Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C)C=O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([C:10](=[O:12])[CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)cc(OC)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Ex-59A: To a solution of 4′-hydroxy-3′,5′-dimethoxyacetophenone (1 g, 5.1 mmol) in N,N-dimethylformamide were added tert-butyldimethylsilyl chloride (1,15 g, 7.6 mmol) and imidazole (0.69 g, 10.2 mmol). The mixture was stirred at room temperature overnight. Upon quenching with 1 M sulfuric acid solution, the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate and brine. It was dried and evaporated. Water (2 mL) was added to the residue, and the precipitate was filtered out and dried over an oil pump to give 1.28 g (81%) of 3′,5′-dimethoxy-4′-(tert-butyldimethylsiloxy)acetophenone as a white solid, m.p. 90-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:14]=[C:15]([NH:22][C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)=[O:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:28][C:25]([OH:26])([CH3:27])[C:23]([NH:22][C:15]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:13]([CH3:12])[CH:14]=1)=[O:24]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc([N+](=O)[O-])c(F)c2)ccc1[N+](=O)[O-]

Procedure:
3-(3-Fluoro-4-nitrophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 3-fluoro-4-nitrophenol and 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. 1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.16 (1H, d, J=10.1 Hz), 4.41 (1H, d, J=10.1 Hz), 6.36 (1H, bs), 6.96 (1H, m), 7.22 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.90 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=9.0 Hz), 8.24 (1H, m), 10.19 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1F
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1F

Procedure:
From 2-fluorobenzoic acid and 3-(1-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=435.1, tR (minutes, Method G)=2.58
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(CCCO)c1cccc[n+]1[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(CCCOS(C)(=O)=O)c1cccc[n+]1[O-]
Yield: 63.6 %

Procedure:
Methanesulfonyl chloride (0.17 mL, 2.20 mmole) was added dropwise to a solution of 2-[N-(3-hydroxy-1-propyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide (0.50 g, 1.86 mmole) and pyridine (0.23 mL, 2.84 mmole) in CHCl3 (5 mL, dried over K2CO3) at 0° C. When complete by TLC, the reaction was diluted with CHCl3, washed with ice water, dried (Na2SO4), and concentrated. Silica gel chromatography (10% MeOH/CHCl3) gave the title compound (0.41 g, 64%) as a colorless oil: 1H NMR (250 MHz, CDCl3) δ8.25 (dd, J=6.0, 1.9 Hz, 1 H), 7.25 (m, 4 H), 4.35 (t, J=6.2 Hz, 2 H), 3.75 (t, J=6.6 Hz, 2 H), 3.00 (s, 3 H), 2.00 (m, 2 H), 1.40 (s, 9 H). Unchanged 2-[N-(3-hydroxy-1-propyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide (0.18 g, 36%) could also be recovered from the chromatographic purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8](=[O:25])[CH:9]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1)[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:31].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8](=[O:25])[CH:9]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1)[S:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:31]
Reactant: COc1cccc(CN(C)C(=O)C(Sc2ccccc2)c2cc(Cl)cc(Cl)c2)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(CN(C)C(=O)C(c2cc(Cl)cc(Cl)c2)S(=O)c2ccccc2)c1

Procedure:
A mixture of the acetamide derivative from step 5 above (1.5 g), sodium metaperiodate (1.15 g), methanol (30 ml) and water (20 ml) was heated under reflux for 2 hours. The reaction mixture was filtered and the filtrate concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate as eluent, giving N-(3-methoxybenzyl)-N-methyl-2-(3,5-dichlorophenyl)-2-(phenylsulfinyl)acetamide (1.2 g) as a viscous oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:28][CH3:29])=[CH:11][C:12]([O:26][CH3:27])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O>>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([O:28][CH3:29])=[CH:11][C:12]([O:26][CH3:27])=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1
Reactant: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(I)cc1
Reactant: OB(O)c1cccs1
Product: COc1cc(OC)c(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1

Procedure:
The title compound (E244) was prepared from the product of Step 1 and 2-thienylboronic acid using a similar method to that described for Examples 237-243. MS (ES+) m/e 488 [M+H]+.
Reaction SMILES: [CH2:1]([Mg:3][Br:4])[CH3:2].[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9]C#C>>[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][C:2]#[C:1][Mg:3][Br:4]
Reactant: CC[Mg]Br
Reactant: C#CCCC(OC)OC
Product: COC(CCC#C[Mg]Br)OC

Procedure:
1,1-dimethoxy-pent-4-yn-5-yl magnesium bromide was prepared in situ from ethyl magnesium bromide and 1,1-dimethoxy-4-pentyne. The latter was prepared as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:5].C(O)(=O)C>C1COCC1.[Zn]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g) was dissolved in THF (70 ml) and acetic acid (5 ml) and Zn (10 g) were added. The mixture was stirred for 1 h and filtered through Celite®. The filtrate was rinsed with EtOAc and the organics were evaporated to a residue which was purified on silica gel chromatography (40% EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H 194.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][C:7]2[C:12]([C:13]=1[N+:14]([O-])=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1c(N2CCOCC2)nc2ccccc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1c(N2CCOCC2)nc2ccccc2c1N

Procedure:
The 3-ethylamino-2-morpholino-4-nitroquinoline (0.7 g, 0.0023 mol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (15 ml) and subjected to catalytic reduction in the presence of 10g palladium-on-carbon (0.3 g), thereby obtaining 4-amino-3-ethylamino-2-morpholinoquinoline in an amount of 0.5 g (yield, 79%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([N:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: O=C1CCCCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCN1CCCCCCCC1=O
Yield: 69.7 %

Procedure:
Following example 17, 4.2 g of 50% sodium hydride-mineral oil dispersion (2.1 g NaH, 0.0875 M), 10 g (0.0708 M) of azacyclononan-2-one and 15 g (0.0777 M) of 1-bromooctane gave 12.5 g (70%) of product; b.p. 150°-160°/0.5 mm.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a mixture of ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (1.50 g), tetraethyl methylenediphosphonate (0.84 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.12 g) at room temperature. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate as colorless crystals (1.20 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (4:1 to 9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 114-115° C.
Reaction SMILES: [CH2:1](Br)[CH3:2].[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)[CH3:2]
Reactant: CCBr
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1ccc(C)c(O)c1

Procedure:
88.6 gm of ethyl bromide were added to a solution of 50 gm of 5-amino-2-methylphenol in 250 ml of ethanol; and the mixture was refluxed for four hours. After the solution had cooled, it was diluted with 1.2 liters of water and was made weakly alkaline with sodium carbonate. After repeated extraction with ether, the ether extracts were dried and concentrated. The residue was recrystallized from ethanol, and had a melting point of 128° C. to 129° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C@:20]2([CH3:26])[CH2:24][O:23]C(=O)[NH:21]2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1)[CH3:2].C(O)C.O.[OH-].[Li+]>O>[NH2:21][C@@:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][C@H:6]3[CH2:5][CH2:4][C@@H:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)[CH:11]=2)[CH:16]=1)([CH3:26])[CH2:24][OH:23]
Reactant: CC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H]1CC[C@@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Yield: 8.9 %

Procedure:
(R)-4-[6-(cis-4-Ethyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.4603 g, 0.001302 mol) was dissolved in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (2.8 mL) was added and the mixture was heated overnight at 80° C. TLC analysis showed the reaction was complete. The mixture was concentrated to dryness under vacuum. Methylene chloride (5 mL) and water (5 mL) were added and the layers were separated by phase separator cartridge. The organic layer was dried with MgSO4, filtered, concentrated and purified by HPLC to give 0.038 g of the title compound (9% yield). MS: m/z=311.26 [M−NH2]+. 1H NMR (400 MHz, MeOD) δ 0.95 (t, J=7.15 Hz, 3H), 1.28-1.38 (m, 3H), 1.39-1.50 (m, 2H), 1.58-1.74 (m, 4H), 1.80 (s, 3H), 2.04-2.14 (m, 2H), 3.83 (d, J=11.55 Hz, 1H), 3.94 (d, J=11.55 Hz, 1H), 4.76 (br. s., 1H), 7.21-7.30 (m, 2H), 7.53 (dd, J=8.91, 1.88 Hz, 1H), 7.82-7.88 (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:11]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccsc1N
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccsc1NCC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-aminothiophene-3-carboxylate (2.0 g, 12.7 mmol) in dichloromethane (40 mL) and glacial acetic acid (0.72 mL) were added isobutyraldehyde (0.87 g, 12.1 mmol) and sodium triacetoxyborohydride (4.0 g, 18.9 mmol). The reaction mixture was stirred for 18 h at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and concentrated. The residual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate-hexane to afford the title compound as a slightly yellow oil (2.19 g, 81% yield). 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1H), 6.18 (d, 1H), 3.80 (s, 3H), 3.20 (m, 2H), 1.68 (m, 1H), 1.00 (d, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1CCCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC1CCCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(tetrahydro-2H-pyran-3-yl)-1-butanol (1.20 g) in dry dichloromethane (30.3 ml), cooled to 0° C., was added triethylamine (2.43 ml) and methanesulphonyl chloride (0.77 ml) to give a yellow solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (25 ml). The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to afford a yellow oil (1.80 g). The product was purified by silica chromatography using a gradient elution of 0-40% ethyl acetate/cyclohexane to afford the title compound as a yellow oil (1.58 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Br:15]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:15][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH:4]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Oc1ccccc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cc(Br)ccc1O
Yield: 97 %

Procedure:
2,2 dimethylpropionic acid 2-hydroxyphenylester (6 g) was dissolved in dichloromethane and bromine (4 ml) was added slowly at 0° C. Then, the blended solution was reacted for 30 minutes at −75° C. After completing the reaction, sodium thiosulfate was added to remove bromine, water was added to dilute, and extracted with ethylacetate. A resulting organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. As a result, the present compound (2.2 g, productive yield 97%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]([F:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:17])[CH:8]=2)[CH2:3]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([NH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]([F:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:17])[CH:8]=2)[CH2:3]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCC(c2cc(F)c(C(=O)O)cc2F)C1
Solvent: CC(=O)O
Product: CC(=O)NC1CCC(c2cc(F)c(C(=O)O)cc2F)C1

Procedure:
A solution of 24.1 g (0.1 mol) of 4-[3(amino)cyclopentyl]-2,5-difluorobenzoic acid in a mixture of 50 ml of acetic anhydride and 100 ml of acetic acid was heated at reflux for 6 hours. The solvent was removed in vacuo and the residue triturated with water. The solid was removed by filtration, washed with water, and dried in vacuo to give 25.3 g of the title compound.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)CCCc1ccc(Br)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCCC(=O)O)cc2)cc1
Temperature: 130 °C

Procedure:
In a microwave reaction vial was placed (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50 mg, 0.185 mmol), 4-(4-bromophenyl)butanoic acid (49.6 mg, 0.204 mmol), dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (2.63 mg, 3.71 μmol), and K2CO3 (51.3 mg, 0.371 mmol) in toluene (1.2 mL) and H2O (0.2 mL). The reaction was heated at 130° C. for 120 min under microwave irradiation. The aqueous layer was collected, acidified with 1M HCl, and purified by HPLC to give the title compound. LCMS m/z=352.4 [M+H]+; 1.26 (d, J=6.8 Hz, 0.4H), 1.46 (d, J=6.5 Hz, 2.6H), 1.70-1.82 (m, 1H), 1.87-1.94 (m, 2H), 2.01-2.10 (m, 2H), 2.21-2.30 (m, 1H), 2.33 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.7 Hz, 2H), 3.06-3.18 (m, 4H), 3.35-3.45 (m, 1H), 3.50-3.60 (m, 1H), 3.74-3.84 (m, 1H), 7.31 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][C@@H:15]2[C@@H:13]([CH2:14]2)[N:12]1[C:17](=[O:31])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:30])[NH2:29])=[N:20]1)=[O:10])C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:18][C:17]([N:12]2[C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][C@@H:15]3[C@H:13]2[CH2:14]3)=[O:31])[N:20]=1)(=[O:30])[NH2:29]
Reactant: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2ccccc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1R,3S,5R)-2-[2-(3-carbamoyl-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (3.9 g, 8.85 mmol) was dissolved in THF (120 mL) and EtOAc (120 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10% (390 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and stirred at RT for 4 h. The catalyst was removed through a pad of Celite and washed with EtOAc. Solvents were removed under reduced pressure and the foam thus obtained was used without further purification in the next step. MS (LCMS): 346.2 [M+NH4]+, 327.1 [M−H]−; tR (HPLC conditions b): 1.12 min.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.N.[H][H]>[Pd].CO>[N:13]1([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:4]([NH2:3])[CH2:5][CH2:6]3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CON=C1CCc2cc(N3CCCCC3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: NC1CCc2cc(N3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Piperidin-1-ylindan-1-one O-methyloxime (2.95 g, 12 mmol), 10% palladium on carbon (1.45 g), and 20% ammonia in methanol (80 ml), were placed in a Parr apparatus, which was charged with hydrogen to 60 psi. The mixture was shaken for 1 hour at ambient temperature and filtered. The filtrate was removed under vacuum to provide the title compound which was used without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].C(O[CH:7]=[C:8]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])C>C(O)C>[F:16][C:15]([F:18])([F:17])[C:14]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:3][N:2]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A solution of hydrazine hydrate (459 mg, 9.16 mol) in ethanol (5 mL) was added to a solution of ethyl 3-ethoxy-2-(trifluoroacetyl)acrylate (2.00 g, 8.33 mmol) in ethanol (15 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 24 hrs. The reaction was concentrated in vacuo, dissolved in ethyl acetate (30 mL), washed with 5% citric acid (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried (Na2SO4) and concentrated in vacuo to afford ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.365 g, 79% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.24 (t, 3 H), 4.22 (q, 2 H), 8.56 (s, 1 H); MS (ESI) m/z: 209.0 (M+H+).