Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13].C([O-])(O)=[O:18].[Na+]>CCOCC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:15])[C:12]([OH:18])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])O
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)C(=O)c1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
Step E (1): To a solution of 6-bromo-1H-indole (1.4 g, 7.14 mmol) in Et2O (15.0 mL) was added oxalyl chloride (1.18 g, 9.29 mmol) dropwise at 0° C. under N2. The reaction mixture was stirred at rt for 4 h. An orange precipitate formed, then 40 mL of saturated NaHCO3 was added. The mixture was then stirred at 80° C. for 30 min. Et2O was added to extract the unreacted starting materials. The resulting aqueous layer was acidified with concentrated HCl, and the product precipitated. The solid was filtered and dried to give 1.6 g (yield 83.6%) of 2-(6-bromo-1H-indol-3-yl)-2-oxoacetic acid. MS (ESI) (M−H)+=265.98. 1H-NMR(500 MHz, CD3OD) δ 8.39-8.78 (m, 1 H), 8.21 (d, J=8.24 Hz, 1 H), 7.69 (s, 1 H), 7.40 (d, J=8.55 Hz, 1 H).
Reaction SMILES: N[C@H:2]1[CH2:22][CH2:21][C@:4]2([O:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:10]=3[O:17][CH:18]([CH3:20])[CH3:19])=[CH:5]2)[C@H:3]1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.O.[CH2:31]=O.[C:33]([BH3-])#[N:34].[Na+]>C(#N)C.C(O)(=O)C.C(#N)C>[CH3:31][N:34]([CH3:33])[C@H:2]1[CH2:22][CH2:21][C@:4]2([O:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:10]=3[O:17][CH:18]([CH3:20])[CH3:19])=[CH:5]2)[C@H:3]1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: CC(C)Oc1ccc(C#N)cc1C1=C[C@@]2(CC[C@H](N)[C@@H]2c2ccc(F)cc2)OC1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)Oc1ccc(C#N)cc1C1=C[C@@]2(CC[C@H](N(C)C)[C@@H]2c2ccc(F)cc2)OC1

Procedure:
(5R,6S,7S)-7-Amino-6-(4-fluorophenyl)-3-(5-cyano-2-isopropoxy-phenyl)-1-oxaspiro[4.4]non-3-ene (17.7 mg, 0.045 mmol) was taken up in acetonitrile (0.72 mL). Water (0.2 mL) and 37% formaldehyde (33 μL) were added followed by a solution of sodium cyanoborohydride (11.2 mg, 0.178 mmol) in acetonitrile (0.2 mL). The reaction mixture was stirred for 1 hour at room temperature with occasional addition of 20% acetic acid/acetonitrile to maintain the pH of the reaction at ~7. The mixture was evaporated, and the residue was partitioned between ethyl acetate and 2.5N NaOH. The organic layer was washed with saturated brine solution and evaporated. Pure title compound (12.3 mg) was obtained by silica gel chromatography eluting with 5-10% methanol/methylene chloride. 400 MHz 1H NMR (CD3OD): δ 1.28 (d, 3H), 1.31 (d, 3H), 2.28 (s, 6H), 3.17 (d, 1H), 3.68 (m, 1H), 4.10 (dd, 1H), 4.65-4.75 (m, 2H), 6.32 (m, 1H), 6.96 (t, 2H), 7.08 (d, 1H), 7.38 (m, 3H), 7.53 (dd, 1H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].I[CH:10]([CH3:12])[CH3:11].[OH-].[K+]>CCO.O>[CH:10]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)I
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(O)cc1

Procedure:
To a solution of hydroquinone (3.37 g, 30.0 mmol, 1.00 eq.) and 2-iodopropane (2 mL, 19.8 mmol, 0.66 eq.) in EtOH (12 mL), a solution of KOH (1.68 g, 30.0 mmol, 1.00 eq.) in water (6 mL) was added. The dark brown solution was refluxed for 18 hours. The solvent was removed in vacuo and the remaining aq. phase was acidified with 2M aq. HCl soln. and extracted with AcOEt (3×15 mL). The comb. org. layers were washed with sat. aq. NaCl soln., dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 340 g, flow: 90 mL/min, 100 fractions of 45 mL, Heptane to Heptane+35% AcOEt) to yield 4-isopropoxy-phenol as an orange oil.
Reaction SMILES: [C:1]1([S:7][CH:8]2[NH:11][C:10](=[O:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[C:1]1([S:7][CH:8]2[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10](=[O:12])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: O=C1CC(Sc2ccccc2)N1
Product: COC(=O)CN1C(=O)CC1Sc1ccccc1
Yield: 53.5 %

Procedure:
Treatment of 4-phenylthioazetidin-2-one (Iwata-Reuyl et. al., J. Nat. Prod., 1993, 56(8), 1373) (8 g) with methyl bromoacetate (7.5 g) under the conditions described for Example 1b gave the title compound as a colourless oil (6 g, 53% yield). 1H NMR δ (CDCl3) 2.87 (1H, dd, H3a), 3.42 (1H, dd, H3b), 3.70 (3H, s, CH3), 3.75, 4.29 (each 1H, d, NCH2), 5.22, (1H, dd, H4), 7.26-7.46 (5H, m, Ph-H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])#[CH:11].C(OCC)(=O)C>CCCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:11]#[C:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:20])[F:21])[CH:3]=1
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: Nc1ccc(Cl)cc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C#Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodoaniline (500 mg, 1.97 mmol) and 1-ethynyl-2-(trifluoromethyl)benzene (330 μl, 2.37 mmol). Off white solid. Rf 0.3 (1:9 Ethyl acetate:heptane) as an intense blue spot under UV light.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>[Pd].[C]>[F:32][C:29]([F:30])([F:31])[C:25]1[CH:24]=[C:23]([C:21]2[N:22]=[C:18]([CH:15]3[CH2:14][CH2:13][CH:12]([CH2:11][NH2:10])[CH2:17][CH2:16]3)[NH:19][CH:20]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1

Procedure:
An ethanolic solution of {4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-carbamic acid benzyl ester (4.15 g, 0.0091 mol) and 10% Pd/Carbon (400 mg) was shaken overnight under 55 psi of hydrogen in a Paar apparatus. The mixture was filtered through celite and concentrated under reduced pressure to give a foam, which was triturated with EtOAc/Hexanes/MeOH to produce C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazole-2-yl]-cyclohexyl}-methylamine as a filterable solid. 1H NMR (DMSO-d6): δ 0.93–1.05 (m, 2H), 1.30–1.4 (m, 2H), 1.42–1.55 (m, 2H), 1.85 (d, J=12.8 Hz, 2H), 1.99 (d, J=11.6 Hz, 2H), 2.4–2.5 (m, 1H), 2.56–2.66 (m, 1H), 7.43–7.48 (m, 1H), 7.50–7.55 (m, 1H), 7.63 (s, 1H), 7.99 (d, J=7.9 Hz, 1H), 8.02 (s, 1H). MS 324 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][C:19]=3[F:32])=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:12]=[C:11]2[CH3:37])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.O>C(O)C>[CH2:33]([C:13]1[N:12]=[C:11]([CH3:37])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)[C:15](=[O:16])[C:14]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][C:19]=1[F:32])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 3 h

Procedure:
To a solution of 4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.17 g) in ethanol (10 mL) was added sodium tetrahydroboron (0.11 g), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.97 g, 82%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:13][CH2:14][CH3:15])[CH:3]=1.[C:16]1(OB(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O>[CH2:14]([O:13][C:4]1[CH:3]=[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:15]
Reactant: OB(O)Oc1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)cc1OCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)cc1OCC
Temperature: 95 °C
Reaction time: 1 h

Procedure:
0.50 g of ethyl 4-chloro-2-ethoxybenzoate, 0.31 g of phenylboric acid, 85 mg of 1,1-bis(diphenylphosphino)ferrocene dichloronickel and 1.4 g of potassium phosphate were dissolved in 8 ml dioxane, followed by stirring at 95° C. for 1 hour in a nitrogen atmosphere. After cooling the reaction solution to room temperature, ethyl acetate and water were added thereto. The mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (9:1), ethyl 2-ethoxy-4-phenylbenzoate was obtained. Then, the resulting ethyl 2-ethoxy-4-phenylbenzoate was dissolved in 4 ml ethanol, and 2 ml of 1N sodium hydroxide was added thereto, followed by stirring at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.22 g of 2-ethoxy-4-phenylbenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.IC.[C:14](=O)([O-])O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1F
Reaction time: 18 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (30.8 g) in DMF (150 mL) was added iodomethane (17.5 mL) and powdered sodium hydrogencarbonate (23.5 g). The mixture was stirred for 18 hours and partitioned between ethyl acetate and brine. The organic phase was isolated, washed with dilute sodium bisulfite solution and brine and concentrated. The concentrate was flash chromatographed on silica gel with 7-20% ethyl acetate/hexanes.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1.[C:18](O)(=[O:22])[C@@H:19]([CH3:21])[OH:20].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:20][C@H:19]([CH3:21])[C:18]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH2:4][CH2:3]1)=[O:22]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-tert-butyl (R)-1-(4-aminocyclohexyl)ethylcarbamate (125 mg, 0.52 mmol) was dissolved in DMF (3 mL). D-Lactic Acid (49.52 mg, 0.52 mmol), diisopropylethylamine (166.6 mg, 224.5 μL, 1.29 mmol) and TBTU (165.6 mg, 0.5158 mmol) were successively added. The reaction mixture was allowed to stir at ambient temperature for 3 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by column chromatography (ISCO Companion□, 12 g column, 0-10% MeOH/DCM) to afford the title compound (66.1 mg, 41% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]2[CH2:11][N:10]([CH3:12])[CH2:9][C@H:8]2[NH2:13])=[CH:4][C:3]=1[F:16].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.[O:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[N:37]=[CH:38][C:39]3[CH2:45][CH2:44][NH:43][CH2:42][C:40]=3[N:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:11][N:10]([CH3:12])[CH2:9][CH:8]2[NH:13][C:22]([N:43]2[CH2:44][CH2:45][C:39]3[CH:38]=[N:37][C:36]([NH:35][CH:32]4[CH2:31][CH2:30][O:29][CH2:34][CH2:33]4)=[N:41][C:40]=3[CH2:42]2)=[O:23])=[CH:4][C:3]=1[F:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1nc(NC2CCOCC2)nc2c1CCNC2
Reactant: CN1C[C@@H](N)[C@H](Oc2ccc(Cl)c(F)c2)C1
Solvent: ClCCl
Product: CN1CC(NC(=O)N2CCc3cnc(NC4CCOCC4)nc3C2)C(Oc2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 428 (0.085 g, 0.347 mmol) and DCM (15 mL) was added TEA (1 mL) and CDI (0.149 g, 0.919 mmol). The mixture was stirred at RT for 1 h and then 28 (0.081 g, 0.35 mmol) was added. The reaction was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was purified by preparative reverse HPLC to afford 31 mg (28%) of I-151 as a white solid: LC-MS (ESI) m/z 505 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[CH:16][CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.II.C(O)C>COCCOC.C(O)(=O)C>[C:9]1([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:16]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Nc1cccnc1Nc1ccccc1
Agent: II
Solvent: CCO
Solvent: CC(=O)O
Solvent: COCCOC
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3-c3ccccc3)cc2)S1
Yield: 6.2 %

Procedure:
A procedure similar to that described in Example 18 was repeated, except that 2.78 g of 3-amino-2-phenylaminopyridine (prepared as described in Preparation 84), 3.98 g of 5-[4-(2-oxoethoxy)benzyl)thiazolidine-2,4-dione (prepared as described in Preparation 47), 4.9 g of iodine, 6 ml of ethanol, 6 ml of acetic acid and 50 ml of 1,2-dimethoxyethane were used. After working up the product as described in Example 18, the resulting crude product was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 400 mg of the title compound, melting at 88-91° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16]/[C:17](/[C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:34]\[OH:35])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(CO)CC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCC(CO)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-[4-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=444.4 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=[O:14])=[O:5]>CO.[Pd].C(OCC)(=O)C>[CH:16]1([N:6]2[C:7]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:13]([OH:14])[C:3](=[O:2])[C:4]2=[O:5])[CH2:18][CH2:17]1
Reactant: COC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c(=O)n(C2CC2)c2ccccc2n1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of N-cyclopropyl-N-(2-nitro-phenyl)-oxalamic acid methyl ester (45.0 g, 0.17 mol, 1.0 equiv) in methanol (400 mL) was added palladium on carbon (4.52 g, 0.0043 mol, 0.025 equiv; 10% Pd/C; [CAS RN 7440-05-3]) and the reaction mixture stirred under an atmosphere of hydrogen (1.2 bar) at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (400 mL), filtered over Celite® and the solvent mixture removed by evaporation under reduced pressure to give 31.2 g (84%) of the title compound as a light yellow solid. MS (ISN): m/z=219.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:13])[CH3:12])=[N:9][CH:10]=1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>O1CCCC1>[F:14][C:15]([F:22])([F:21])[C:16](=[O:17])[CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([S:4][CH3:3])=[CH:10][N:9]=1)=[O:13]
Reactant: CSc1ccc(C(C)=O)nc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)CC(=O)C(F)(F)F)nc1
Reaction time: 17 h

Procedure:
A stirring solution of sodium hydride (0.253 g, 6.31 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled under nitrogen to 0° C. before the addition of 1-(5-methylsulfanyl-pyridin-2-yl)-ethanone (0.880 g, 5.26 mmol) in anhydrous tetrahydrofuran (20 mL). Ethyl trifluoroacetate (0.751 mL, 6.31 mmol) was added dropwise and the reaction allowed to rise in temperature to 22° C., then heated to reflux and stirred under nitrogen for 17 hours. The solvent was removed and the residue partitioned between saturated aqueous ammonium chloride (10 mL) and dichloromethane (10 mL). The aqueous layer was separated and extracted with DCM (×3). The organic layers were combined, dried and the solvent removed to yield the title compound: MS m/z 264 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([N:31]([CH3:39])[C@@H:32]([CH:36]([CH3:38])[CH3:37])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH3:39])[CH:36]([CH3:38])[CH3:37])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyric acid to yield (3aR,4S,7aR)-4-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryloxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((S)-3-methyl-2-methylamino-butyryloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=5.490 min; HPLC Method I
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17]CC2C=CC=CC=2)=[C:12]([CH2:25][CH3:26])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH2:25][CH3:26])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
Then, 8.4 g of crude 4-benzyloxy-3-ethyl-5-methylphenyl benzoate was dissolved in 100 ml of ethyl acetate, which was put into a reaction vessel, and the air in the vessel was replaced with nitrogen gas. Then, 0.5 g of 10% palladium on carbon was added, and the nitrogen gas in the vessel was replaced with hydrogen gas, followed by vigorous stirring at room temperature for 24 hours. The hydrogen gas in the vessel was replaced with nitrogen gas, after which the reaction mixture was filtered through cerite and the filtrate was concentrated under reduced pressure, which afforded 5.9 g of crude 3-ethyl-4-hydroxy-5-methylphenyl benzoate (95% yield).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:34]([C:36](OCC)=[O:37])[NH2:35]>CCOC(C)=O>[O:37]=[C:36]1[NH:34][N:35]=[C:1]([C:3]2[N:4]=[C:5]([O:13][CH2:14][C@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(C#N)cc2ccccc12
Reactant: CCOC(=O)NN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (R)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (0.749 g) was added NMP (2 mL) and ethyl hydrazinecarboxylate (0.883 g, 8.48 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with saturated aqueous NH4Cl followed by water. The organic layer was separated and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][OH:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(CO)=C(c2ccc(Cl)cc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of EXAMPLE 30D (1.25 g) in dichloromethane (20 ml) was slowly added Dess-Martin Periodinane (2.78 g). The reaction mixture was stirred at room temperature for 3 hours and diluted with ether. The resulting mixture was washed with aqueous NaOH and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the title compound.