Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][N:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1CCCC1=O.N>C1(C)C=CC=CC=1>[C:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][N:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1)#[N:26]
Reactant: CCCCCc1cnc(-c2cnc(-c3ccc(Br)cc3)nc2)nc1
Reactant: CN1CCCC1=O
Agent: N
Solvent: Cc1ccccc1
Product: CCCCCc1cnc(-c2cnc(-c3ccc(C#N)cc3)nc2)nc1
Temperature: 40 °C

Procedure:
A mixture of 2-(p-bromophenyl)-5'-pentyl-5,2'-bipyrimidinyl (5.0 g, 0.013 mol), N-methyl-2-pyrrolidone (100 mL) and cuprous cyanide (1.16 g, 0.013 mol) was heated under reflux for 5 hours, followed by cooling the reaction mixture down to 40° C., adding toluene (500 ml) and 28% aqueous ammonia (100 ml), separating the resulting layers, washing the toluene layer with water till the washing water became neutral, drying the toluene layer over anhydrous sodium sulfate, distilling off toluene, and three times recrystallizing the residual solids from toluene to obtain 2-(p-cyanophenyl)-5'-pentyl-5,2'-bipyrimidinyl (2.1 g, 0.006 mol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Ni]
Product: COc1ccc(COc2ccc(N)cc2)cc1

Procedure:
The above nitro compound was hydrogenated in THFethanol in the presence of Raney nickel catalyst, providing 4-[(4-methoxyphenyl)methoxy]benzenamine, mp 118°-120° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].C1(O)C=CC=CC=1.[CH2:18]([O:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C(Cl)Cl>[CH2:18]([O:25][NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(Cl)ccnc1C
Reactant: NOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: COc1c(NOCc2ccccc2)ccnc1C

Procedure:
16 g of 4-chloro-3-methoxy-2-methylpyridine, 63 g of phenol and 40 g of O-benzylhydroxylamine are stirred at 120° C. under nitrogen for 4 hours. After cooling, the mixture is shaken with 500 ml of 2N NaOH and CH2Cl2. The aqueous phase is extracted a second time with CH2Cl2. After concentrating the combined CH2Cl2 phases, excess O-benzylhydroxylamine is distilled off in vacuo at 0.6 mm. The residue crystallizes on stirring with hexane. After filtering off with suction and washing with hexane 21.6 g=88.4% of product remain. The product is recrystallized from ethyl acetate. M.p.: 130° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:26][CH3:27])=[N:12][C:11]=1[CH3:28]>C1COCC1>[CH2:26]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH2:24][CH3:25])[C:18]=1[C:13]1[N:12]=[C:11]([CH3:28])[C:10]([CH2:9][OH:8])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:27]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cc(OC)c(CO)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of LiAlH4 (1 M in THF, 1 mL, 1 mmol) is added to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-nicotinic acid methyl ester (122 mg, 0.39 mmol) in THF (5 mL) at 0° C. The mixture is warmed to room temperature and stirred for 2 hours. The mixture is cooled to 0° C. and Na2SO4.10H2O is added to quench the reaction. The mixture is filtered through Celite and the filtrate is concentrated in vacuo. The crude product is purified by PTLC (hexanes/ethyl acetate 3:1) to give [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-methanol as a white solid. 1H NMR: (CDCl3) 7.26 (m, 1H), 7.13 (d, 2H), 6.68 (S, 1H), 4.82 (d, 2H), 3.87 (s, 3H), 2.65 (s, 3H), 2.33 (m, 4H), 1.05 (t, 6H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6].[C:13]([O:17][C:18]([NH:20][C:21]1([C:36](O)=[O:37])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[OH:6][CH2:5][CH2:4][C@H:3]([NH:2][C:36]([C:21]1([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:25][CH2:26]1)=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccccc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 48.9 %

Procedure:
(S)-3-Amino-3-phenylpropan-1-ol hydrochloride (260 mg, 1.38 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 21) (500 mg, 1.38 mmol) and DIPEA (0.967 mL, 5.53 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (579 mg, 1.52 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(3-hydroxy-1-phenylpropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (334 mg, 48.8%) as a white solid. The product (334 mg, 0.67 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.961 mL, 27.67 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The resulting gum was triturated with EtOAc to give a solid which was collected by filtration and dried under vacuum to give (S)-4-amino-N-(3-hydroxy-1-phenylpropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (93 mg, 17.0%) as an off white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][OH:11].[H-].[Li+]>O1CCOCC1>[Cl:12][C:5]1[N:4]=[N:3][C:2]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:6]=1
Reactant: OCCOc1cc(Cl)nnc1Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Clc1cc2c(nn1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[(3,6-dichloro-4-pyridazinyl)oxy]ethanol containing some bromo-derivative (15.46 g; 0.0703 mol) in dry 1,4-dioxane (1.2 L) was treated with lithium hydride (2.3 g; 0.28 mol) in portions and stirred at room temperature for 1 hour under argon, then heated at 110° C. overnight. The reaction mixture was quenched with wet 1,4-dioxane, then iced-water. The solution was evaporated to half volume, taken to pH 8 with 5M hydrochloric acid and evaporated to dryness. Water was added and the residue was extracted 5× with chloroform, dried (sodium sulphate) and evaporated to afford a white solid (12.4 g, ca.77%) (containing ca. 15% of a bromo species).
Reaction SMILES: C[Mg]Br.CCO[CH2:7][CH3:8].[Cl:9][C:10]1[N:15]=C(Cl)[N:13]=[C:12]([Cl:17])[N:11]=1.C(Cl)Cl.[O-][Mn](=O)(=O)=O.[K+]>>[Cl:9][C:10]1[N:11]=[C:12]([Cl:17])[N:13]=[C:7]([CH3:8])[N:15]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: C[Mg]Br
Agent: [K+]
Solvent: ClCCl
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Methylmagnesium bromide, 3M in ether (Aldrich, St. Louis, Mo.) (10.0 mL, 30 mmol) was added slowly to a white suspension of 2,4,6-trichloro-1,3,5-triazine (Aldrich, St. Louis, Mo.) (3.68 g, 20 mmol) in DCM (25.0 mL, 389 mmol) at 0° C. and the resulting yellow suspension was warmed up to room temperature and stirring was continued until disappearance of starting material (TLC, KMnO4 stain, 3H). The reaction was carefully quenched with NH4Cl(aq) at 0° C. and then diluted with water and DCM (25.0 mL). The separated organic layer was dried, filtered and concentrated to give 2,4-dichloro-6-methyl-1,3,5-triazine as a yellow solid (2.94 g, 90%) which was used for further reaction without purification. 1H-NMR (CDCl3, 400 MHz) δ 2.74 (s, 3H).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].S([O-])([O-])(=O)=O.[Mg+2].B(F)(F)F.CCOCC.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([CH:31]=O)=[CH:25][C:24]=1[CH:33]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([CH:31]2[S:5][CH2:1][CH2:2][CH2:3][S:4]2)=[CH:25][C:24]=1[CH:33]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: CCCCCC(CC(=O)OC)c1cc(C=O)c(OC)cc1OC
Reactant: SCCCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCC(CC(=O)OC)c1cc(C2SCCCS2)c(OC)cc1OC
Reaction time: 2 h

Procedure:
150 mg (1.39 mmol) of 1,3-propanedithiol, 1.0 g of magnesium sulfate and a catalytic amount of boron trifluoride etherate were added, with ice-cooling, to a solution of 447 mg (1.39 mmol) of methyl 3-(2,4-dimethoxy-5-formylphenyl)-octanoate [prepared as described in Preparation 32(ii)] in 12 ml of methylene chloride, and the resulting mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and then the dehydrating agent was removed by filtration using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after is which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 10 g of silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 589 mg (a quantitative yield) of the 1,3-dithiane derivative as an oily substance.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1(C)[CH:12]=CC=[CH:9][CH:8]=1.ClC=C(Cl)Cl.ClC(Cl)C>C(Cl)CCl.ClC(Cl)=C(Cl)Cl.C1(C)C(C)=CC=CC=1>[CH2:1]1[C:6]2[C:5](=[CH:12][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccccc1
Reactant: Cc1ccccc1
Agent: *CC(*)C
Solvent: Cc1ccccc1C
Solvent: ClCCCl
Solvent: ClC(Cl)=C(Cl)Cl
Product: c1ccc2c(c1)CCCC2

Procedure:
The solutions useful in the method of the present invention include those obtained by a combination of a polyolefin and a petroleum hydrocarbon such as benzene, toluene, xylene, solvent naphtha or the like or a chlorinated hydrocarbon such as trichloroethylene, tetrachloroethylene, dichloroethane, dichloroethylene or the like. Low density polyethylene, medium density polyethylene, high density polyethylene, atactic (amorphous) polypropylene, isotactic (crystalline) polypropylene, ethylene-propylene copolymer, propylene-butylene copolymer can be mentioned as useful polyolefins. It is preferable to use a solution having a gelation point of 40°-60° C at a concentration in the range of 1-5% by weight. However, among the above-mentioned, a combination of benzene (b.p. 80.1° C), cyclohexane (b.p. 80.7° C), dichloroethylene (b.p. 83.5° C) with a resin other than atactic polypropylene is not of practical value because of poor solubility. Though tetraline (b.p. 210.5° C) or kerosene (b.p. 150°-320° C) provides nice gel-forming property, they are the examples which are not useful on account of too high boiling point. For the foregoing reason, toluene, xylene and tetrachloroethylene are preferable as a solvent for polyolefins and inflammable tetrachloroethylene is most suitable if safety is also taken into consideration.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=2)=[C:6]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[F:28])[CH:5]=[CH:4][N:3]=1.CN(C=O)C.CCO.[NH4+].[Cl-]>[Fe].O>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=2)=[C:6]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=2[F:28])[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)Cc1ccc(-c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2N)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Cc1ccc(-c2c(Oc3ccc(N)cc3F)ccnc2N)cc1
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of 2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetamide (32 mg, 0.086 mmol), DMF (1 mL), EtOH (1 mL) and H2O (1 mL) was treated with Fe powder (67 mg, 1.2 mmol), and NH4Cl (128 mg, 2.4 mmol) and the mixture heated at 100° C. for 20 min. The mixture was filtered through Celite®, the pH of the filtrate adjusted to pH 7 using phosphate buffer and then the mixture was extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated to give the desired product (20 mg, 67%) as a yellow-brown solid. MS(ESI+): m/z 353.32 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].OC1C(O)=CC=CC=1C(NN)=O.CN([Si:28]([CH3:31])([CH3:30])[CH3:29])C(=O)C(F)(F)F>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: NNC(=O)c1cccc(O)c1O
Solvent: CC#N
Product: C[Si](C)(C)OC(=O)C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
(2,3-Dihydroxybenzoyl)hydrazine, trifluoroacetate salt (2.82 g) was suspended in 50 ml of acetonitrile and 13.5 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide were added. After stirring for one hour at 40° C., the solvent and trifluoroacetic acid, trimethylsilyl ester formed were distilled off in vacuo. The remaining oil was dissolved again in 50 ml of dried acetonitrile, cooled to 0° C. and added dropwise to a solution of 3.48 g of an adduct of chlorosulfonylisocyanate and (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester in 100 ml of acetonitrile at 0° C. with stirring. After continuous stirring overnight, the solvent was distilled off in vacuo and the residue stirred (1 hour) with 200 ml of isopropanol. (S)-3-[[(Phenylmethoxy)carbonyl]amino]-N-[[2-(2,3-dihydroxybenzoyl)hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide precipitated from the solution. Isolation by filtration and washing with ether yielded 3.87 g of white powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[C:30](=[O:31])[CH2:29][Cl:28])[CH3:2]
Reactant: CCOC(CNCC1OCCO1)OCC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CN(CC1OCCO1)C(=O)CCl)OCC

Procedure:
N-(2,2-Diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine (4 grams), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of 5° to 10° C and chloroacetyl chloride (1.5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [CH3:1][C:2]1([CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11]C)[CH:8]=2)[C:3]1=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH3:1][C:2]1([CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:15]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred suspension of 2-methyl-2-isopropyl-5-methoxy-6,7-dichloro-1-indanone (7.0 g., 0.0244 mole) and aluminum chloride (9.0 g., 0.068 mole) in heptane (400 ml.) is refluxed for one hour and cooled. The heptane is decanted from the reaction mixture and the solid residue is poured into water (300 ml.) and concentrated hydrochloric acid (20 ml.). The crude product is extracted into ether (300 ml.), washed with water, dried over magnesium sulfate, distilled to a volume of 100 ml. and treated with hexane (100 ml.). The 2-methyl-2-isopropyl-5-hydroxy-6,7-dichloro-1-indanone which separates (6.5 g.) melts at 215° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:56](OC)[CH3:57])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].[CH3:60]O[C@H](C)[C@H](NC(OC)=O)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:57])[CH3:60])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:44])[CH3:45])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:24][CH:25]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid for (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 789 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.O=S(Cl)Cl.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.N1C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:16]2[CH2:18][CH2:17]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NC1CC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-2-methylbenzoic acid and SOCl2 was refluxed for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 30 mL CH2Cl2 and combined with cyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine (2.05 g, 26.0 mmols). The solution was stirred for 18 hours and then diluted with EtOAc before being washed with 5% aqueous HCl, saturated NaHCO3, and saturated aqueous NaCl. The solution was dried (MgSO4) and concentrated under reduced pressure leaving the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[Cl:14].[CH3:15][O:16][C:17]([C:19]1(OC)[CH2:23][CH2:22][CH:21](OC)O1)=[O:18]>C(O)(=O)C>[Cl:14][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:1]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]([O:16][CH3:15])=[O:18])[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Reactant: COC(=O)C1(OC)CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Yield: 43.7 %

Procedure:
10 g (47.25 mmol) of 7-amino-6-chloro-2,3(1H,4H)-quinoxalinedione and 8.9 g (47.25 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran in 150 ml of acetic acid were refluxed for 2 h. The precipitate was then filtered off with suction to yield 6.6 g (44%) of the product. Melting point >260° C.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C[Al](C)C.[C:21]1(=[O:27])[O:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][OH:27])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=C1CCCCO1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCO)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-amine (300 mg, 1.43 mmol) in toluene (4 mL) was added trimethylaluminium (1.8M in toluene solution, 1.189 mL, 2.14 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of δ-valerolactone (0.129 mL, 1.43 mmol) in toluene (4 mL) at room temperature, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxypentanamide (420 mg, 1.352 mmol, 95%) as a pale-yellow powder.