanol 9:1 yielded 0.003 g (25%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid ethyl ester as yellow solid; MS (ISP): m/e=444 (M+H+).
Reaction SMILES: [O:1]1[CH:5]2[CH:6]([C:12](OC)=[O:13])[CH:7]([C:8](OC)=[O:9])[C:2]1(OCC)[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:4]2.O.[NH2:26][NH2:27].O>C(O)(=O)C>[OH:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:12](=[O:13])[C:6]=2[CH:5]=[N:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC12OC(N=C1c1ccccc1)C(C(=O)OC)C2C(=O)OC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c(O)c(-c3ccccc3)ncc12
Temperature: 100 °C

Procedure:
3,6-Epoxy-3-ethoxy-4,5-dimethoxycarbonyl-2-phenyl-3,4,5,6-tetrahydropyridine (500 mg; 1.5 mmol) was added to hydrazine monohydrate (5 ml), and the mixture was heated in a stream of nitrogen at 100° C. for 1 hour. Under ice-cooling, water was added to reaction mixture, and the mixture was neutralized with acetic acid. The resulting yellow crystalline precipitate was recovered by filtration. Yield: 210 mg (55.0%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.B.CO>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 80.7 %

Procedure:
8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to −10±5° C. in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h. The reaction was then stirred an additional 45 min at −10° C. and then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81% yield, 95% ee, 95% pure by HPLC).
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].[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(Cl)cc4)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c32)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 16 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-methylbenzenesulfonyl chloride. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.98-8.08 (m, 2H) 7.84-7.92 (m, 1H) 7.52-7.59 (m, 1H) 7.43-7.52 (m, 2H) 7.30-7.37 (m, 3H) 6.07-6.17 (m, 1H) 5.21-5.28 (m, 1H) 3.53-3.65 (m, 3H) 3.47-3.63 (m, 3H) 2.42 (s, 3H) 0.98 (s, 9H); LCMS (m/z) ES+=543 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:31]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:31].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[C:4]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (110 mg, 0.230 mmol) in TFA (5 mL) was stirred at room temperature for 30 minutes, and the TFA was removed in vacuo. The oily residue obtained was dissolved in CH2Cl2 (1 mL), and 2M HCl in Et2O was added. The mixture was stirred at ambient temperature for 30 minutes. The solid formed was filtered and triturated with CH3CN to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropane-carboxamide hydrochloride (70 mg, 67% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.82 (s, 1H), 9.65 (s, 1H), 8.26 (br s, 3H), 8.22 (s, 1H), 7.47 (s, 1H), 3.46-3.40 (m, 3H), 3.31-3.23 (m, 1H), 3.12-3.06 (m, 1H), 2.15-2.09 (m, 1H), 1.87-1.80 (m, 2H), 1.76-1.69 (m, 1H), 1.53-1.43 (m, 1H), 0.83-0.81 (m, 4H); LCMS (APCI+) m/z 378.8, 379.9 (M+H)+, Retention time=2.18 minutes (Method 2).
Reaction SMILES: [CH3:1][C:2](=[CH2:54])[C:3]([NH:5][C:6]1[N:7]=[C:8]([CH2:51][CH2:52][CH3:53])[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:10]=1[C:11]([O-:13])=[O:12])=[O:4].Cl.[CH2:56](O)[CH3:57]>>[CH3:1][C:2](=[CH2:54])[C:3]([NH:5][C:6]1[N:7]=[C:8]([CH2:51][CH2:52][CH3:53])[N:9]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:28][N:29]=[N:30][N:31]=3)=[CH:19][CH:20]=2)[C:10]=1[C:11]([O:13][CH2:56][CH3:57])=[O:12])=[O:4]
Reactant: C=C(C)C(=O)Nc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1C(=O)[O-]
Reactant: CCO
Agent: Cl
Product: C=C(C)C(=O)Nc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)OCC
Yield: 42 %

Procedure:
To 250 mg of ethyl ,4-[N-(2-methylacryloyl)amino]-2-n-propyl-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate was added 10 mL of 2N--HCl-ethanol (1:1) and the mixture was stirred at an external temperature of 90° C. for 4 hours. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (chloroform-methanol=20:1) and recrystallized from acetonitrile to provide 71 mg of ethyl 4-[N-(2-methylacryloyl)amino]-2-n-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylate (yield 42%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH2:26]CC(O)=O)[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9]>ClCCl.CN(C=O)C>[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:1][C:2]([Cl:4])=[O:3])[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCCCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2cnc3cccnc3c2n1CCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A solution of oxalyl chloride (2.04 mL, 23.4 mmol) in dichloromethane (15 mL) was added dropwise to a suspension of 6-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoic acid (2.56 g, 7.8 mmol) in dichloromethane (38 mL) containing one drop of DMF. The reaction mixture was stirred at ambient temperature for 1.75 hours, and then additional oxalyl chloride (0.35 mL, 4.1 mmol) was added. The reaction was stirred for an additional 45 minutes and then concentrated under reduced pressure to provide 6-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]acetaldehyde (D78) (160 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate hydrochloride (182 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D90) (200 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C27H31ClN2O3S requires 498. found 499.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=3)[CH:3]=2)=[O:18])=[CH:12][N:13]=1
Reactant: Nc1cc(NC(=O)c2ccc(Cl)nc2)ccc1Cl
Reactant: O=C(O)c1cccc(F)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(F)c2)c1)c1ccc(Cl)nc1

Procedure:
N-(3-amino-4-chlorophenyl)-6-chloronicotinamide (0.16 mmol) was used in general procedure 2 with 3-fluorobenzoic acid (0.83 mmol). The product was purified by RP-HPLC to give 6-chloro-N-(4-chloro-3-(3-fluorobenzamido)phenyl)nicotinamide. MS (Q1) 404.3 (M)+
Reaction SMILES: [CH2:1]([O:3][P:4](C#CC1N(C2C=CC(F)=CC=2)C2C(C=1C(C)C)=CC=CC=2)([CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].P(OCC)(OCC)[O:37][CH2:38][CH3:39]>>[CH2:38]([O:37][P:4]([O:3][CH2:1][CH3:2])([CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:39]
Reactant: CCOC(=O)CC(=O)CP(=O)(C#Cc1c(C(C)C)c2ccccc2n1-c1ccc(F)cc1)OCC
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)CC(=O)CP(=O)(OCC)OCC
Temperature: 115 °C
Yield: 66.9 %

Procedure:
The title A compound of Example 3 (41.0 g, 0.174 mol) was dissolved in (EtO)3P (150 mL, 0.87 mol) and heated at 115° C. (bath temperature) for 18 hours and then cooled to room temperature. The excess (EtO)3P was distilled off at reduced pressure (1 mm Hg, 45° C. bath temperature). The resulting brown residue was purified by chromatography on silica gel, isopropanol:hexane (1:9), to give the title compound as a pale yellow liquid (31 g, 67%).
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Al].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>CN(C)C=O>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 254 mg (9.42 mmol) of aluminum (foil) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at 100° C. for 30 min. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 sulfuric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 737 mg (3.96 mmol) of diphenylphosphine in 84% yield.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[N:12]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(=O)c1ccc(C=O)cc1
Reactant: C1COCCN1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(CN2CCOCC2)cc1

Procedure:
4.7 g of 1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylate and 1.3 g of scandium triflate were added to 2.75 g of 4-acetylbenzaldehyde (18.56 mmol), 1.7 ml of morpholine and 3 g of 4 Å molecular sieves in 100 ml of tetrahydrofuran under argon, and the mixture was heated to reflux for 3 hours. The mixture was concentrated. The residue was mixed with ethyl acetate and washed with sat. NaHCO3 solution and sat. NaCl solution. Drying and evaporation of the mixture resulted in a crude product which was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40-80%). 1.85 g of a yellowish oil were obtained.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>ClC(Cl)C>[ClH:26].[CH2:2]([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C(C1CN(Cc2ccccc2)CCO1)N1CCOCC1
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
A 250 mL reactor under N2 is successively loaded with 91 (5 g, 19.41 mmol), dichloroethane (50 mL), DMF (0.014 mL, 1% mol) and oxalyl chloride (1.86 mL, 21.35 mmol). The mixture is heated up to 60-65° C. for 2 h, before being cooled to 0° C. Then, morpholine (6.93 g, 79.60 mmol) in dichloroethane (20 mL) is added over 15 min keeping the temperature below 10° C. The heterogeneous solution is post-agitated for 1 h 30 min at room temperature and quenched with water (30 mL). The biphasic mixture is filtered on a Hyflo Super Cel® (10 g), then after separation, the organic layer is concentrated under reduce pressure. The mixture is taken up with isopropanol (80 mL) and 12N HClaq (1.61 mL, 19.41 mmol), stirred for 10 min and concentrated under reduce pressure. The mixture is taken up with isopropanol (13 mL), heated to reflux until a homogeneous solution is formed, then it is cooled to room temperature. The precipitate is filtered, rinsed with isopropanol (10 mL) and dried under vacuum at 40° C. overnight to obtain 92 as an off-white powder with 79% overall yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1cccc(CCl)c1
Reactant: CCOC(=O)C1CCCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1Cc1cccc(OC)c1

Procedure:
A solution of ethyl 2-piperidinecarboxylate (10.0 ml), 3-methoxybenzyl chloride (9.2 ml), and triethylamine (26.6 ml) in N,N-dimethylformamide (64.0 ml) was stirred at room temperature overnight and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (four times) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford ethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate (12.06 g) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.O.O.[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>CCOCC>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[CH3:13][N:12]([CH2:11][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][C:35]1[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=1)[CH3:14]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CN(C)CC(CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: O
Product: CN(C)CC(COc1ccc(C(F)(F)F)cc1)Cc1ccccc1

Procedure:
A mixture of 2-benzyl-3-dimethylaminopropanol (4.2 g), dicyclohexylcarbodiimide (4.6 g) and cuprous chloride (0.2 g) is maintained at 80° for 40 hours. 4-Trifluoromethylphenol (5.0 g) is added, and the mixture maintained at 130° for 12 hours. The reaction mixture is cooled and ether (100 ml) is added. The insoluble material is filtered off and the filtrate extracted with 2N hydrochloric acid (3×100 ml). The acidic solutions are combined and made basic by the addition of concentrated aqueous ammonia. The aqueous solution is extracted with ether (3×150 ml), and the combined extracts dried over magnesium sulfate and evaporated under reduced pressure to give the ether as a yellow oil. This material is converted to the oxalate salt by dissolving in ether and adding the calculated quantity of oxalic acid dihydrate in ether. Filtration gives N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine oxalate, m.p. 147°-149°.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.[NH2:28][C@@H:29]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:56][CH:55]=1)[C:30]([N:32]([C@@H:44]([CH3:52])[CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:28][C@@H:29]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:56][CH:55]=1)[C:30]([N:32]([C@@H:44]([CH3:52])[CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To the solution of 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 182 mg (0.77 mmol), hydroxybenzotriazole 104 mg (0.77 mmol) and 1-ethyl-3-(3-s dimethylaminopropyl)carbodiimide 148 mg (0.77 mmol) in dichloromethane 3 ml, a solution of (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 260 mg (0.51 mmol) and 4-dimethylaminopyridine 31 mg (0.26 mmol) in dichloromethane 3 ml was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Buch silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound 333 mg (90%).
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)[Br:20]>C(Cl)Cl>[C:1]([NH:4][CH:5]([Br:20])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)NC(Br)C(=O)NCc1ccccc1
Reaction time: 3.5 h

Procedure:
A solution of 2-acetamido-2-ethoxy-N-benzylacetamide (2.00 g, 8 mmol) in dry CH2Cl2 (200 mL) was stirred at room temperature as a solution of BBr3 (8.8 mL, 8.8 mmol, 1.0M in CH2Cl2) was introduced by means of a syringe under a nitrogen atmosphere. A while mist formed and alter it disappeared, the N2 line was removed and the reaction sealed. The resulting yellow solution was stirred (3.5 h) and then concentrated in vacuo to give yellow crystals of α-acetamido-2-bromo-N-benzyl acetamido which was stored under vacuum overnight.