Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:40][N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:39])[CH:20]([NH:31]C(=O)OC(C)(C)C)[C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1>O1CCOCC1.Cl>[NH2:31][CH:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=1)[C:19]([N:17]1[CH2:16][CH2:15][N:14]2[CH2:40][C@H:11]([O:10][C:7]3[CH:6]=[N:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:12][C@H:13]2[CH2:18]1)=[O:39]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of the product from Example 181 (0.132 g, 0.235 mmol) in 1,4-dioxane (1 mL) and 4 N HCl in 1,4-dioxane (1 mL, 4.00 mmol) was stirred at room temperature for 90 minutes and then concentrated in vacuo to give the title compound as a hydrochloride salt. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.76-1.01 (m, 4 H) 1.86-4.94 (m, 12 H) 5.25-5.56 (m, 1 H) 5.70-6.01 (m, 1 H) 7.79 (d, J=6.41 Hz, 2 H) 7.85-7.98 (m, 2 H) 8.09-8.24 (m, 2 H) 8.78-9.11 (m, 3 H) 11.73-12.34 (m, 1 H); MS (APCI) m/z 462 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:10])[C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: CNCCCO
Reactant: COCCOCC(=O)O
Product: COCCOCC(=O)N(C)CCCO

Procedure:
By using 1.4 mL of (2-methoxyethoxy)acetic acid and 1.0 g of 3-(methylamino)propan-1-ol as starting materials, the reaction similar to Preparation Example 16 was performed, thereby obtaining 2.19 g of N-(3-hydroxypropyl)-2-(2-methoxyethoxy)-N-methylacetamide.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH: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.[OH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cnn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Reactant: Oc1cnccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cnn(-c2ccc(-n3ccncc3=O)cc2)c1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 14.3 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (75 mg, 0.17 mmol), 2-hydroxypyrazine (43 mg, 0.45 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed with Argon before being charged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the title compound (10 mg). MS 412.0 and 414.0 (M+H, Cl pattern).
Reaction SMILES: [C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl.C1(N)C2C(=CC=CC=2)C=CC=1.C([BH3-])#N.[Na+]>CO>[C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:2]2[NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1(C)C2CCC1(C)C(Nc1cccc3ccccc13)C2
Reaction time: 48 h

Procedure:
Camphor (10 gm), 9.4 gm α-naphthylamine, 0.1 gm α-naphthylamine-HCl and 30 gm 1 A molecular sieves were added to 40 ml anhydrous methanol. Sodium cyanoborohydride (2.5 gm) was added dropwise and stirred under N2 for 48 hours. The sieves were removed by filtration and 5 drops of concentrated HCl were added to the filtrate until it was acidic (pH>7). The solvent was stripped by boiling and 10 gm potassium hydroxide was added to the remaining mixture. The aqueous phase was extracted with ether over potassium carbonate. The extractions were filtered to remove the potassium carbonate. After the ether was evaporated, the mixture was distilled under high vacuum. The material boiling at 120° C. and 0.1 mm of mercury was collected. IR spectra verified that this material was the product.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[CH3:14][C:15]1([CH3:40])[NH:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>O1CCOCC1>[F:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][N:27]1[C:15]([CH3:40])([CH3:14])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[CH:26]1[C:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:33]=1
Reactant: COC(=O)/C=C/c1ccc(C2NC(C)(C)Cc3c2[nH]c2ccccc32)cc1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)cc1
Temperature: 22 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 3, preparation of starting materials) (5.32 g, 21.36 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (3.5 g, 9.71 mmol) and N-ethyl-N-isopropylpropan-2-mine (6.34 ml, 36.41 mmol) in 1,4-dioxane (17.5 ml). The mixture was stirred at 22° C. for 3 days. The mixture was evaporated and the residue was partitioned between DCM (150 ml) and water (150 ml). The aqueous layer was extracted with DCM (50 ml) and the extracts combined with the organic layer. The combined extracts were filtered though a phase-separating paper and evaporated. The residue was purified by flash silica chromatography, elution solvent 15% EtOAc in heptane. Fractions containing significant amounts of product began to form crystals; the tubes were agitated to encourage further crystallisation. The crystals were collected by filtration and washed with a small amount of 15% EtOAc in heptane to afford (E)-methyl 3-(4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (2.91 g, 69.0%) as a white crystalline solid. Liquors from the crystallisation and other product-containing fractions were combined and evaporated. The residue was recrystallised from EtOAc/heptane to afford more 3-(4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-diethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) as a white crystalline solid (635 mg, 15.1%). 1H NMR (400 MHz, CDCl3, 30° C.) δ 0.53 (3H, d), 0.95-1.07 (1H, m), 1.09 (3H, s), 1.32 (3H, s), 2.16 (1H, dd), 2.66 (1H d), 2.94 (1H, d), 2.97 (1H, d), 3.80 (3H, s), 4.14 (1H, ddd), 4.31 (1H, ddd), 4.59 (1H, s), 6.42 (1H, d), 7.05-7.11 (2H, m), 7.13 (1H, s), 7.17 (1H, dd), 7.35 (2H, d), 7.45 (2H, d), 7.50 (1H, dd), 7.67 (1H, d). m/z: ES+ [M+H]+ 435.
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]=[CH:32][C:27]=2[C:26]([C:33](O)=[O:34])=[N: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:26]3[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:24][N:25]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1noc2ccccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3noc4ccccc34)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 benzo[d]isoxazole-3-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=478.2.
Reaction SMILES: CCCCCC.C([Li])CCC.[F:12][C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=1.[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]=[O:34])[CH:24]=1.[Cl-].[NH4+]>C1COCC1>[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]([C:18]2[S:17][C:16]3[CH:20]=[CH:21][C:13]([F:12])=[CH:14][C:15]=3[CH:19]=2)[OH:34])[CH:24]=1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Reactant: Fc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cc(Br)c2ccccc2c1)c1cc2cc(F)ccc2s1
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.68 ml, 2.68 mmol) was added dropwise to a solution of 5-fluorobenzo[b]thiophene (410 mg, 2.68 mmol) in THF (10 ml) and the reaction solution was stirred at the same temperature for 10 minutes. To this solution, a solution of 4-bromonaphthalene-2-carbaldehyde (600 mg, 2.55 mmol) in THF (5 ml) was added dropwise at −78° C. The obtained mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution was added and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (680 mg, 69%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([N:14]2[C:15](=[O:18])[CH2:16][CH2:17][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Reactant: O=C1CCOCCN1
Product: Cn1ncc([N+](=O)[O-])c1N1CCOCCC1=O
Yield: 13 %

Procedure:
Following the procedure for Intermediate 202 starting from 5-bromo-1-methyl-4-nitro-1H-pyrazole and 1,4-oxazepan-5-one gave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-oxazepan-5-one as an orange solid (40 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 4.18 (dd, J=13.3, 6.4 Hz, 1H), 4.12-3.99 (m, 2H), 3.96-3.82 (m, 2H), 3.77 (s, 3H), 3.64 (dd, J=15.7, 6.4 Hz, 1H), 3.08 (ddd, J=15.6, 8.5, 2.1 Hz, 1H), 2.94 (ddd, J=15.6, 7.5, 1.8 Hz, 1H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[Si:14]([O:21][CH2:22][C@@H:23](/[N:28]=[CH:29]/[CH:30]([F:32])[F:31])[CH2:24][CH:25]([CH3:27])[CH3:26])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[Cl-].[NH4+]>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:29]([NH:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][O:21][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH:30]([F:31])[F:32])=[CH:8][CH:9]=1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)F
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(Br)cc1)C(F)F
Reaction time: 1.5 h

Procedure:
n-BuLi (2.5 M in hexanes, 1.43 mL) was added to a −70° C. THF (8.5 mL) solution of 1,4-dibromobenzene (884 mg) and the mixture was stirred for 15 minutes. A THF (8.5 mL) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2-difluoroethylidene]pentan-2-amine (1.0 g) was then added dropwise and the mixture was stirred for 1.5 hours. The mixture was then poured slowly into an icy saturated aqueous solution of ammonium chloride under vigorous stirring and was extracted with 3 portions of ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue, which was purified on SiO2 using a gradient of hexanes and ethyl acetate (90:10 to 75:25) as eluent to yield (2S)—N-[(1S)-1-(4-bromophenyl)-2,2-difluoroethyl]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine. (2S)—N-[(1S)-1-(4-Bromophenyl)-2,2-difluoroethyl]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (200 mg) was dissolved in CH3CN (4 mL) and the solution was cooled to 0° C. HF-pyridine (40 μL) was added dropwise and the mixture was reacted for 16 hours. The mixture was poured into a saturated solution of sodium bicarbonate, ethyl acetate was added and the resultant mixture was vigorously shaken. The organic layer was separated and the aqueous further extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo to yield a residue which was purified on SiO2 using a gradient of hexanes and ethyl acetate (80:20 to 60:40) as eluent to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:15]([O-])=O>C(O)C.[Pt](=O)=O>[NH2:15][C:3]1[CH:4]=[C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(C2=NNC(=O)CC2)cc1N

Procedure:
4.68 gm of 6-(4'-amino-3'-nitro-phenyl)-4,5-dihydro-3(2H)-pyridazinone werehydrogenated in 500 ml of ethanol at 40° C. for 4 hours in the presence of 1 gm of platinum dioxide at 5 atmospheres. Thereafter, the solution was cooled and filtered, and the filter cake was boiled with a mixture of 4 parts of isopropanol and 1 part of water. The resulting mixture was filtered, and upon cooling, the desired product crystallized out of the filtrate; m.p. 226° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:45])[C:8]2=[N:9][CH:10]=[C:11]([N:14]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:36]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH2:5]1)[CH:2]=C.[OH2:46].CC#N.C(Cl)(Cl)(Cl)Cl.[OH2:55]>>[NH:38]([C:36]([C@H:6]1[N:7]2[C:12](=[O:13])[C:11]([N:14]([C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)=[CH:10][N:9]=[C:8]2[C@@:4]([CH2:1][C:2]([OH:55])=[O:46])([CH3:45])[CH2:5]1)=[O:37])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O
Reactant: C=CC[C@]1(C)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: C[C@@]1(CC(=O)O)C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Reaction time: 16 h

Procedure:
To a solution of 117a (1.073 g, 1.740 mmol) in 15.4 mL CH3CN/CCl4/H2O (2:2:3), were added NaIO4 (1.56 g, 7.31 mmol) and a solution of RuCl3.H2O (18 mg, 0.087 mmol) in 2.25 mL of CH3CN/CCl4/H2O (2:2:3). The mixture was stirred vigorously for 16 h, then was poured into H2O and extracted with CH2Cl2 (2×). The combined organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to afford 1.17 g of 117b as a brown foam, which was used in the following step without further purification. MS (ESI) 657.3 (M+Na+); 633.4 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)C1CCCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)C3CCCC3)ccc2n1
Yield: 48 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (96 mg, 0.33 mmol) was converted, using cyclopentanecarboxylic acid instead of cyclopropylacetic acid, to the title compound (56 mg, 48%) which was obtained as an off-white solid. MS: m/e=387.3 [M+H]+.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][CH:20]=[N:21][N:22]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][CH:20]=[N:21][N:22]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnco2)N1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1N(O)[C@@H]2CC[C@@H](c3nnco3)N1C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-2-(1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (4.6 g, 15.3 mmol) in THF (150 mL) was added 10% Pd/C (1 g). The mixture was stirred under H2 atmosphere at rt for 3 hrs. The reaction mixture was then filtered and concentrated to afford (2S,5R)-6-hydroxy-2-(1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (2.9 g, 91%), which was used directly in the next step. ESI-MS (EI+, m/z): 211.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([NH:16]C(=O)C(C)(C)C)=[C:11]([CH3:23])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.O>C(O)(=O)C>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH3:23])[C:12](=[CH:13][C:14]=2[CH3:15])[NH2:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C)cc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C)cc1N
Temperature: 100 °C
Reaction time: 72 h

Procedure:
The product from stage b) (10.4 g) in glacial acetic acid (36 ml) was treated with hydrochloric acid (24.5 ml of 15% solution) at 70° C. The mixture was stirred for 3 days at 100° C. On cooling, water was added and the mixture extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried (MgSO4) and concentrated to give the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SiH](CC)(CC)CC>C[N+]([O-])=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(CCOC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 112 h

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (229 mg, 1.0 mmol) and cyclohexanone (86 μL, 0.83 mmol) in MeNO2 (2 mL), followed by Et3SiH (160 μL, 1.0 mmol) were added successively to a suspension of FeCl3 (35 mg, 0.20 mmol) in MeNO2 (3 mL) at room temperature under Ar protection. After the mixture was stirred at rt for 112 h, the reaction was quenched by addition of phosphate buffer (pH 7). The mixture was extracted with CH2Cl2, and the organic layer was dried over Na2SO4. After evaporation, the residue was purified by CC (SiO2, hexane/EtOAc 10:1 to 6:1) to afford 1-(tert-butoxycarbonyl)-4-[2-(cyclohexyloxy)ethyl]piperidine together with a with by-product (182 mg total) as a colorless oil. This mixture was used in the following step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])#[N:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:1]#[N:2])[CH2:10][CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccccc1C#N)C(=O)O
Product: CCC(Oc1ccccc1C#N)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 80.6 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 739 mg of (2RS)-2-(2-cyanophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.08 g of the title compound as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(=O)C)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][OH:23])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:22][OH:23])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Reaction time: 3 h
Yield: 72.6 %

Procedure:
A solution of 1-{4-[5-(4-fluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl}-ethanone (1.0 g; 3.14 mmol) in 95% ethanol (10 ml) is treated with a solution of sodium hydroxide (2.5 g; 62.9 mmol) in water (5 ml) and the heterogeneous mixture heated at 75 C. for three hours. The ethanol is removed in a rotary evaporator and the residue is diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml) and chloroform (3×20 ml). The organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol/dichloromethane gradient (5%-30%) containing 5% triethylamine afforded the product as an orange solid (0.63 g; 73%). HNMR (CD3OD): 7.34 (dd, 2H, J=8.7; 5.6 Hz), 6.80 (t, 2H, J=8.7 Hz), 4.29 (s, 2H), 2.82 (m, 2H), 2.66 (m, 1H), 2.41 (m, 2H), 1.76 (m, 2H), 1.49 (m, 2H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1.[C:16](Cl)(Cl)=O.C(=O)=O.[N-]=C=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.O1CCOCC1>[N+:3]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)#[C-:16]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: O=C(Cl)Cl
Agent: O=C=O
Agent: [N-]=C=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: [C-]#[N+]c1ccc2c(C)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A three neck round bottom flask fitted with an argon inlet, an addition funnel with rubber septum, and a dry ice condenser attached to a sodium hydroxide scrubber, was heat dried while purging with argon for 10 min, and cooled to ambient temperature under argon. The apparatus was charged with 2.0 g of 7-amino-4-methyl coumarin (11.4 mMol), 100 mL p-dioxane via an oven dried syringe followed by 15 mL 20% phosgene in toluene (28.95 mMol). The mixture was refluxed strongly for 2 hr, 15 mL of 20% phosgene in toluene was added; refluxed an additional 6 hr, and cooled to ambient temperature. The dry ice was allowed to evaporate overnight under a stream of argon which purged the excess phosgene from the system. The toluene and p-dioxane were removed under reduced pressure at 40° C. resulting in a yellow solid. The pure product was obtained by the addition of 100 mL of chloroform and stirring for 15 min. to dissolve the isocyanate. Followed by filtration (to remove AMC HCl), and removal of solvent under reduced pressure. The solid was stored under reduced pressure overnight.