Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28](B(O)O)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:28]4[C:29]([O:31][CH3:32])=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ncc(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c(OC)n1
Temperature: 125 °C

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (4.1, 48 mg, 0.11 mmol, synthesized by procedures similar to those that were used to make compound 1.5 described in SCHEME 1), 2,4-dimethoxypyrimidin-5-ylboronic acid (4.2, 24 mg, 0.13 mmol), PdCl2(PPh3)2 (38 mg, 0.05 mmol), K2CO3 (23 mg, 0.16 mmol) in 1 mL acetonitrile and 1 mL water was degassed using argon stream and heated in microwave reactor at 125° C. for 15 min. The mixture was filtered and directly subjected to reverse phase prep HPLC to isolate the title compound. MS found for C20H17ClN6O3S (M+H)+ 457.1, 459.1 (Cl pattern).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH:12]=1)=O>C1COCC1>[CH2:22]([O:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH:12]=[C:11]([CH2:9][OH:8])[CH:20]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2cc(F)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a suspension of LiAlH4 (1.76 g, 46.4 mmol) in dry THF (20 mL) was added a solution of 4-benzyloxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (4.80 g, 15.5 mmol) in THF (30 mL) drop wise at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched through the addition of an aqueous solution of HCl (50%; 50 mL) and the resulting mixture was filtered through a bed of celite. The filtrate was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (30 mL) followed by brine (30 mL), dried and concentrated in vacuo to obtain (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (3.6 g, 82.2%). The crude product was pure enough to proceed to the next step without further purification.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>CN1CCCC1=O>[CH2:26]([N:29]1[C:21](=[O:22])[C:5]2[C:4]3[C:19]4[C:8](=[CH:7][CH:6]=2)[C:9]2[C:20]5[C:13]([CH:12]=[CH:11][CH:10]=2)=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]=4[CH:1]=[CH:2][C:3]=3[C:24]1=[O:23])[CH:27]=[CH2:28]
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: C=CCN
Solvent: CN1CCCC1=O
Product: C=CCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 85 °C

Procedure:
A mixture of 5 g (15.5 mmol) of perylene-3,4-dicarboxylic anhydride (prepared in accordance with Liebigs Ann. 1995, 1229–1244), 11.4 g (0.2 mol) of allylamine and 1200 ml of N-methylpyrrolidone was heated at 85° C. in a 2 1 autoclave for 7 h and then cooled to room temperature, the autoclave was let down, the solvent was reduced to about 25% of its original volume by concentration, and the precipitation of the crude product was completed by adding four times the amount of methanol. The precipitate formed was isolated by filtration, washed with methanol and dried at 60° C. under reduced pressure. Chromatographic separation on silica gel using 40:1 chloroform/methanol as eluent, followed by twofold recrystallization from chloroform, gave 4.83 g (86%) of the desired end product in the form of brownish red crystals which underwent decomposition at temperatures above 260° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.N.O1CCOCC1.CC[N:21](C(C)C)C(C)C>CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:21])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CCOCC
Solvent: C1COCCO1
Product: NC(=O)c1cc(Cl)nc(Cl)n1
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of 2,6-dichloropyrimidine-4-carbonyl chloride (26.13 g, 123.6 mmol) in Et2O (500 mL) was added a mixture of 0.5M ammonia in dioxane (250 mL, 125 mmol) and iPr2NEt (22 mL, 126 mmol) dropwise over approximately 50 minutes. After stirring overnight the reaction was concentrated in vacuo to a residue and chromatographed over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo, and the resulting solid residue triturated with 10 mL 10% EtOAc/hexanes and filtered to give 2,6-dichloropyrimidine-4-carboxamide as an orange crystalline solid (9.743 g, 50.74 mmol, 41% yield). LC/MS: m/z=192.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): 8.40 (1H, br s), 8.16 (1H, br s), 8.10 (1H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:22][C:16]2([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:27][CH2:26]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CN1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: CN1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 56.7 %

Procedure:
A solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.58 mmol, 1 wt), 1-methylpiperazine (300 mg, 2.99 mmol), absolute ethanol (20 ml, 40 vol), activated 3 Å molecular sieves (500 mg), titanium (IV) isopropoxide (2.32 ml, 7.83 mmol) and STAB (1.43 g, 6.73 mmol) were reacted in accordance with the general procedure D. The isolated oil was purified by column chromatography on silica (20 g, 28.6 wt) eluting with DCM(95):MeOH(4):NH3(I) to give the title compound as a clear viscous oil (360 mg, 56%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.75 (dt2H), 3.60-3.47 (m, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.38 (s, 2H), 2.34-2.14 (m, 11H), 2.13-1.73 (m, 10H).
Reaction SMILES: [Sn](Cl)Cl.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]([CH:17]=1)[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[N:19]([O-])=O.[Na+]>Cl>[Cl:18][C:8]1[CH:7]=[CH:6][C:5]([NH:4][NH2:19])=[CH:17][C:9]=1[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=Cc1cc(N)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CCOC(=O)C=Cc1cc(NN)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
First, 60 g of tin (II) chloride was dissolved in 60 ml of concentrated hydrochloric acid, and the mixture was cooled to −30° C., to which a diazonium solution prepared from 19 g of ethyl 5-amino-2-chlorocinnamate and 6.3 g of sodium nitrite was added dropwise at 0° C. or lower. The reaction mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration. These crystals were added to ice-water, neutralized with 2N aqueous sodium hydroxide, and extracted with chloroform. The chloroform layer was dried and concentrated, which afforded 7.0 g of ethyl 2-chloro-5-hydrazinocinnamate.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([Cl:19])[CH:15]=[C:16]([CH2:17]O)[C:11]=2[O:10][C:9]1=[O:20])=O)(C)(C)C.[CH2:21]([O:23][C:24](=[O:40])[CH2:25][CH:26]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][C:31]1=[O:39])[CH2:27][CH2:28][CH3:29])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:21][O:23][C:24](=[O:40])[CH2:25][CH:26]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:17][C:16]2[C:11]3[O:10][C:9](=[O:20])[NH:8][C:12]=3[CH:13]=[C:14]([Cl:19])[CH:15]=2)[C:31]1=[O:39])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)n1c(=O)oc2c(CO)cc(Cl)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Cl)cc3[nH]c(=O)oc23)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 3.6 %

Procedure:
5-Chloro-7-hydroxymethyl-2-oxo-benzooxazole-3-carboxylic acid tert-butyl ester 600 mg (2 mmol) is dissolved in tetrahydrofuran 1.5 mL and then 3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester is added (608 mg (2.2 mmol). The reaction is cooled to 0° C. and then triphenylphosphine (630 mg, 2.4 mmol) is added followed by the drop wise addition of diisopropyl azodicarboxylate (465 μL, 2.40 mmol). The reaction is stirred for 15 minutes at 0° C. and then the solvents evaporated in vacuo. The compound is purified on silica with dichloromethane methanol as the eluent. This crude material is then taken up in dichloromethane (1.5 mL) and trifluoroacetic acid (500 uL) is added drop wise to the reaction. The reaction is stirred at room temperature and monitored by LC/MS. Upon completion the reaction is evaporated in vacuo and purified by preparative reverse phase LC to give the title compound 33 mg (0.07 mmol, 3.6%). LCMS (ESMS): m/z 444.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:23]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[CH:37]2>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:23]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:33][C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[NH:39][CH:38]=[CH:37]5)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc5[nH]ccc5c4)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-(7-Benzenesulfonyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (150 mg, 0.31 mmol) in butanol (5 mL) was treated with 5-aminoindole (50 mg, 0.38 mmol) and heated to 80° C. for 2 h and then 85° C. for 1 h. The mixture was evaporated to dryness and pre-absorbed onto silica. Purification on silica by elution with dichloromethane:methanol (97:3) yielded a slightly pink solid. 1H NMR (d6-DMSO, 400 MHz) 9.4(NH), 8.3(1H, s), 8.0(2H,d), 7.9(1H,s), 7.7(1H,m), 7.6(2H,m), 7.4(2H,m), 7.2(1H,m), 6.8(1H, br.s), 6.4(1H, s), 6.0(1H,s), 4.1(2H, m), 3.6(2H,m), 2.5(2H, m), and 1.5(9H, s); LC/MS: m/z 570 [M+H]+, Rt=4.07 min.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:6][C@H:5]([C:4]([OH:3])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)=[O:29]
Reactant: Cc1ncccc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: Cc1ncccc1C(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2-methylnicotinic acid. δH (DMSO-d6) 8.73 (1H, br d), 8.48 (1H, m), 7.7-7.46 (4H, m), 7.4-7.23 (3H, m), 7.00 (2H, d, J 8.4 Hz), 5.2) (2H, s), 4.60 91H, m), 3.27-3.12 (1H, m), 3.0-2.82 (1H, m); m/z (ESI, 60V) 509 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH:3]([NH:10]S(C(C)(C)C)=O)[C:4]1[O:5][C:6]([CH3:9])=[N:7][N:8]=1.Cl.O1CCOCC1>CO>[CH3:1][C:2]([CH3:18])([CH3:17])[CH:3]([C:4]1[O:5][C:6]([CH3:9])=[N:7][N:8]=1)[NH2:10]
Reactant: Cc1nnc(C(NS(=O)C(C)(C)C)C(C)(C)C)o1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nnc(C(N)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of N-[2,2-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl]-2-methyl-propane-2-sulfinamide (example 174a, 462 mg, 1.69 mmol) in methanol (10 ml) was added a 4M solution of hydrochloric acid in dioxane (845 μl, 3.38 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was then concentrated in vacuo and the residue was dissolved in ethylacetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (165 mg, 58%). MS (ESI, m/z): 170.5 (M+H+).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:43][C@H:44]([C:52]([OH:54])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[C:1]([O:18][CH:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][C:21]([NH:23][CH2:24][C:25]([NH:43][C@H:44]([C:52]([OH:54])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 64.8 %

Procedure:
Starting from N-(3-hexadecanoyloxyoctadecanoyl)glycine (2.6 g) prepared by the method described in Example 27 and L-phenylalanine (1.65 g), N-[N-(3-hexadecanoyloxyoctadecanoyl)glycyl]-L-phenylalanine (2.1 g) was obtained as powders according to a similar manner to that of Example 29.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 74.1 %

Procedure:
The compound of Example 211 (0.96 g) in TFA (10 ml) was kept at room temperature for 2 hours. The solution was evaporated and the residue dissolved in water (15 ml) and the solution basified with sodium carbonate. The mixture was extracted three times with dichloromethane. Evaporation of the combined extracts gave the title compound (0.56 g); m.p. 125°-127° C.; NMR(d6DMSO) δ 8.2(2H,d), 6.92(6H,m), 4.0(2H,m), 3.64(3H,s), 3.46(4H,t), 3.15(4H,t), 2.04(2H,m), 1.84(1H,m); m/e 371(M+H)+. Calculated for C20H26N4 O3. 0.75 H2O: C, 62.5; H, 7.17; N, 14.6. Found: C, 62.8; H, 6.8; N, 14.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][NH:11][CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:4][CH:3]=1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: CCCC1CNCC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of 210 mg (0.425 mmol) of tert-butyl (3RS,4RS, 5SR)-4-(4-chloro-phenyl)-3-naphthalen-2-ylmethoxy-5-propyl-piperidine-1-carboxylate in 18 ml of methanol was treated with 12 ml of 1 N hydrochloric acid and stirred at 50° C. overnight. Subsequently, the solution was evaporated under reduced pressure, the residue was taken up in warm toluene and again evaporated, the product beginning to separate out. There were obtained 153 mg (84% of theory) of (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-naphthalen-2-ylmethoxy-5-propyl-piperidine as a colourless solid. MS: 252 (M-naphthylmethyl)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([CH2:22][CH2:23][CH3:24])=[C:15]([OH:25])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1.NN.[OH-].[K+].O>C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([CH2:22][CH2:23][CH3:24])=[C:15]([OH:25])[C:12]=3[C:13]=2[CH3:14])=[CH:26][CH:27]=1
Reactant: CCCc1cc(CCC)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCc1cc(CCC)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Temperature: 195 °C
Yield: 49.7 %

Procedure:
A mixture of 2 (p-methoxybenzoyl)-3 methyl-4-hydroxy-5,7-dipropylbenzofuran (0.30 gm; 0.80 mmoles), 99% hydrazine (0.2 mL), potassium hydroxide (0.40 gm; 7mmoles) in ethylene glycol (10 mL) was heated at 140° C. for a period of 2.5 hours and at 195° C. for one hour. The reaction mixture was cooled, poured into water, and extracted with ethylacetate. The organic phase was washed with 20% citric acid, with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 140 mg (50%) of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5,7-dipropylbenzofuran, mp. 70°-72° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8][CH2:9][CH3:10])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[F:11][C:12]1[CH:19]=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH2:8][CH2:9][CH3:10])[C@@H:2]2[CH3:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: CCC[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCC[C@]1(O)CCN(c2ccc(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-propylpyrrolidin-3-ol 0.5 oxalate (250 mg), 2,4-difluorobenzonitrile (367 mg) and lithium carbonate (195 mg), the title compound was obtained as colorless oil (yield: 287 mg, yield: 83%).
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].OO.O.C(OCC)(=[O:25])C>CO>[CH2:1]([S:3]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:25])[CH3:2]
Reactant: CCS[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Reactant: CCOC(C)=O
Agent: OO
Solvent: CO
Solvent: O
Product: CCS(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.224 g of (3R,4S)-4-ethylthio-3-phenoxyacetamido-2-oxoazetidine in 3 ml of methanol is added 0.16 ml of 30% aqueous hydrogen peroxide and the mixture is stirred at room temperature for 4 hours. Then, 0.1 ml of 30% aqueous hydrogen peroxide is added, and the mixture is further stirred for 4 hours, followed by addition of 10 ml of water Extraction is carried out with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of (3R,4S)-4-ethylsulfinyl-3-phenoxyacetamido-2-oxoazetidine.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
The product from Example 185A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68-11.71 (bs, 1H), 7.39-7.51 (m, 5H), 7.04-7.20 (m, 3H), 3.72 (s, 2H), 2.51-2.55 (m, 2H), 2.37-2.41 (m, 2H), 1.69-1.77 (m, 2H), 1.58-1.65 (m, 2H); MS (APCI+) M/Z 396 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:15](=[O:28])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)[CH:18]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl>CO>[CH3:1][C:2]1([C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)[CH:18]=2)=[O:28])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(-c3cnco3)c2)CC1
Agent: Cl
Solvent: CO
Product: CC1(C(=O)Nc2cccc(-c3cnco3)c2)CCNCC1
Reaction time: 15 h

Procedure:
To a solution of tert-butyl 4-methyl-4-(3-(oxazol-5-yl)phenylcarbamoyl)piperidine-1-carboxylate from step A (77.7 mg, 0.202 mmol) in methanol (3 mL) was added HCl (4.0 N in dioxane, 0.4 mL, 1.6 mmol). The reaction was stirred for 15 hours and then concentrated to dryness to give the title compound as the hydrochloride salt. MS (ES+) [M+H]+=286.2.
Reaction SMILES: N1[CH:5]=[CH:4][CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10]CC[CH2:7]1>>[CH3:10][N:6]([CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH2:3][CH2:4][C:5]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1)[CH3:7]
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Reactant: c1cn[nH]c1
Product: CN(C)C[C@@H](CCc1ccccc1)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N,N-dimethyl-4-phenyl-1,2-butanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: B.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=O)[CH:6]=[CH:7][CH:8]=1.[ClH:15]>O1CCCC1>[ClH:15].[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:12]([CH3:13])[CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)Cc1cccc(Br)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCc1cccc(Br)c1
Temperature: 90 °C

Procedure:
Borane in tetrahydrofuran (1.0M, 24.7 ml) was added dropwise to a tetrahydrofuran solution of 2-(3-bromophenyl)-N,N-dimethyl-acetamide (1.5 g, Example 25a)) at 0° C. Once addition was complete the solution was refluxed at 90° C. for 20 hours. The solution was cooled to room temperature, acidified with hydrochloric acid (6M, 10 ml) and refluxed for a further hour. The solution was cooled to room temperature and extracted with diethyl ether. The aqueous layer was basified with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to the hydrochloride salt by treatment with a solution of 4M hydrogen chloride in dioxan to give the sub-title compound as a hygroscopic gum (0.949 g).