Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@@H:10]3[N:16]([CH:17]=2)[C:15](=[O:18])[C:14]2[CH:19]=[C:20]([O:61][CH3:62])[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]4[C:58]([O:59][CH3:60])=[CH:57][C:31]5[C:32](=[O:56])[N:33]6[CH:48]=[C:47](S(C(F)(F)F)(=O)=O)[CH2:46][C@H:34]6[C:35](=[O:45])[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=5[CH:29]=4)=[CH:22][C:13]=2[N:12]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:11]3=[O:71])=[CH:4][CH:3]=1.[CH3:72][O:73][C:74]1[CH:79]=[CH:78][C:77](B(O)O)=[CH:76][CH:75]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.CCO.O.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@@H:10]3[N:16]([CH:17]=2)[C:15](=[O:18])[C:14]2[CH:19]=[C:20]([O:61][CH3:62])[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]4[C:58]([O:59][CH3:60])=[CH:57][C:31]5[C:32](=[O:56])[N:33]6[CH:48]=[C:47]([C:77]7[CH:78]=[CH:79][C:74]([O:73][CH3:72])=[CH:75][CH:76]=7)[CH2:46][C@H:34]6[C:35](=[O:45])[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=5[CH:29]=4)=[CH:22][C:13]=2[N:12]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:11]3=[O:71])=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(S(=O)(=O)C(F)(F)F)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Reaction time: 20 h
Yield: 193.7 %

Procedure:
Solid Pd(PPh3)4 (10 mg, 8.69 μmol) was added to a stirred solution of the mono-triflate 9 (230 mg, 0.22 mmol) in toluene (3 mL), EtOH (10 mL), with 4-methoxyphenyl boronic acid (43 mg, 0.28 mmol), Na2CO3 (37 mg, 0.35 mmol), in H2O (1.5 mL) at room temperature. The reaction mixture was allowed to stir under a nitrogen atmosphere for 20 h, at which point the reaction was deemed complete as judged by LC/MS and TLC (EtOAc). The solvent was removed by rotary evaporation under reduced pressure in vacuo and the resulting residue partitioned between EtOAc (75 mL) and H2O (75 mL). The aqueous phase was extracted with EtOAc (3×30 mL) and the combined organic layers washed with H2O (30 mL), brine (40 mL), dried (MgSO4), filtered and evaporated to provide the crude product. The crude product was purified by flash chromatography (60% Hexane: 40% EtOAc→80% EtOAc: 20% Hexane) to provide the pure dimer as an orange foam. Removal of the excess eluent under reduced pressure afforded the desired product 10 (434 mg) in 74% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].ClC(N(C)C)=C(C)C.O[C@H:19]([C@@H:37]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:20][N:21]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].N1C=CC=CC=1C(Cl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][C@H:19]([C@@H:37]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:20][N:21]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[O:8]
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](CN(CC1CCCCC1)NC(=O)OC(C)(C)C)OC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
At 0° C. under a nitrogen atmosphere, 500 mg (4.07 mmol) of picolinic acid (Fluka; Buchs/Switzerland) in 25 ml of methylene chloride are converted into the acid chloride with 0.57 ml (4.07 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine [B. Haveaux, A. Dekoker, M. Rens, A. R. Sidani, J. Toye, L. Ghosez, M. Murakami, M. Yoshioka, and W. Nagata, Organic Syntheses 59, 26 (1980)]. After 45 min, 10 ml of THF, 8.3 ml of pyridine, 10 mg of DMAP and 1.00 g (2.03 mmol) of 1-[2(S)-hydroxy-3(S)-(tert-butoxycarbonyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-(tert-butoxycarbonyl)-hydrazine (=Boc-[PheNNCha]-Boc, Example 4) are added and the mixture is stirred for 16 h at RT. Since according to HPLC there is still 1-[2(S)-hydroxy-3(S)-(tert-butoxycarbonyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine present in the reaction mixture, a further 2 equivalents of picolinic acid chloride (prepared as described above) dissolved in 20 ml of methylene chloride are added. After 18 h at RT the mixture is diluted with methylene chloride and washed twice with saturated NaHCO3 solution, water and brine, and the organic phases are extracted with 2 portions of methylene chloride, dried with Na2SO4 and concentrated by evaporation. The brown residue is dissolved in methylene chloride/ethyl acetate, 10 g of silica gel are added and the mixture is concentrated by evaporation. The resulting powder is applied to a silica gel column (hexane/ethyl acetate 1:1). Elution with hexane/ethyl acetate 1:1 yields the title compound: TLC Rf (N)=0.17; tRet (V)=19.9 min; 1H-NMR (200 MHz, CD3OD): 0.6-1.85 (m, 11H, cyclohexyl), 1.36 and 1.40 (2 s, 18H, 2 Boc), 2.4-3.1 (m, 6H), 4.28 (m, 1H), 5.28 (m, 2H), 7.1-7.3 (m, 5H), 7.72 (m, 1H), 8.08 (m, 1H), 8.28 (d, J=7 Hz, 1H), 8.75 (d, J=5 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:7]2[NH:6][CH2:5][CH2:4]1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>C(Cl)Cl.CCN(CC)CC>[C:28]([NH:1][CH2:2][CH:3]1[N:8]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:7]2[NH:6][CH2:5][CH2:4]1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: NCC1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCC1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a solution of 7-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (125 mg, 0.344 mmol) in 5 mL of DCM was added Et3N (four drops) and acryloyl chloride (46.5 mg, 0.52 mmol). After stirring at rt for 30 mins. The mixture was partitioned between water (10 mL) and DCM (5 mL). The organic layer was concentrated and purified by pre-TLC (DCM/MeOH=20/1) to give 40 mg (28%) of product. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.54-7.43 (m, 2H), 7.25 (t, J=7.6 Hz, 1H), 7.16-7.11 (m, 4H), 6.76 (s, 1H), 6.33 (dd, J=10.1, 17.0 Hz, 1H), 6.18 (dd, J=1.9, 17.0 Hz, 1H), 5.69 (dd, J=1.9, 10.1 Hz, 1H), 4.28-4.22 (m, 1H), 3.92-3.80 (m, 1H), 3.50-3.30 (m, 3H), 2.14-1.94 (m, 2H). MS (ESI) m/e [M+1]+ 417.9.
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[CH2:35]1C[O:38][CH2:37][CH2:36]1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[CH:35][CH2:36][CH2:37][OH:38])=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Li]CCCC
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: OCCC=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-((2-methoxy)-2-propoxy)propyl)triphenyl phosphonium bromide (4.42 g, 10 mmoles) in THF (100 mL) was added n-BuLi (6 mL of 1.6M) at -78°. The reaction mixture was stirred at -78° for 30 min. 4-Chlorobenzaldehyde (1.4 g, 10 mM) was added and the reaction was warmed to RT. The reaction mixture was quenched with buffer and extracted with ethyl acetate. After evaporation of the ethyl acetate, the crude residue was dissolved in 25 mL THF and 5 mL of AcOH plus 5 mL H2O was added. The mixture was stirred for 2 hours at RT and evaporated. The residue was extracted with ethyl acetate, and the ethyl acetate evaporated. Flash chromatography of the residue using 25% ethyl acetate/hexane afforded the title compound as a mixture of cis and trans isomers.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]([OH:6])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:45])=[C:33]([NH:35][C:36]([C:38]4[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=4)=[O:37])[CH:34]=3)=[N:24][N:23]2[CH:46]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:43][N:42]1[C:38]([C:36]([NH:35][C:33]2[CH:34]=[C:29]([O:28][C:25]3[CH:26]=[CH:27][C:22]4[N:23]([CH:46]=[C:20]([NH:19][C:4]([CH:2]5[CH2:3][O:1]5)=[O:6])[N:21]=4)[N:24]=3)[CH:30]=[CH:31][C:32]=2[CH3:45])=[O:37])=[CH:39][C:40]([CH3:44])=[N:41]1
Reactant: O=C(O)C1CO1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CO5)cn4n3)ccc2C)n(C)n1
Yield: 52.3 %

Procedure:
In the same manner as in Example 279 and using oxirane-2-carboxylic acid (54 mg, 0.62 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (53 μL, 0.62 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (170 mg, 0.41 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (96 mg, 52%) was obtained as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Agent: [Na+]
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Yield: 48.7 %

Procedure:
In the same manner as in step b) in Example 125, 150 mg of the title compound was prepared from 133 mg of chloromethyl N,N-diisopropylcarbamate and 231 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:20]([O:22]CC)=O)[CH2:19][C:14]2=[N:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].[F:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=[N:32]O)[NH2:31])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[C:7]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:20]3[O:22][N:32]=[C:30]([C:29]4[CH:34]=[CH:35][C:26]([F:25])=[CH:27][CH:28]=4)[N:31]=3)[CH2:19][C:14]2=[N:13][N:12]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: CCOC(=O)C1CCn2c(nnc2C(C)(C)C)C1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc2n1CCC(c1nc(-c3ccc(F)cc3)no1)C2
Reaction time: 16 h
Yield: 53.4 %

Procedure:
Add dropwise potassium tert-butoxide 1M in tetrahydrofuran (2.08 Kg, 2.08 mol) to a solution of ethyl 3-tert-butyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (455 g, 1.81 mol) and 4-fluorobenzamidoxime (320 g, 2.08 mol) in tetrahydrofuran (11 L) at room temperature. Stir the reaction mixture for 16 hours. Pour the mixture over a solution of saturated sodium bicarbonate (6 L) and add brine (3×2 L). Separate phases and extract aqueous phase with ethyl acetate (3×1 L). Combine organics, dry over magnesium sulfate, filter, and concentrate to dryness under reduced pressure. Purify the resulting residue by silica gel chromatography eluting with ethyl acetate to ethyl acetate:methanol (9:1) to provide the title compound as a white solid (330 g). Mass spectrum (m/z): 342 (M+1).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 15 mg, 0.37 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (87 mg, 0.33 mmol) in THF (2 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ˜0.37 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 128 mg (95%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][CH3:22])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:14]=1)[C:8]([O:10]C)=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>O1CCCC1.CO.O.O.[OH-].[Li+].C(OCC)(=O)C>[F:80][C:78]1[CH:79]=[C:74]([CH:75]=[C:76]([F:81])[CH:77]=1)[CH2:73][C@H:59]([NH:58][C:8](=[O:10])[C:7]1[CH:12]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:14]=[C:5]([C:3]([N:2]([CH3:1])[CH2:20][CH2:21][CH3:22])=[O:4])[CH:6]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2nccs2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2nccs2)c1
Reaction time: 2 h

Procedure:
Methyl 3-{[methyl(propyl)amino]carbonyl}-5-(1,3-thiazol-2-yl)benzoate (390 mg, 1.22 mmol) is dissolved in 1:1:1 tetrahydrofuran/methanol/water (9 mL), and lithium hydroxide monohydrate is added (103 mg, 2.4 mmol), and the reaction stirred 2 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (355 μL, 2.0 mmol), HATU (230 mg, 0.61 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (206 mg, 0.51 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/methylene chloride) provides the title compound. ESI MS m/z 621.3 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][CH2:32][C:31]([CH2:36]C)([CH2:34]C)[CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:34][C:31]1([CH3:36])[CH2:30][CH2:29][CH:28]([C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([O:26][CH3:27])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:33][CH2:32]1
Reactant: CCC1(CC)CCC(c2cc(N3CCC[C@H](OC)C3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1CCCN(c2ccc(N3CCNCC3)c(C3CCC(C)(C)CC3)c2)C1
Reaction time: 0.33 h

Procedure:
(S)-4-[2-(4,4-Diethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine-1-carboxylic acid t-butyl ester (59 mg, 0.1148 mmol) produced in Example (50b) was dissolved in a mixed solvent of dichloromethane (0.7 mL)-water (1 drop). Trifluoroacetic acid (0.177 mL, 2.296 mmol) was added thereto followed by stirring for 15 hours and 20 minutes under the same conditions. Aqueous solution of potassium carbonate was added to the reaction mixture to make the mixture basic. The mixture was then extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure to give a crude product of (S)-1-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine as a brown oil. This was directly used without purification for the following reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:20])=[CH:4][CH:3]=1.[CH:23](O)=[O:24]>C1(C)C=CC=CC=1>[CH:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:20])=[CH:21][CH:22]=1)=[O:24]
Reactant: O=CO
Reactant: COc1ccc2c(c1)CCN(CCc1ccc(N)cc1)C2C
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCN(CCc1ccc(NC=O)cc1)C2C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline (16.8 g, 0.057 m) in 800 ml toluene was added formic acid (25.0 g, 0.5 m). The reaction was brought to reflux, and water was collected by a Dean-Stark apparatus. After 1 hour, the reaction was poured into ice water (500 g) and basified to pH 11-12 with 10% NaOH. The toluene layer was separated, and the aqueous layer was extracted further with toluene (1×200 ml) and then with chloroform (2×200 ml). The organic extracts were combined, dried and concentrated to an oil. The oil was dissolved in 100 ml ether and a solid formed which was filtered off and dried to give N-(4-formamidophenethyl)-1,2,3,4-tetrahydro-6 -methoxy-1-methylisoquinoline, wt. 12.0 g (71%), m.p. 93°-96°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[O:24][CH2:25][CH2:26][C:27]=34)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1CCO2
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3CCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,3-dihydro-benzo furan-4-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=479.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1C2C=CC([C:16]3(C(OCC)=O)[CH:25]=[C:24]4[C:19]([CH:20]=[CH:21][C:22]5[O:28][CH2:27][O:26][C:23]=54)=[N:18][CH:17]3[C:29]([O:31][CH2:32]C)=[O:30])=CC=2OC1.[OH2:39]>C1COCC1>[O:39]1[C:22]2[CH:21]=[CH:20][C:19]([C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]5[O:28][CH2:27][O:26][C:23]5=4)[N:18]=[C:17]4[C:29](=[O:30])[O:31][CH2:32][C:16]=34)=[CH:24][C:23]=2[O:26][CH2:27]1
Reactant: CCOC(=O)C1N=c2ccc3c(c2=CC1(C(=O)OCC)c1ccc2c(c1)OCO2)OCO3
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OCc2c1nc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of and lithium aluminum Hydride (LAH) (2.0 g) in THF (50 ml) was gradually added diethyl 8-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7,8-dicarboxylate (2.4 g) which was synthesized by the ordinally method described in E. A. Fehnel, Journal of organic Chemistry, vol.31, 2899-2092, 1966 or W. Ried, et al., Chemische Berichte, vol.85,204-216, at 0° C. The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water to stop the reaction, then the insoluble solid was filtered off with Celite. The filtrate was extracted with ethyl acetate and the extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation and the obtained residue was dissolved in ethanol (100 ml), and 10% Pd--C (2.5 g) was added thereto. The mixture was stirred overnight at room temperature. The catalyst was filtered off, and the solvent was removed by distillation. The obtained residue was dissolved in chloroform (300 ml) and manganese dioxide (20 g) was added thereto, then the mixture was stirred for 3 hours at room temperature. The manganese dioxide was filtered off with Celite and the filtrate was concentrated under reduced pressure. The obtained crude crystals were washed with diisopropyl ether and the entitled compound (0.9 g) was obtained. For elemental analysis, some of the entitle compound was recrystallized from THF.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1N1CCCCC1
Temperature: 160 °C
Yield: 13.6 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (300 mg, 0.74 mmol) in DMSO (6 ml). Piperidine (0.024 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (16 mg).