Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:17])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12]([SH:14])=[N:11][C:10]=3[CH:15]=[C:6]2[O:5]1.[Cl-].Cl[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][NH+:22]=1>C(O)C.O>[F:17][C:4]1([F:3])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12]([S:14][CH2:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][N:22]=4)=[N:11][C:10]=3[CH:15]=[C:6]2[O:5]1
Reactant: COc1c[nH+]c(CCl)cc1OC
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)cc1OC
Temperature: 20 °C
Reaction time: 5 h

Procedure:
6.3 ml of 1N sodium hydroxide solution are added dropwise to a solution, warmed to 50° C., of 0.69 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol and 0.67 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride in 9 ml of ethanol and 4 ml of water in the course of one minute. On cooling the clear reaction mixture to 20° C., a colorless precipitate separates out after a short time. The mixture is stirred at 20° C. for a further 5 hours and the precipitate is filtered off with suction over a suction filter, rinsed with 1N sodium hydroxide solution and water and dried to constant weight. The beige solid is dissolved in 10 ml of methylene chloride, insoluble constituents are filtered off, the filtrate is concentrated and the residue is made to crystallize by addition of diisopropyl ether after cooling. 1.02 g (90% of theory) of the title compound of m.p. 189°-191° C. are obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C(=O)=O.CC(C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][C:31]2=[O:34])=[CH:27][CH:26]=1.Cl>O1CCCC1>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][C:31]2([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])[OH:34])=[CH:27][CH:26]=1
Reactant: O=C1CCc2ccc(F)cc21
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
Ethyl acetate (1.8 g, 20 mmol) was added dropwise to a stirred, chilled (dry ice-acetone bath) 1N solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (20 mL, Aldrich) under nitrogen. After 15 min, a solution of 6-fluoro-1-indanone (3.0 g, 20 mmol) in tetrahyrofuran (20 mL) was added dropwise and the resulting mixture was stirred for 1h (dry ice-acetone bath). A 1N solution of hydrochloric acid (20 mL) was added and the mixture was allowed to warm to more temperature. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to a pale yellow oil (5.3 g). The mixture was chromatographed on Silica Gel 60 (silica gel) using a linear gradient of dichloromethane- hexanes (1:1) to dichloromethane as eluent. The fractions containing only ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate were combined and concentrated in vacuo to give 3.1 g (65%) of a colorless oil; NMR (DMSO-d6): d 6.98-7.27 (m, 3H, Ar), 5.40 (s, 1H, OH), 4.01 (q, 2H, OCH2), 2.64-2.96 (m, 4H, 2XCH2), 2.44-2.57 (m, 1H, CH), 2.04-2.18 (m, 1H, CH), 1.12 (t, 3H, CH3).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@:11]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12](=[O:25])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@:11]1([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@H:12]([OH:25])[CH2:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reaction time: 8 h

Procedure:
Sodium borohydride (8.7 g, 0.23 mol) was added to a stirred suspension of (1R*,5S*,6R*)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 19a; 76 g, 0.23 mol) in methanol (700 ml) at room temperature. The reaction mixture was stirred overnight, quenched with water and concentrated in vacuo. The residue was extracted into ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[N:9]=1.C=O.[BH3-][C:36]#N.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:36][N:5]1[CH2:6][CH:1]2[CH2:7][CH:4]1[CH2:3][N:2]2[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH:19]=2)[N:9]=1
Reactant: C[C@H](Nc1cc(-c2nc(N3CC4CC3CN4)c3ccccc3n2)ccn1)c1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](Nc1cc(-c2nc(N3CC4CC3CN4C)c3ccccc3n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-{4-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)quinazolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine (105 mg, 0.25 mmol) in 2 mL of CHCl3 at RT was added formaldehyde (37%, 407 μL, 5.00 mmol), NaCNBH3 (47 mg, 0.75 mmol) and MeOH (0.4 mL). The reaction stirred at RT overnight and then NaHCO3 (sat.) was added and the product was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient elution 1 to 5% MeOH in CH2Cl2) to give (S)-{4-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-quinazolin-2-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine as a pale yellow solid. MS (ES+): 437 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2.[H-].[Na+].F[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>CN(C=O)C.FC1C=CC(C(F)(F)F)=CN=1>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=3)=[C:18]([O:23][CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: COc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1O
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methoxyphenol (3.73 g, 11.25 mmol) in DMF (25 mL) in a dry 250 mL round bottom flask equipped with a dry nitrogen line and a magnetic stir bar was added sodium hydride (324 mg, 13.5 mmol). After gas evolution had subsided, 2-fluoro-5-trifluoromethyl-pyridine (2.05 g, 12.3 mmol) was added, and the reaction mixture was stirred at 25° C. After 20 h, additional sodium hydride (50 mg, 2.1 mmol) and 2-fluoro-5-trifluoromethyl-pyridine (100 mg, 0.6 mmol) were added. After 20 min, the reaction mixture was quenched by addition of sat. aq. NH4Cl (30 mL) and concentrated in vacuo. The residue was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed on the filter with water. The filter cake again was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed with water. The filter cake was dried with suction on the filter overnight to provide 5.26 g (98% yield) of (5,8-difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(5-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as an off-white powder, M.P. 119-121° C. LC-MS: 477 (M++1); 1H NMR (CDCl3): δ 8.69 (s, 1H), 8.4 (m, 1H), 7.89 (dd, 1H), 7.36 (m, 1H), 7.12 (m, 1H), 7.01 (m, 2H), 6.93 (m, 2H), 6.78 (bd, 1H), 3.97 (m, 2H), 3.75 (s, 3H), 3.06 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9]1=[C:20]([CH2:31][C:32]([O:34]CC1C=CC=CC=1)=[O:33])C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+].C(Cl)Cl>CO.[Pd]>[CH2:1]([N:8]1[C@H:12]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:10][C@@H:9]1[CH2:20][CH2:31][C:32]([OH:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=C(CC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](CCC(=O)O)N1Cc1ccccc1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
To a degassed solution of (S)-dibenzyl 2-(1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-ylidene)succinate (1500 mg, 2.70 mmol) was added 10% Pd/C (900 mg, 0.846 mmol) and ammonium formate (2,550 mg, 40.5 mmol) in MeOH (20 ml). The reaction mixture was then heated to reflux under argon. After 12 hrs, heating was stopped and the reaction mixture was left to stand at rt overnight. The next day another 0.5 g of ammonium formate was added to the reaction and reaction was heated for another 5 hrs. The reaction mixture was diluted with MeOH and filtered. The catalyst was rinsed with MeOH and the filtrate was concentrated to give a yellow solid. CH2Cl2 was added to the residue and the mixture was stirred for 5 min. The mixture was then filtered to remove ammonium formate. The filtrate was concentrated to give 3-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid (200 mg, 0.60 mmol, 22.2% yield) as a yellow syrup. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (2 H, d, J=13.7 Hz), 7.36-7.26 (5 H, m), 3.97 (1 H, d, J=13.7 Hz), 3.75 (1 H, d, J=13.7 Hz), 3.36 (1 H, t, J=7.4 Hz), 3.14-3.05 (1 H, m), 2.61-2.52 (1 H, m), 2.40-2.31 (1 H, m), 2.10-1.98 (1 H, m), 1.96-1.77 (4 H, m), 1.77-1.65 (1 H, m), 1.34 (9 H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:25]1[CH:30]2CNCCN2C[CH2:27][O:26]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[CH:14]([CH2:27][O:26][CH2:25][CH2:30]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN2CCOCC2CN1
Reactant: O=C1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCOCC4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]-pyrimidin-6-ylmethyl)-piperazin-2-one using octahydro-pyrazino[2,1-c][1,4]oxazine in place of piperazin-2-one. The title compound was obtained as a white solid (79 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Br:11])[C:8]([Br:12])=[CH:7][C:5]=2[N:6]=1.C[Si](/N=C(/O[Si](C)(C)C)\C(F)(F)F)(C)C.C(O[C@@H:32]1[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]1[O:34][C:35](=[O:37])[CH3:36])(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]([C@@H:32]2[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]2[O:34][C:35](=[O:37])[CH3:36])[C:4]2[CH:10]=[C:9]([Br:11])[C:8]([Br:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2cc(Br)c(Br)cc2[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)/N=C(/O[Si](C)(C)C)C(F)(F)F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)c(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A suspension of 931 mg (3 mmole) of 2-chloro-5,6-dibromobenzimidazole (17) in 15 ml of dry CH3CN was treated with 0.8 mL (3 mmole) of N,O-bis(trimethylsilyl) trifluoroacetamide (BSTFA) at 75° C. for 10 min to give a clear solution. To this solution, was added 955 mg (3 mmole) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 0 64 mL (3.3 mmole) of trimethylsilyl triflate (TMSTf). Stirring was continued at 75° C. for 1 hr. The reaction mixture was cooled to room temperature and then diluted with 100 mL of EtOAc. The EtOAc solution was washed with a sat. NaHCO3 solution (100 mL×2), sat. NaCl solution (100 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (3×20 cm, eluted with CHCl3). Evaporation of fractions 4-10 and recrystallization of the residue from MeOH gave 946 mg (56%) of 56 as white crystals. mp 140°-142° C.; MS m/e 565.9082 (0.9%, M+ =565.9091); 1H NMR (DMSO-d6) d 8.20 (s, 1,7-H), 8.11 (s, 1, 4-H), 6.25 (d, 1, 1'-H), 5.55 (t, 1, 2'-H), 5.43 (dd, 1, 3'-H), 4.47 (m, 2, 5'-H, 4'-H), 4.37 (m, 1, 5"-H), 2.15, 2.14, 2.02 (3×s, 3×, 3.3×Ac). Evaporation of fractions 13-15 gave 392 mg (23%) of the a anomer as a white foam. 1H NMR (DMSO-6) d 8.07, 8.06 (2×s, 2, 4-H, 7-H), 6.70 (d, 1, 1'-H), 5.71 (t, 1, 2'-H), 5.50 (dd, 1, 3 '-H), 4.81 (m. 1, 4'-H), 4. 36 (dd, 1, 5'-H), 427 (dd, 1, 5"-H).
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[C:20]([CH2:22][OH:23])[CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].OI1(=O)C2C=CC=CC=2C(=O)O1>C(#N)C>[C:1]([C:3]1([C:16]2[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cc(CO)ccn2)CC1
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cc(C=O)ccn2)CC1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 4-cyano-4-[4-(hydroxymethyl)pyridine-2-yl]piperidine-1-carboxylate (see Example 23, 0.465 g, 1.46 mmol) in 7 mL of acetonitrile was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (1.23 g, 4.39 mmol). The mixture was heated to 80° C. for 1 h, cooled to rt, and filtered through a glass frit. The filter cake was washed 3× with dichloromethane and the organic filtrate was concentrated in vacuo. The resultant residue was subjected to silica gel chromatography eluting with 0-30% EtOAc in hexanes to provide tert-butyl 4-cyano-4-(4-formylpyridin-2-yl)piperidine-1-carboxylate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1.[CH2:10](O)[CH2:11][CH2:12][OH:13].O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH2:4][CH2:3]1
Reactant: O=CC1CCC(Cl)CC1
Reactant: OCCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: ClC1CCC(C2OCCCO2)CC1

Procedure:
A solution of 10.62 g of 4-chlorocyclohexanecarboxalde-hyde in 150 ml of toluene is treated with 11.5 ml of 1,3-propanediol and 1 g of Amberlyst® 15 and heated to boiling for 2 hours on a water separator while stirring. The reaction mixture is treated with 2 ml of triethylamine and, after cooling, is filtered. The filtrate is washed three times with 30 ml of water, dried over sodium sulphate and concentrated. There is obtained 2-(4-chlorocyclohexyl)-1,3-dioxane.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]1[C:18](=O)[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].C(O)(=O)C.[NH3:28].[BH4-].[Na+]>CO>[CH2:4]([CH:5]1[CH2:6][N:7]2[CH2:8][CH2:9][C:10]3[C:15]([CH:16]2[CH2:17][CH:18]1[NH2:28])=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH:2]([CH3:3])[CH3:1]
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(cc1OC)C1CC(N)C(CC(C)C)CN1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
With reference to FIG. 11, tetrabenazine (317 mg, 1 mmol) was dissolved in methanol (MeOH, 10 ml) and cooled with ice-water. To this solution, ammonia acetate (500 mg) was added, followed by the addition of sodium borohydride (50 mg) in portion. The reaction was stirred at room temperature for 24 hours and quenched with water. The aqueous solution was extracted with methylene chloride (10 ml) twice. The combined organic phase was washed with brine and dried with sodium sulfate. After removing the solvent, the residue was purified by chromatography. One hundred and fifty milligrams of (HG-6) (3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-amine) was obtained as white solid (yield: 47%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]12[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]1[CH2:17][O:16][NH:15]2>ClCCl>[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:14]12[CH2:21][NH:20][CH2:19][CH:18]1[CH2:17][O:16][NH:15]2
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2cnccn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(C23CNCC2CON3)cn1
Reaction time: 1 h
Yield: 71 %

Procedure:
Trifluoroacetic acid (40 mL) is added to a stirred solution of tert-butyl 6a-pyrazin-2-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (5.14 g, 17.58 mmol) in dichloromethane (200 mL) at room temperature. The mixture is stirred for 1 hour and the solvents are evaporated under reduced pressure. The resulting residue is dissolved in methanol (100 mL) and loaded onto an ion exchange column (50 g) and the column is first eluted with methanol (110 mL) followed by 7 M ammonia/methanol solution (150 mL). This basic fraction is concentrated under reduced pressure to give a crude product which is further purified by silica gel column chromatography using a 0-10% gradient of 0.14 M ammonia/methanol in dichloromethane to give the title compound (2.4 g, 71%). ES/MS (m/e): 193 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[N:39]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:45])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[N:39]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1nccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (152 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:27]([CH:32]2[CH2:36][C@@:35]([CH:40]([CH3:42])[CH3:41])([C:37]([OH:39])=O)[CH:34]=[CH:33]2)[C:28]([CH3:31])=[CH:29][CH:30]=1.[C:43]([O:47][C:48]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][C:49]=1[CH2:50][NH2:51])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[C:43]([O:47][C:48]1[CH:55]=[CH:54][C:53]([C:56]([F:57])([F:58])[F:59])=[CH:52][C:49]=1[CH2:50][NH:51][C:37]([C@:35]1([CH:40]([CH3:42])[CH3:41])[CH2:36][CH:32]([N:27]2[C:28]([CH3:31])=[CH:29][CH:30]=[C:26]2[CH3:25])[CH:33]=[CH:34]1)=[O:39])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)Oc1ccc(C(F)(F)F)cc1CN
Reactant: Cc1ccc(C)n1C1C=C[C@@](C(=O)O)(C(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1C1C=C[C@@](C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)(C(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 120.2 %

Procedure:
HATU (33 g, 88.4 mmol) was added to a cooled (0° C.) mixture of (1S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylic acid (20 g, 80.3 mmol), [2-tert-butoxy-5-(trifluoromethyl)benzyl]amine (24 g, 96.4 mmol), and iPr2EtN (42 mL, 241 mmol) in DMF (400 mL). The resulting mixture was allowed to warm to r.t. and was stirred at r.t. for 18 hr. The reaction mixture was diluted with EtOAc and washed with brine (5×). The organic phase was then dried over sodium sulfate and evaporated to dryness. The dark oily residue was purified by column chromatography on silica gel eluting with hexane:EtOAc (7:3) to yield 46 g of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxamide as a yellow oil.
Reaction SMILES: [CH:1]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]=[C:32]([C:37]([O:39]C)=[O:38])[CH:31]=[CH:30]4)=[CH:23][CH:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CO>[CH:1]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]=[C:32]([C:37]([OH:39])=[O:38])[CH:31]=[CH:30]4)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCCC4)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCCC4)cc3)ccc2n1
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (73 mg, 0.13 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1N sodium hydroxide (0.19 mL, 0.19 mmol). A solid was seen to precipitate. The mixture was heated in a microwave reactor at 120° C. for 500 seconds and then was concentrated and the residue was taken up with water and hydrochloric acid (0.19 mL, 0.19 mmol) was added. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine and concentrated to afford 6-[4-({[5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (58 mg, 82%). 1H-NMR (400 MHz, DMSO-d6) δ 13.36 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.92 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.59-3.51 (m, 1H), 2.11-2.03 (m, 2H), 1.84-1.64 (m, 6H). HRMS (ESI) C31H24Cl2N2O4 calculated: 559.1186 (M+H)+, found: 559.1183 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Na+].[I-:11]>CC(C)=O>[C:1]([O:7][CH2:8][I:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [I-]
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCI
Temperature: 40 °C
Yield: 74.4 %

Procedure:
To a stirred solution of 8.00 g (53.30 mmol) of chloromethyl pivalate in 100 mL of acetone at RT under argon was added 24.00 g (160.00 mmol) of NaI. The mixture was heated to 40° C. for 4 h at which time the solids were removed by filtration and the filtrate was evaporated. The residue was diluted with ether, washed sequentially with water, 5% Na2S2O7, brine, and dried over MgSO4. Evaporation of the solvent provided 9.60 g (75%) of title compound as a light green oil.