Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)CCC2
Temperature: 85 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
A solution of 7-nitro-3,4-dihydro-1(2H)-naphthalenone (10.0 g, 52.3 mmol) in ethanol/water (4:1 mixture, 200 mL) was treated with iron (10.3 g), and ammonium chloride (1.1 g), stirred at 85° C. for 4 hours, and filtered. The filtrate was concentrated and the concentrate was dissolved in 400 mL of ethyl acetate, washed with brine (5×), dried (Na2SO4), filtered, and concentrated. The concentrate was treated with diethyl ether and filtered. The filter cake was washed with diethyl ether and dried under vacuum to provide 7.56 g of the desired product. The filtrate was concentrated to provide 0.39 g of additional product. MS (DCI) m/e 162 (M+H)+, 179 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.O=S(Cl)Cl.[CH2:15](O)[CH3:16]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[CH:4][N:3]=1
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)nc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 2-amino-5-pyridinecarboxylic acid (98; 5.0 g, 36.2 mmol) in ethanol (100 mL) was added SOCl2 (8.6 g, 72.4 mmol) at 0° C. The resulting reaction mixture was stirred under reflux for 12 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and then enough saturated aqueous Na2CO3 solution was added to the reaction mixture to adjust the pH=9. The resulting solids were collected by filtration and dried to afford ethyl 6-aminonicotinate 99 (5.64 g, 94%).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:16][O:17][CH3:18]>>[CH3:16][O:17][CH2:18][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:14]=2)[CH:10]=[CH:11]1
Reactant: c1cc2ccc(N3CCCC3)cc2[nH]1
Reactant: COCCl
Product: COCn1ccc2ccc(N3CCCC3)cc21

Procedure:
1-Methoxymethyl-6-pyrrolidin-1-yl-1H-indole was prepared from 6-pyrrolidin-1-yl-1H-indole ( example 12 e) in the same manner as example 1(a) using chloromethyl methylether as the alkylating agent.
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[CH:15][C:8]=12.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.O>CCO>[F:16][C:17]1[C:22]([C:7]2[N:12]=[CH:11][N:10]=[C:9]3[NH:13][N:14]=[CH:15][C:8]=23)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2[nH]ncc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of potassium acetate (13 g, 130 mmol), PdCl2(P-t-Bu2Ph)2 (1.1 g, 1.7 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (6.70 g, 43 mmol) and 2-fluoropyridin-3-ylboronic acid (7.3 g, 52 mmol) in EtOH (300 ml)-water (100 ml) was sonicated until the solid became a fine powder and degassed under vacuum. The mixture was refluxed under N2 overnight. After cooling to rt solvent was removed in vacuo and to the residues was added water (200 ml) and NaHCO3 (sat. 150 ml). The mixture was stirred for 15 min. The solid was filtered and washed with water. The solid was dissolved in MeOH-DCM and preloaded on silica gel and purified by flash chromatography eluting with MeOH/DCM (1-5%) to give 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. MS Found: (ESI pos. ion) m/z 216 (M+H+).
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[S:19]1[CH:23]=[C:22]([C:24]2[NH:25][C:26]3[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)[N:21]=[CH:20]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[C:1]1([C:7]2([C:10]([NH:33][C:31]3[CH:30]=[CH:29][C:27]4[NH:28][C:24]([C:22]5[N:21]=[CH:20][S:19][CH:23]=5)=[N:25][C:26]=4[CH:32]=3)=[O:12])[CH2:8][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: Nc1ccc2nc(-c3cscn3)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2[nH]c(-c3cscn3)nc2c1)C1(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-phenylcyclopropane-1-carboxylic acid (2.0 g, 12.3 mmol) in dichloromethane (40 mL) was treated at ambient temperature with oxalyl chloride (1.06 mL, 12.3 mmol) and three drops of DMF. A drying tube was placed on the flask and the reaction bubbled (HCl, CO, and CO2) for three hours. 2-Thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-6, 2.67 g, 12.3 mmol) and diisopropyl ethyl amine (3.22 mL, 18.5 mmol) were dissolved in 30 mL of dry N,N-dimethylformamide and cooled to 0° C. The acid chloride solution was concentrated, re-dissolved in 10 mL of dichloromethane, and cannulated into the stirring amine solution over a five minute period. The reaction was allowed to warm slowly to ambient temperature after the addition was complete. The reaction was complete after half an hour by TLC analysis and was partitioned between ethyl acetate and dilute sodium bicarbonate solution. The aqueous was extracted (3×10 mL) with ethyl acetate and the layers were separated. The organic layer was washed twice with water, once with brine, separated, dried (MgSO4), filtered, and concentrated in vacuo. The resulting yellow oil was filtered thru a plug of silica gel eluted with ethyl acetate. The filtrate was concentrated in vacuo and the residue was triturated in ethyl acetate/hexanes mixtures to afford the pure 1-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide as a white solid (3-10); 1H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.49 (d, 1H), 7.36 (m, 6H), 1.48 (dd, 2H, J=4.4, 2.4 Hz), 1.15 (dd, 2H, J=4.4, 2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:50]1([CH2:56][CH2:57][O:58][C:59]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]([NH2:69])=[CH:61][CH:60]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C=O)C.O>[N:50]1([CH2:56][CH2:57][O:58][C:59]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]([NH:69][C:8]([C:6]3[CH:5]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:3]=[C:2]([Cl:1])[N:7]=3)=[O:10])=[CH:61][CH:60]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1cc(N2CCOCC2)nc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(N2CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 83.8 %

Procedure:
2-Chloro-6-morpholin-4-ylpyrimidine-4-carboxylic acid (0.280 g, 1.15 mmol) in DMF (5 ml) is treated with HBTU (0.466 g, 1.5 eq) and diisopropylethylamine (0.367 ml). The mixture is stirred at room temperature for 5-10 min. 4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (0.224 g, 0.82 mmol) is then added. The mixture is stirred at room temperature for an additional 15 h, diluted with water and extracted with ethyl acetate. The organic layer is dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 2% MeOH in ethyl acetate to provide 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylic acid[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide as a solid (0.342 g). Mp: 95-93° C., 1H NMR (300 MHz, DMSOd6) δ 10.43 (s, 1H), 8.20 (m, 1H), 7.79 (s, 1H), 7.56 (m, 3H), 7.39 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 4.31 (t, J=6.3 Hz, 2H), 3.60 (brt, 8H) 2.88 (t, 2H), 2.56 (brt, 8H). MS: 498 (M+1).
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[Cl-].[C-:31]#[N:32].[K+]>C(Cl)(Cl)(Cl)Cl.O>[C:31]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:32]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.2 %

Procedure:
In 120 ml of carbon tetrachloride are dissolved 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 2.44 g of tri-n-octlymethylammonium chloride and, under stirring, a solution of 2.15 g of potassium cyanide in 30 ml of water is added. The mixture is stirred vigorously at the same temperature for 15 minutes and the organic layer is separated, while the aqueous layer is extracted with chloroform. The organic layers are combined, washed with water and treated in the same manner as (1) of Example 13 to give 7.66 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH2:16]([O:15][C:13]([C:9]1[C:10]2[CH:11]=[CH:12][C:3]([CH2:2][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])=[N:4][C:5]=2[CH:6]=[CH:7][CH:8]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cccc2nc(CBr)ccc12
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Temperature: 110 °C

Procedure:
Compound 73c (240 mg, 0.816 mmol) was treated with triethyl phosphite (2.12 mL, 12.2 mmol) and the resultant slurry was heated to 110° C. for 4 h. The reaction was concentrated in vacuo, diluted with DCM (50 mL), washed with sodium bicarbonate, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH/DCM) to afford compound 73d as an oil. Mass spectrum (LCMS, ESI pos.) Calcd. For C17H22NO5P: 352.1 (M+H). found 352.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH2:8][N:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1)[CH2:10][CH:11]=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][NH:27][CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:23])[F:22])=[C:15]([Cl:24])[CH:14]=1
Reactant: CC(C)(C)OC(=O)CCN(CC=O)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: COC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)CCCNCCN(CCC(=O)OC(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.50 g (1.3 mmol) of 3-[(3-chloro-4-trifluoromethoxy-phenyl)-(2-oxo-ethyl)-amino]-propionic acid tert-butyl ester in 6 ml dichloromethane was added dropewise to a cooled (0° C., pH ca. 5) suspension of 0.22 g (1.4 mmol) methyl 4-aminobutyrate hydrochloride, 0.18 ml (1.3 mmol) triethylamine, 0.15 ml (2.6 mmol) acetic acid and 0.32 g (1.5 mmol) sodium triacetoxyborohydride in 4 ml of dichloromethane and stirred 30 min at 0° C. The reaction was extracted with aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3 and dried over Na2SO4 to yield after evaporation of the solvent 0.61 g (83%) of the titled compound as yellow oil. MS: 483.19 (MH+, Cl).
Reaction SMILES: [CH2:1]([CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][CH3:3].[OH-].[Na+:14]>O>[CH2:10]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7]([O-:9])=[O:8])[CH2:11][CH3:12].[Na+:14]
Reactant: CCCC(CCC)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(CCC)CCC(=O)[O-]

Procedure:
In a flask, 17.2 g (0.1 mol) of 4-n-propyl-heptanoic acid, prepared as described in the above Example 2, were dissolved in a sufficient volume of water. After that 4 g (0.1 mol) of a sodium hydroxide solution in water were added and the mixture was evaporated to dryness. The residue so obtained was rinsed with ethyl ether and maintained in a dessicator under vacuum.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]1([C:31]2([OH:35])[CH2:34][CH2:33][CH2:32]2)[CH2:21][CH2:20][C@@H:19]([NH:22][C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16])=O)(C)(C)C.[ClH:36]>O1CCOCC1.CO>[ClH:36].[ClH:36].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]([C@@:17]1([C:31]2([OH:35])[CH2:34][CH2:33][CH2:32]2)[CH2:21][CH2:20][C@@H:19]([NH:22][C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16]
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(O)CCC2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 902 mg (1.827 mmol) of 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(1-hydroxycyclobutyl)cyclopentyl]amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol was added 10 mL of 4M HCl in dioxane, and a few drops of methanol sufficient to give a clear solution. The solution was stirred at ambient temperature for 45 minutes, then concentrated under reduced pressure to give 973 mg of the intermediate salt as a foam. 1H NMR (400 MHz, MeOD) δ ppm 1.57-1.70 (m, 1 H) 1.73-1.93 (m, 4H) 1.93-2.10 (m, 4H) 2.14-2.28 (m, 2H) 2.29-2.44 (m, 3H) 2.46-2.59 (m, 2H) 3.35-3.77 (m, 12H) 3.98 (dd, J=11.6, 4.4 Hz, 1H) 4.26 (d, J=13.3 Hz, 1H) 4.45 (s, 1H) 5.21 (br. s., 1H). LC-MS ES+ 394.2.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[O:8])=[CH:3][CH:2]=1.[N+:17]([O-])([O-])=O.[NH4+].N>>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[NH2:17])=[O:8])=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(C(=O)C2CCCCC2=O)cc1
Agent: N
Agent: [NH4+]
Product: Cc1ccc(C(=O)C2=C(N)CCCC2)cc1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Ammonia gas was bubbled into a cooled flask containing a suspension mixture of 2-p-toluoylcyclohexanone (21.6 g, 0.1 mole) and 8.8 g (0.11 mole) of ammonium nitrate until 17 g (1 mole) of ammonia was absorbed. The flask was stoppered and the mixture stirred for 30 min when a solution resulted. The flask and its mixture was allowed to stand overnight and the resulting brown solution was evaporated. The residue was extracted with boiling diethyl ether, 4×250 ml portions, filtered, and the extract was concentrated until crystallization began in the hot, and the mixture was allowed to cool. A total of 10 g of pale yellow needle crystals was obtained, mp 130°-131° C. A second crop of 6.35 g, mp 129°-130.5° C., for a total of 76% yield was obtained. The UV, mass spectrum and NMR spectra were consistent with the sub-titled intermediate amine.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[N:6]=1)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[N:6]=1
Reactant: CC(=O)Nc1cccc(C(=O)O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(C(=O)O)n1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
A suspension of 2-acetylaminopyridine-6-carboxylic acid (4.1 g) in 2.5 N NaOH (36.5 ml) was heated at 80° C. for 1.5 hours, under nitrogen atmosphere. The resulting solution was cooled and acidified with cold 3N HCl. The precipitate obtained was filtered, washed successively with water and acetonitrile. The resulting white solid was dried under vacuum to afford 2-aminopyridine-6-carboxylic acid (2.4 g, 76% yield). 1H-NMR (DMSO-d6) δ 7.57 (t, 1H, J=8.1 Hz), 7.14 (d, 1H, J=7.2 Hz), 6.67 (1H, J=8.1 Hz), 6.51 (br, 2H); FAB MS m/z 139 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[OH-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)CO
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-2-methyl-1-propanol (7.1 mmol) in tetrahydrofuran (THF) (25 mL) was added dropwise to a slurry of 60% sodium hydroxide/oil (3 g, 75 mmol) in THF (75 mL). The mixture was stirred at room temperature for 1 hour and then cooled in an ice bath. A solution of benzyl bromide (5.9 mL, 50 mmol) was added dropwise. After stirring for 2 hours at 0° C., the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated to an oil which was subjected to flash chromatography on silica gel eluting with 5% methanol/chloroform. Fractions containing the desired product were combined and concentrated to yield an oil. Yield: 4.2 g (47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[N:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])[N:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(F)cc2)C1Cc1cccc(OC(F)(F)C(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)n1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}-1,3-oxazolidine-3-carboxylate (840 mg, 1.72 mmol) in methanol (4 ml) was added a solution (4.12 ml, 2.06 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 15 min. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give the objective substance (390 mg, 49%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:25])\[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[C:16](=[O:20])[NH:17]3)=[CH:13][CH:12]=2)[CH:5]=1.[C:26](OC(=O)C)(=O)[CH3:27]>>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:25]=[C:26]([CH3:27])[O:1][N:2]=2)=[CH:5][C:6]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:21][CH2:22][CH2:23][CH2:24]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(/C(N)=N\O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2ccc(C)c(-c3ccc4c(c3)NC(=O)C43CCCC3)c2)no1
Temperature: 130 °C
Yield: 30.9 %

Procedure:
A mixture of (E)-N′-hydroxy-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzimidamide (preparation 54, 31 mg, 0.09 mmol) and acetic anhydride (0.03 mL, 0.28 mmol) was heated in a sealed tube 130° C. for 1 h. The solvent was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, brine, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (8:2 hexanes/ethyl acetate to ethyl acetate) to yield the title compound (0.01 g, 32%) as a white solid.
Reaction SMILES: [ClH:1].C([Cl:5])(=O)C.[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[ClH:5].[ClH:1].[CH2:6]([O:13][C:14]([N:16]([CH:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]1)[CH2:17][CH2:18][CH3:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Reaction time: 0.17 h

Procedure:
To a solution of 2.4 mmol of HCl in 2 mL of methanol (prepared by the addition of 0.17 mL of acetyl chloride at 0° C. and stirring for 10 min) was added 90 mg of 4-(N-(benzyloxycarbonyl)-N-(prop-1-yl)amino)-1-t-butoxycarbonylpiperidine. The mixture was stirred at rt for 16 h at which time the reaction was complete by TLC (20% ethyl acetate/hexanes) and was evaporated to dryness in vacuo to afford 75 mg of the title compound as the di-hydrochloride salt and which was used in the above reductive alkylations.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([CH:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1)=[O:10])[CH3:7].[OH-].[Na+].CN(C)[C:29](=[O:31])[CH3:30]>>[C:29]([C:16]1[C:15]2[C:19](=[CH:20][C:12]([NH:11][C:9](=[O:10])[CH:8]([CH2:6][CH3:7])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=2)[NH:18][CH:17]=1)(=[O:31])[CH3:30]
Reactant: CCCCC(CC)C(=O)Nc1ccc2cc[nH]c2c1
Reactant: CC(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC(CC)C(=O)Nc1ccc2c(C(C)=O)c[nH]c2c1
Yield: 80 %

Procedure:
1.9 g. of phosphorus oxychloride was slowly added to 1.48 g. of N,N-dimethylacetamide at 0° C. The mixture was allowed to attain room temperature and a solution of 1.0 g. 6-(2-ethylhexanamido)indole in 2 ml. N,N-dimethylacetamide was added. After 15 minutes the reaction solution was basified to pH 14 with 20% w/v sodium hydroxide solution, briefly heated under reflux, then cooled and extracted with ethyl acetate. The combined extracts were washed with water, then with brine, dried (MgSO4) and evaporated to give 0.93 g (80%) of 3-acetyl-6-(2-ethylhexanamido)indole (DD) as an orange powder; partial NMR: 2.5 (s, 3H), COCH3), 7.7 (d, 1H, H2 -indole), 9.8 (br, s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([CH:11]2[CH2:13][CH2:12]2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1F)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.500 g, 2.463 mmol) in THF (10.71 mL) cooled to −78° C. was added cyclopropylmagnesium bromide (5.91 mL, 2.96 mmol). The reaction mixture was maintained at −78° C. for at least 2 hr, then allowed to warm to room temperature. During this time, additional cyclopropylmagnesium bromide (5.91 mL, 2.96 mmol) was added. After 30 min, the reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated and the aqueous phase extracted with CH2Cl2 (2×). The organics were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound (0.604 g, 2.464 mmol, 100% yield) as a yellow residue.