Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([CH3:10])[CH:9]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:10][C:8]1[CH:9]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
The reaction apparatus consisted of a 50-mL single-necked round-bottom flask equipped with a water-jacketed condensor, magnetic stirrer, and an argon-filled balloon. A solution of 5-methoxy-2-nitrotoluene (0.25 g, 1.50 mmol), carbon tetrachloride (25 mL), a catalytic amount of benzoyl peroxide (25 mg, 0.83 mmol), and N-bromosuccinimide (0.32 g, 1.8 mmol) were added to the reaction flask. The mixture was refluxed and irradiated under a 90-watt lamp (GE watt-miser light bulb, 130 V, 1000 hrs) for 5 h and then cooled to room temperature. The precipitated succinimide was removed by gravity filtration and the filtrate was extracted with sodium metabisulfite (28 M, 1×50 mL) and water (1×50 mL). The organic layer was separated, dried over sodium sulfate, filtered and then evaporated to afford a crude oil (382 mg, 105%). The crude product was chromatographed on silica gel (hexane/EtOAc=9:1) to give the product as yellow crystals (172 mg, 47%): m.p. 64–65° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[NH:17][C:18](=[O:21])[S:19][CH:20]=1.Cl>ClCC(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:20]2[S:19][C:18](=[O:21])[NH:17][C:16]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1csc(=O)[nH]1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Product: Cc1[nH]c(=O)sc1C(=O)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
4-Fluorobenzoyl chloride (25.3 g, 0.16 mol) was added dropwise to a mixture of aluminum chloride (60 g, 0.45 mol) and 4-methyl-2(3H)-thiazolone (17.3 g, 0.15 mol) in tetrachloroethane (200 ml). After the addition was complete, the mixture was stirred for 5 hours at 90° C. After the mixture cooled to room temperature, 2N hydrochloric acid (200 ml) was added dropwise. The resulting precipitate was collected, washed with water and then with dichloromethane. The solid was then dissolved in ethanol and heated with charcoal. Subsequent recrystalization from ethanol gave the title compound (18.4 g), M.p. 209°-210° C.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH:17]2[CH2:18][CH2:19][O:15][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1CCOC1
Product: N#Cc1c(OC2CCOC2)cccc1[N+](=O)[O-]
Yield: 50 %

Procedure:
Prepared as in Example 166d of WO 2008/154221 from 2,6-dinitrobenzonitrile and tetrahydrofuran-3-ol in 50% yield as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.32 (m, 1H), 3.81 (td, J=8.3, 4.6 Hz, 1H), 3.89 (m, 2H), 3.98 (dd, J=10.8, 4.5 Hz, 1H), 5.36 (m, 1H), 7.75 (dd, J=8.1, 1.5 Hz, 1H), 7.91 (t, J=8.2 Hz, 1H), 7.95 (dd, J=8.2, 1.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:3]=1[F:28].Cl.[N:30]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[F:28][C:3]1[C:2]2[N:1]=[N:30][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (2.07 g, 5.17 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO2 (0.43 g, 6.21 mmol) in water (10 mL) was added dropwisely at 0° C. in 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO3 (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.53 g, 92.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.57 (s, 1H), 7.08 (m, 4H), 4.03 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)=[O:27]>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[O:27])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccccn1
Yield: 39.9 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and pyridine-2-carboxylic acid (41 mg, 0.33 mmol) as starting materials. The title compound (50 mg, 36.2%) was isolated as off white solid; MS (ESI): 380 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCO)CC2)n1
Yield: 40.2 %

Procedure:
7 g of acetic acid 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-propyl ester (18.7 mmol) and 0.67 g of lithium hydroxide (28.0 mmol) were stirred overnight in a mixture of 40 ml of tetrahydrofuran and 40 ml of water. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%) as eluent to yield 2.5 g of the title compound as an oil that crystallized upon standing.
Reaction SMILES: O1CCCC1.C(CC[N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1[S:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)#N.Cl.O>C(OCC)(=O)C>[N+:15]([C:13]1[N:12]=[C:11]([S:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[NH:10][CH:14]=1)([O-:17])=[O:16]
Reactant: N#CCCn1cc([N+](=O)[O-])nc1Sc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Sc2nc([N+](=O)[O-])c[nH]2)cc1
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To tetrahydrofuran (1 ml) solution of 1-(2-cyanoethyl)-4-nitro-2-(4-nitrophenylthio)imidazole (27 mg) was added 1,8-diazabicyclo[5.4.0]undecene-7 (0.02 ml) at a room temperature, and stirred at the same temperature for 3 hours. To the reaction mixture were added 1N hydrochloric acid (0.7 ml), water and ethyl acetate, then the organic layer was taken by liquid separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/ethyl acetate=9/1), there was obtained 4-nitro-2-(4-nitrophenylthio)imidazole (13 mg, yield 58%) as reddish brown powdery product.
Reaction SMILES: C([N:8]([CH2:20][CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])C1C=CC=CC=1>[Pd].C(O)C>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][CH2:21][CH2:20][NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:24]1
Reactant: COc1ccccc1OCCN(CCCc1c[nH]c2ccccc12)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1OCCNCCCc1c[nH]c2ccccc12
Reaction time: 20 h

Procedure:
A mixture of benzyl-[3-(1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)-ethyl]amine (2 g, 4.7 mmol) and 5% palladium on carbon in ethanol was hydrogenated for 20 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromato-graphy (ethyl acetate-hexanes-methanol-ammonia hydroxide: 4/4/1/1) affored 0.79 g (52%) of product as a white solid: mp 101-102° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C(N(CC)CC)C.[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[CH:18]>CN(C)C=O.O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:8][C:4]1[C:3]([C:18]#[C:17][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1
Reactant: Nc1ncnc(Cl)c1I
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2c(N)ncnc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a degassed solution of Example 1A (400 mg, 1.6 mmol) in N,N-dimethylformamide (6 mL) was added copper (I) iodide (120 mg, 0.63 mmol) and triethylamine (2 mL, 14.33 mmol). The mixture was degassed for 5 minutes and tert-butyl 4-ethynylpiperidine-1-carboxylate (1.67 g, 7.98 mmol) and bis(triphenylphosphine) palladium(II)chloride (220 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 3 hours and diluted with water and extracted with ethyl acetate. The ethyl acetate layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound. LCMS: 337.1 (M+1)+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=3)[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:6]2[N:5]=1)=O.[NH2:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31]([CH3:38])([CH3:37])[C:32](=[O:36])[NH:33]2)=[CH:29][CH:28]=1>>[CH3:37][C:31]1([CH3:38])[C:30]2[C:34](=[CH:35][C:27]([NH:26][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=5)[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:6]4[N:5]=3)=[CH:28][CH:29]=2)[NH:33][C:32]1=[O:36]
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: CN(Cc1cccc(-c2ccc3cnc(S(C)=O)nn23)c1)S(C)(=O)=O
Product: CN(Cc1cccc(-c2ccc3cnc(Nc4ccc5c(c4)NC(=O)C5(C)C)nn23)c1)S(C)(=O)=O

Procedure:
N-{3-[2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-6-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzyl}-N-methyl-methanesulfonamide was prepared from N-[3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-N-methyl-methanesulfonamide and 6-amino-3,3-dimethyl-1,3-dihydro-indol-2-one in an analogous manner to Example 1049. Product isolated as a yellow foam (23 mg, 19%). LCMS (m/e) 491 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 8.09 (s, 1H), 7.56-7.52 (m, 1H), 7.52-7.46 (m, 1H), 7.44 (s, 1H), 7.35 (d, 1H, J=7.6 Hz), 7.10 (d, 1H, J=8.0 Hz), 7.05-6.98 (m, 2H), 6.93 (s, 1H), 6.86 (d, 1H, J=4.8 Hz), 4.41 (s, 2H), 2.90 (s, 3H), 2.83 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1>CO>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([NH:5][CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH3:30])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1ccc(CC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 82.5 %

Procedure:
A solution of sodium cyanoborohydride (1.07 grams, 17 mmole), 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine (3.0 grams, 14.3 mole) and 1-(4-methoxyphenyl)propan-2-one (2.35 grams, 14.31 mmole) in methanol (50 ml) was stirred at 22° C. for 17 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The dried (anhydrous magnesium sulfate) organic phase was concentrated under reduced pressure to leave N-[2-(4-methoxyphenyl)-1-methylethyl]-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine as an oil (4.28 grams, 82%); hydrochloride, m.p. 198-199° C. (methanol/ethyl ether), M+H 391.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:19]=[CH:18][C:6]2[O:7][CH2:8][CH2:9][N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]=2[CH:4]=1>ClCCl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[N:19]=[CH:18][C:6]2[O:7][CH2:8][CH2:9][N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:5]=2[CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCOc2cnc(CO)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOc2cnc(C=O)cc21
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of 1,1-dimethylethyl 7-(hydroxymethyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (0.78 g, 2.9 mmol) in dichloromethane (100 ml) was treated with manganese(IV) oxide (2.02 g, 23.3 mmol) and stirred overnight. Filtration and evaporation afforded a white solid (0.62 g, 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][OH:14])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[CH2:27][CH2:26]3)O1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O.C(O)C>[OH:14][CH2:13][C:4]1[O:5][C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:2]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[CH2:27][CH2:26]3)[CH:3]=1
Reactant: OCc1cc(Br)c(-c2ccncc2)o1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=C1CCc2cc(-c3cc(CO)oc3-c3ccncc3)ccc21
Yield: 125.4 %

Procedure:
The product from Step 2 (737 mg, 2.9 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)indanone (0.25 g, 1 mmol) (WO98/45265) (750 mg, 2.9 mmol), potassium acetate (854 mg, 8.7 mmol), triphenylphosphine (79 mg, 0.3 mmol) and palladium (II) acetate (34 mg, 0.15 mmol) were heated at 95° C. in 1:1:1 ethanol:water:N,N-dimethylformamide (10 ml) for 16 hours. After cooling the solution was partitioned between ethylacetate/water and the aqueous phase extracted with ethylacetate (×3). The combined organic extracts were washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethylacetate to afford the title product (383 mg, 43%); MS(ES+) m/e 306 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH2:15][NH:16][C:17]([C:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]=1[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])[CH:9]=[CH:8]2)#[N:2].[N-:39]=[N+:40]=[N-:41].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[NH:39]1[C:1]([CH2:3][O:4][C:5]2[C:6]([C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([CH2:15][NH:16][C:17]([C:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=2[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])[CH:9]=[CH:8]3)=[N:2][N:41]=[N:40]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C)cc3)c(OCC#N)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C)cc3)c(OCc3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide (182 mg, 0.36 mmol), prepared in the previous step, sodium azide (77.6 mg, 1.19 mmol) and ammonium chloride (102 mg, 1.90 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 21 h (overnight). If starting material remains additional sodium azide and ammonium chloride are added and the stirring continued at 100° C. until the reaction is complete. The reaction was diluted with water, made basic by the addition of 1 N NaOH and extracted multiple times with ethyl acetate. The ethyl acetate extracts were combined, acidified with 1 N HCl and then concentrated under reduced pressure. The solid present was collected by filtration and dried under reduced pressure to give the title compound (130 mg, 66%) as a white solid, mp 162-166° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12]C.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: COc1ccc(S(C)(=O)=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of the product from Step B (480 mg, 2.35 mmol) in dichloromethane (10 mL) was added boron tribromide (12.0 mL, 1.0 M in dichloromethane, 12.0 mmol) at −78° C. The reaction was then allowed to warm to room temperature slowly. After stirring at room temperature for 12 h, the reaction was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel, 50:50 hexanes/ethyl acetate) to give the desired compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C([O-])=O.[C:32]([C:34]1[C:35]([CH3:51])=[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][NH2+:48][CH2:49][CH2:50][N:43]3[CH2:42]2)[CH:37]=[CH:38][C:39]=1[F:40])#[N:33].[N:52]1([C:57]2[N:62]=[CH:61][C:60]([CH2:63][C:64](O)=[O:65])=[CH:59][N:58]=2)[CH:56]=[N:55][N:54]=[N:53]1.C(N(CC)CC)C>CN(C=O)C>[F:40][C:39]1[C:34]([C:32]#[N:33])=[C:35]([CH3:51])[C:36]([C@@H:41]2[O:46][CH2:45][C@@H:44]3[CH2:47][N:48]([C:64](=[O:65])[CH2:63][C:60]4[CH:59]=[N:58][C:57]([N:52]5[CH:56]=[N:55][N:54]=[N:53]5)=[N:62][CH:61]=4)[CH2:49][CH2:50][N:43]3[CH2:42]2)=[CH:37][CH:38]=1
Reactant: O=C(O)Cc1cnc(-n2cnnn2)nc1
Reactant: Cc1c([C@H]2CN3CC[NH2+]C[C@H]3CO2)ccc(F)c1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
HATU (192 mg, 0.504 mmol) was added to a solution of (3S,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium trifluoroacetate (104 mg, 0.504 mmol) in DMF (1.5 mL). The reaction mixture was stirred at RT for 15 minutes and a solution of [2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetic acid (284 mg, 0.564 mmol) and triethylamine (0.37 ml, 2.65 mmol) in DMF (1 mL) was added. The flask was rinsed with DMF (0.5 mL). The solution was stirred at RT overnight then diluted with EtOAc and washed with dilute NaHCO3 solution, water (3×) and brine, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by silica gel chromatography (24 g cartridge) using CH2Cl2 (A) and CH2Cl2:MeOH 90:10 (B) with gradient elution from 100% A to 100% B over 12 column volumes and holding at 60% A for 2 column volumes to afford the title compound: LC/MS: 505 (M+CH3CN+Na), 464 (M+H). The title compound was converted to its hydrochloride salt by dissolving in methylene chloride and adding 1 equivalent 1M HCl in ether. The suspension was stirred at RT for 30 minutes and the solvent evaporated: NMR 500 MHz (CD3OD(mixture amide rotamers) 10.03 (s, 1H); 8.87 (s, 1H); 8.86 (s, 1H); 7.94 (q, 1H); 7.31 (d t, 1H); 5.08-5.15 (m, 1H); 54.68 (d, 0.5H); 4.60 (d, 0.5H); 4.01-4.38 (m, 5.5H); 3.82 (t, 2H); 3.58-3.71 (m, 1.5H); 3.40-3.53 (m, 2.5H); 3-31-3.37 (m, 1.5H); 2.61 (br s, 3H); LC/MS 527 (M+Na+CH3CN), 505 (M+H+CH3CN), 486 (M+Na), 464 (M+H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][CH:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:30])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N1c2ccc(-c3ccc(CCO)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 31 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (136. mg, 0.327 mmol), 2-(4-bromophenyl)ethanol (79 mg, 0.392 mmol), potassium carbonate (113 mg, 0.817 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.87 mg, 0.016 mmol) was degassed under house vacuum for 15 min and quenched several times with nitrogen, then was then stirred at 100° C. under nitrogen for 50 min before being cooled to room temperature. Most of the solvent was removed in vacuo and the residue was partitioned between AcOEt (20 mL) and water (15 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 50 to 80% AcOEt in Hexanes) gave a residue which was further purified by MDAP (modifier ammonium formate) to give 1-methylethyl {(2S,4R)-1-acetyl-6-[4-(2-hydroxyethyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (42 mg, 0.102 mmol, 31%).