Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2N=1)(C)(C)C.Cl.ClCC1N(C)N=NC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:35]([CH3:30])[N:34]=[N:33][CH:31]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Agent: Cn1nncc1CCl
Product: Cn1nncc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as light-yellow gum. MS(m/e): 378.3 (MH+).
Reaction SMILES: [NH2:1][C@:2]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=1)[C@@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10](=[O:14])[CH:11]=[CH:12][CH:13]=1)=O)[CH3:4]>C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C@@:2]2([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=3)[C@H:3]([CH3:4])[NH:5][C:6]([C:8]3[NH:9][C:10](=[O:14])[CH:11]=[CH:12][CH:13]=3)=[N:1]2)=[CH:23][CH:24]=1
Reactant: C[C@H](NC(=O)c1cccc(=O)[nH]1)[C@@](N)(c1ccc(F)cc1)c1ccnc(F)c1
Solvent: Cc1ccccc1
Product: C[C@@H]1NC(c2cccc(=O)[nH]2)=N[C@]1(c1ccc(F)cc1)c1ccnc(F)c1

Procedure:
N-[(1S,2R)-2-amino-2-(4-fluorophenyl)-2-(2-fluoro-4-pyridyl)-1-methylethyl]-6-oxo-1,6-dihydro-2-pyridine-carboxamide (16 g) was suspended in toluene (400 mL), and the suspension was heated under reflux for 10 hours while removing water azeotropically. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate:methanol=100:0→10:1) to give the title compound as a yellow oil. The yellow oil was dissolved in isopropanol (80 mL), and to this solution was added water (130 mL) at room temperature. The solution was allowed to stand at room temperature for 3 hours to give a colorless crystal, which was then collected by filtration. The crystal was suspended in water (500 mL) and the suspension was stirred at room temperature for 14 hours. The resulting crystal was collected again by filtration and dried in vacuo at 30° C. for 24 hours to give the title compound (crystal form A)(11.2 g) as a colorless massive crystal (m.p. 125–126° C.).
Reaction SMILES: [OH:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2.[CH3:11][C:12]([O:14][C:15]1[C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>>[C:12]([O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=1[C:21]([O:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2)=[O:22])(=[O:13])[CH3:11]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(=O)NC12CC(O)(C1)C2
Product: CC(=O)NC12CC(OC(=O)c3ccccc3OC(C)=O)(C1)C2

Procedure:
The general procedure of Example 1 Step 3 is repeated starting with N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) and using O-acetylsalicyloyl chloride in place of the acetyl chloride to produce compound 8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[F:10][C:11]([F:18])([F:17])[C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>[Cu]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N:14]2[CH:15]=[CH:16][C:12]([C:11]([F:18])([F:17])[F:10])=[N:13]2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Product: Oc1ccc(Cl)cc1-n1ccc(C(F)(F)F)n1

Procedure:
A mixture of 4-chloro-2-iodophenol and 3-(trifluoromethyl)-1H-pyrazole was treated with copper oxide, cesium carbonate and 2-hydroxybenzaldehyde oxime to produce 4-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.C[S-:23].[Na+].O>CC(N(C)C)=O>[CH:16]1([O:15][CH2:14][C:8]2[N:5]3[CH:6]=[CH:7][C:2]([SH:23])=[CH:3][C:4]3=[N:10][C:9]=2[CH:11]([CH3:13])[CH3:12])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C[S-]
Reactant: CC(C)c1nc2cc(Br)ccn2c1COC1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)c1nc2cc(S)ccn2c1COC1CCCCC1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
7-Bromo-3-cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine (50.0 mg, 0.142 mmol) obtained in step 3 of Example 28 was dissolved in DMA (1.0 mL), and the solution was stirred at 160° C. for 30 minutes after adding sodium thiomethoxide (80.0 mg, 1.14 mmol). After adding water to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol=95/5) to give 3-cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine-7-thiol (35.3 mg, yield 82%).
Reaction SMILES: CC(O)=O.[CH:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@@H:12]2[NH:36][C:34](=[O:35])[C@H:33]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=3)[NH:32][C:30](=[O:31])[CH2:29][CH2:28][S:27][S:26][CH2:25][C@@H:24]([C:45]([N:47]3[C@H:51]([C:52]([NH:54][C@@H:55]([C:63]([NH:65][CH2:66][C:67]([NH2:69])=[O:68])=[O:64])[CH2:56][CH2:57][CH2:58][NH:59][C:60]([NH2:62])=[NH:61])=[O:53])[CH2:50][CH2:49][CH2:48]3)=[O:46])[NH:23][C:21](=[O:22])[C@H:20]([CH2:70][C:71]([NH2:73])=[O:72])[NH:19][C:17](=[O:18])[C@H:16]([CH2:74][CH2:75][C:76]([NH2:78])=[O:77])[NH:15][C:13]2=[O:14])=[CH:9][CH:10]=1.C1C=CC(C[C@@H]2NC(=O)[C@H](CC3C=CC(O)=CC=3)NC(=O)[C@@H](N)CSSC[C@@H](C(N3[C@H](C(N[C@H](C(NCC(N)=O)=O)CCCCN)=O)CCC3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)[NH:89]C2=O)=CC=1>>[CH2:49]1[CH2:48][N:47]([C:45]([CH:24]2[NH:23][C:21](=[O:22])[CH:20]([CH2:70][C:71]([NH2:73])=[O:72])[NH:19][C:17](=[O:18])[CH:16]([CH2:74][CH2:75][C:76]([NH2:78])=[O:77])[NH:15][C:13](=[O:14])[CH:12]([CH2:11][C:8]3[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=3)[NH:36][C:34](=[O:35])[CH:33]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=3)[NH:32][C:30](=[O:31])[CH:29]([NH2:89])[CH2:28][S:27][S:26][CH2:25]2)=[O:46])[CH:51]([C:52]([NH:54][CH:55]([C:63]([NH:65][CH2:66][C:67]([NH2:69])=[O:68])=[O:64])[CH2:56][CH2:57][CH2:58][N:59]=[C:60]([NH2:62])[NH2:61])=[O:53])[CH2:50]1
Reactant: NCCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1)C(=O)NCC(N)=O
Reactant: N=C(N)NCCC[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CSSCCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1)C(=O)NCC(N)=O
Solvent: CC(=O)O
Product: NC(=O)CCC1NC(=O)C(Cc2ccccc2)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(N)CSSCC(C(=O)N2CCCC2C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC1=O

Procedure:
desmopressin acetate; lypressin.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1)[CH:24]=O)[CH3:19].O>CO>[CH2:30]([O:29][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH2:18][CH3:19])[CH:28]=1)[CH2:24][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4])[CH3:31]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1
Solvent: CO
Solvent: O
Product: CCOc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
To a solution of the amine (4) (127 mg, 0.486 mmol) and 3,5-diethoxybenzaldehyde (123 mg, 0.632 mmol) in methanol (3.3 mL) was added borane-pyridine complex (155 μL, 1.46 mmol) at 40° C. and the resulting mixture was stirred for 2.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (10) as a yellow solid (114 mg, Yield: 54%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][CH2:16][C@@H:9]12)([CH3:4])[CH3:3].[F:19][C:20]([F:54])([F:53])[C:21]1[CH:22]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39](Cl)=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]([CH3:52])([CH3:51])[C:32]([N:34]([C:36]2[CH:37]=[N:38][C:39]([N:13]3[CH2:12][CH2:11][N:10]4[CH2:14][CH2:15][CH2:16][C@H:9]4[C@@H:8]3[CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:18])[CH3:17])=[CH:40][C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])[CH3:35])=[O:33])[CH:22]=[C:21]([C:20]([F:54])([F:19])[F:53])[CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1NCCN2CCC[C@@H]12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@H]3[C@@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 9.7 %

Procedure:
To a solution of cis-1-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrrolo[1,2-a]pyrazine (D73, 50 mg) in dry toluene (0.5 mL), a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (75 mg) in dry toluene (0.5 mL) was added at rt. Hexadecyltrimethylammonium chloride (25% aqueous solution, 132 microL), bis(tri-tert-butyl phosphine) palladium (19 mg) and NaOH (50% aqueous solution, 245 microL) were added. The resulting mixture was degassed by two freeze-thaw cycles and allowed to reach rt under a nitrogen atmosphere. The mixture was then heated at 90° C. for 5 hours. The mixture was allowed to cool down to rt, diluted with ethyl acetate (1 mL) and washed with a saturated solution of NaHCO3 (1 mL). The aqueous phase was extracted with ethyl acetate (3×2.5 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (Cycl/EtOAc 1:1) to give the desired compound (10.5 mg) as yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:33][CH2:34][CH3:35])[N:10]([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]([C:29]([O:31]C)=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-:36].[Na+]>>[OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:33][CH2:34][CH3:35])[N:10]([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]([C:29]([OH:31])=[O:30])=[O:28])=[CH:19][CH:20]=2)[C:11]=1[C:12]([NH2:13])=[O:36])[C:3]([CH3:6])([CH3:4])[CH3:5]
Reactant: [OH-]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Na+]
Product: CCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1

Procedure:
246 mg of 4-(1-hydroxy-2,2-dimethylpropyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]-2-propylimidazole-5-carbonitrile [prepared as described in step (a) above] were subjected to hydrolysis using 6 ml of a 1N aqueous solution of sodium hydroxide in the same manner as described in Example 10(b), to give 182 mg of the title compound as crystals, melting at 198°-200° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Br)=[C:11]([O:16][CH3:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[F-].[Cs+].N>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:11]([O:16][CH3:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnn(Cc2ccccc2)c(=O)c1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Cs+]
Solvent: COCCOC
Product: COc1cnn(Cc2ccccc2)c(=O)c1-c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a mixture of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone, prepared according to the method of (S. Cho et al. described in J. Het. Chem., (1996), 33, 1579–1582), (2.94 g; 10 mmol), 4-fluorobenzeneboronic acid (1.54 g; 11 mmol), and CsF (3.04 g; 22 mmol) in 25 mL of anhydrous DME, under N2, was added Pd(Ph3P)4 (347 mg 0.3 mmol). After addition, the mixture was heated at reflux for at 100° C., for 18 hours. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The acetate layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The solid residue was suspended in ethyl ether-hexanes and filtered to provide a solid product (yield: 3.1 g; about 100%; >95% purity). 1H NMR (300 MHz, CDCl3) δ 3.90 (s, 3H), 5.36 (s, 2H), 7.09 (t, J=9 Hz, 2H), 7.31 (m, 3H), 7.50 (m, 4H), 7.91 (s, 1H). MS (DCI/NH3) m/z 311 (M+H)+, 328 (M+NH4)+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@H:5]([N:36]([C:38]([C@@H:40]([NH:44][C:45]([C@@H:47]([N:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[O:46])[CH:41]([CH3:43])[CH3:42])=[O:39])[CH3:37])[C@H:6]([O:34][CH3:35])[CH2:7][C:8]([N:10]1[C@H:14]([C@H:15]([O:32][CH3:33])[C@H:16]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])[CH3:17])[CH2:13][CH2:12][CH2:11]1)=[O:9])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:87][CH2:88][CH2:89][CH2:90][OH:91]>CN(C=O)C>[CH3:1][CH2:2][C@@H:3]([C@H:5]([N:36]([C:38]([C@@H:40]([NH:44][C:45]([C@@H:47]([N:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[O:46])[CH:41]([CH3:43])[CH3:42])=[O:39])[CH3:37])[C@H:6]([O:34][CH3:35])[CH2:7][C:8]([N:10]1[C@H:14]([C@H:15]([O:32][CH3:33])[C@H:16]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])[CH3:17])[CH2:13][CH2:12][CH2:11]1)=[O:9])[CH3:4].[OH:91][CH2:90][CH2:89][CH2:88][NH-:87]
Reactant: NCCCO
Agent: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [NH-]CCCO
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
Auristatin F (150 mg, 0.201 mmol), HATU (153.0 mg, 0.402 mmol), and diisopropylethylamine (108 μL, 0.603 mmol) were taken up in DMF (5 mL) and 3-aminopropan-1-ol (45.9 μL, 0.603 mmol) was added. The mixture was stirred at 23° C. for 45 minutes at which time LCMS analysis showed complete disappearance of the starting material. Reduction of the volume to 1.4 mL under high vacuum followed by purification via preparative HPLC (10-90 solvent B gradient over 20 minutes eluting with 0.1% TFA/Water, 0.1% TFA/CH3CN) afforded the title compound as white solid (109 mg, 68% yield).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH2:64][C@H:65]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:66][CH2:67][C:68](=[O:70])[OH:69]>C1COCC1.CN1C(=O)CCC1>[C:74]([O:73][C:71](=[O:72])[C@@H:65]([NH:64][C:30](=[O:32])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:34][CH:33]=1)[CH2:66][CH2:67][C:68]([OH:70])=[O:69])([CH3:77])([CH3:75])[CH3:76]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)cc1

Procedure:
4-[(15-tert-butoxycarbonylpentadecanoylamino)methyl]benzoic acid (413 mg, 0.868 mmol) was dissolved in THF (5 mL), the solution was cooled with an icebath. DIPEA (0.33 mL, 1.91 mmol) and TSTU (314 mg, 1.04 mmol) were added. The mixture was stirred under nitrogen while cooling was maintained. After 30 minutes the icebath was removed and the mixture was stirred for additional 3 hours at room temperature. The mixture was diluted with NMP (5 mL) and H-GluOtBu (0.21 g, 1.04 mmol) was added, the mixture was stirred overnight at room temperature. The mixture was separated between ethyl acetate (100 mL) and water (100 mL), the organic phase dried (Na2SO4) and solvent removed in vacuo. The crude material was purified on silica using DCM/ethanol (90:10) to give (S)-2-{4-[(15-tert-Butoxycarbonyl-pentadecanoylamino)-methyl]-benzoylamino}-pentanedioic acid 1-tert-butyl ester.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reaction time: 1 h

Procedure:
To a mixture of 2.00 g (4.63 mmol) (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 126, Step B) in water (0.125 g, 6.94 mmol) and DCM (50 mL) was added Dess-Martin periodinane (2.94 g, 6.94 mmol) at ambient temperature. After being stirred for 1 h (no SM detected by TLC), the reaction was quenched by addition of 10 mL of 0.5 M Na2S2O3, extracted with DCM, and washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (80 g SiO2, 5 to 20% EtOAc/hexanes) provided the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:14])[C:10]([NH:12][NH2:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1>[CH2:1]([O:8][C@@H:9]([C:10]1[O:11][C:20](=[O:21])[NH:13][N:12]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)c1n[nH]c(=O)o1
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(benzyloxy)propanehydrazide (194 mg, 1 mmol) in anhydrous THF (2 mL) was added CDI (178 mg, 1.1 mmol) and the resulting mixture was allowed to stir one hour. Solvent was removed under reduced pressure and the residue was purified on silica gel. Elution with EtOAc yielded title product.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[C@H:11]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C:9]([CH3:22])([CH3:21])[O:8]1)(=O)=O.[I-:23].[Na+]>C(#N)C>[CH2:14]([O:13][CH2:12][C@H:11]1[C@@H:7]([CH2:6][I:23])[O:8][C:9]([CH3:22])([CH3:21])[O:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)O[C@@H](COCc2ccccc2)[C@H](COS(C)(=O)=O)O1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)O[C@@H](COCc2ccccc2)[C@@H](CI)O1
Temperature: 80 °C
Reaction time: 22 h
Yield: 97.2 %

Procedure:
A solution of 46.19 g of the crude {(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl methanesulfonate obtained in Reference Example (1b) (140 mmol) and 62.87 g of sodium iodide (419 mmol) in acetonitrile (420 ml) was stirred at 80° C. for 22 hours. The reaction mixture was cooled and then concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with a 1.5 M sodium sulfite aqueous solution, water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 49.20 g of the crude title compound.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15]CC)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1cccc2ccccc12
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2ccccc12)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To a stirred mixture of ethyl 2-(naphthalen-1-yloxy)acetate (150 mg, 0.641 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (132 mg, 0.641 mmol). The mixture was stirred at 120° C. for 30 minutes under microwave mediated heating. After evaporation of the solvent, the reaction mixture was purified by prep-HPLC to afford the desired product (64 mg, Yield 25%). 1H NMR (400 MHz, METHANOL-d4) δ=8.41-8.31 (m, 1H), 7.90-7.80 (m, 1H), 7.58-7.46 (m, 3H), 7.44-7.35 (m, 1H), 7.18-6.95 (m, 5H), 6.91 (d, J=7.8 Hz, 1H), 4.76 (s, 2H), 4.05 (quin, J=6.0 Hz, 1H), 3.72-3.59 (m, 2H), 3.56-3.48 (m, 1H), 3.41 (dd, J=6.5, 13.6 Hz, 1H), 2.93-2.83 (m, 2H), 2.80-2.72 (m, 2H), 2.59-2.52 (m, 2H). LCMS (m/z): 391.2 (M+1).
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][C:24]1[C:25]([NH2:30])=[N:26][NH:27][C:28]=1[NH2:29].CCOCC.Cl>C(O)(=O)C.CO>[ClH:15].[NH2:29][C:28]1[C:24]([CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=2[Cl:15])=[C:25]2[N:30]=[C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[CH:3]=[C:4]([OH:6])[N:26]2[N:27]=1
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: Nc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1nn2c(O)cc(C3CCOCC3)nc2c1Cc1cccc(Cl)c1Cl
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.100 g, 0.498 mmol) and 4-[(2,3-dichlorophenyl)methyl]-1H-pyrazole-3,5-diamine (0.128 g, 0.498 mmol) was added in Acetic Acid (2 mL). The reaction vessel was subjected to MW irradiation at 100° C. for 40 min then 70° C. for 180 min. The mixture was concentrated. The residue was purified by reversed phase HPLC (25% CH3CN (0.1% TFA)/Water (0.1% TFA)) and then repurified (10˜50% CH3CN (0.1% TFA)/Water (0.1% TFA) to give the product. 1 M ether/HCl (3 mL) was added to the solution of the product in MeOH (10 mL). The mixture was stirred for 3 h. The solvent was removed to give the titled product as solid (55 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.84 (m, 4H) 2.63-2.83 (m, 1H) 3.22-3.46 (m, 2H) 3.93 (m, 2H) 4.01 (s, 2H) 5.63 (s, 1H) 6.90 (d, J=7.07 Hz, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.43-7.59 (m, 1H) 11.92 (br. s., 1H). LC/MS: MS (ES+) m/e 393.0 [M+H]+.