Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[C:19]=2[CH:32]=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:34]([OH:37])(=O)[CH3:35]>[Zn]>[CH3:29][O:28][C:23]1[C:22]([O:30][CH3:31])=[CH:21][C:20]2[C:19]3[CH:32]=[N:15][C:13]4[CH:14]=[CH:9][C:10]([O:37][CH2:34][C:35]5[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=5)=[CH:11][C:12]=4[C:18]=3[CH:27]=[CH:26][C:25]=2[CH:24]=1
Reactant: CC(=O)O
Reactant: COc1cc2ccc(-c3ccc(OCc4ccccc4)cc3[N+](=O)[O-])c(C=O)c2cc1OC
Agent: [Zn]
Product: COc1cc2ccc3c4cc(OCc5ccccc5)ccc4ncc3c2cc1OC
Yield: 56 %

Procedure:
2-( 4-Benzyloxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (100 mg, 0.23 mmol) was dissolved in glacial acetic acid (15 mL) and heated to reflux with zinc dust (163 mg, 2.5 mmol) for 3.5 h. Acetic acid was evaporated in vacuo and the residue was dissolved in chloroform. The solution was filtered through a celite bed and the filtrate was washed successively with saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed over 50 g of silica gel using 1:2 mixture respectively of hexanes and ethyl acetate to give the title compound as a white solid in 56% yield; 1H NMR(CDCl3) δ4.08(3H, s), 4.18(3H, s), 5.29(2H, s), 7.33(1H, s), 7.42(5H, m), 7.52(1H, d, J=8.9), 7.72(1H, d, J=2.6), 8.02(1H, d, J=8.9), 8.17(1H, s), 8.39(1H, d, J=8.9), 8.52(1H, d, J=8.9), 10.04(1H, s); 13C NMR(CDCl3) δ56.5, 56.6,70.8, 102.3, 108.6, 110.9, 112.8, 118.4, 119.6, 120.7, 124.2, 125.8, 127.7, 128.2, 128.6, 129.2, 131.4, 131.7, 137.1, 146.8, 148.6, 150.1, 151.2, 159.5; HRMS calcd for C26H24N3: 395.1521 , found: 395.1522.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]#[N:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O.[N:27]([Na])=[N+:28]=[N-:29]>CS(C)=O.Br[Zn]Br>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]4[N:27]=[N:28][NH:29][N:25]=4)[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[Na]
Reactant: C[C@H]1CCCN1c1nc2cc(C#N)ccc2nc1-c1ccc(F)cc1
Agent: Br[Zn]Br
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(-c3nn[nH]n3)ccc2nc1-c1ccc(F)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carbonitrile (100 mg, 0.30 mmol) in DMSO (10 mL) was added dibromozinc (33.8 mg, 0.15 mmol), water (10 mL), azidosodium (48.8 mg, 0.75 mmol) and water (5 mL). The resulting solution was stirred for 1 days at 125° C. and then quenched by the addition of water (100 mL), extracted with dichloromethane (3×30 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% dichloromethane in methanol) to afford (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)-6-(2H-tetrazol-5-yl)quinoxaline as a yellow solid (70.9 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(Cl)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloro-benzoyl chloride (46 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32ClN3O3+H: 518, observed: 518.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](=[O:6])[CH:4]=[CH2:5].[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17].C(N(CC)CC)C>CO>[CH3:29][C:26]([C:21]1[CH:22]=[C:23]([S:25][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:6])[CH:24]=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[C:20]=1[OH:30])([CH3:27])[CH3:28]
Reactant: C=CC(=O)N(C)CCc1ccccn1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methyl-N-[2-(2-pyridinyl)ethyl]-2-propenamide (0.95 g, 0.005 mole) was dissolved in methanol (200 ml) containing 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole). After addition of triethylamine (0.5 ml), the solution was stirred at room temperature overnight. The solvent was removed by a nitrogen stream to give a residue which was purified by chromatography on silica to give the title compound, m.p. ca . 82°-84° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:12]([CH3:14])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][N:5]=[C:6]([C:12]([CH2:14][Br:1])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC)C(=O)CBr

Procedure:
Bromine (100 g.) was dropwise added over 40 minutes under reflux to a solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (100 g.) in a mixture of carbon tetrachloride (300 ml.) and acetic acid (300 ml.). The mixture was stirred at 70° to 80° C. until the evolution of hydrogen bromide ceased. The reaction mixture was washed twice with water (300 ml.), a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solution was treated with activated charcoal (2 g.) and concentrated under reduced pressure to give ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (120.8 g.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][C:19]4([CH3:34])[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][N:26]=5)[CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2].[H][H]>CO.O1CCCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([N:21]2[CH2:20][C:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[O:10][C:6]5[C:5]([CH:38]([CH3:40])[CH3:39])=[CH:4][C:3]([C:1]#[N:2])=[CH:37][C:7]=5[N:8]=4)=[CH:36][CH:35]=3)([CH3:34])[O:23][C:22]2=[O:24])=[N:26][CH:27]=1
Reactant: [H][H]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc([N+](=O)[O-])cn5)C(=O)O4)cc3)oc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(N)cn5)C(=O)O4)cc3)oc12
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a mixture of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[5-methyl-3-(5-nitropyridin-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}benzamide (154 mg, EXAMPLE 57) in 10 ml of methanol and 10 ml of tetrahydrofuran was added 50 mg of palladium on carbon (10% wet). The mixture was stirred at 40° C. under a balloon of hydrogen for 15 h. The sample was cooled to room temperature, and was filtered through a small plug of Celite, eluting with methanol. The eluent was concentrated and purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 6 column volumes to provide the title compound (122 mg, 84%). Mass spectrum (ESI) 511.1 (M+1).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[CH:30][N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:44]=[O:45])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:27][C:28]2[N:29]=[C:30]([CH:44]=[O:45])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)cn1)C1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N(Cc1cn(COCC[Si](C)(C)C)c(C=O)n1)C1CCN(Cc2ccccc2)CC1
Yield: 61 %

Procedure:
A solution of n-butyllithium in hexane (1.5 M, 5.7 ml) was added dropwise a solution of tert-butyl (1-benzyl-4-piperidinyl)((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate (3.9 g) obtained in Example 83c) in THF (50 ml) at −40° C. under argon atmosphere. The reaction solution was mixed at −40° C. for 15 minutes, and then DMF (72 ml) was mixed, and mixed at room temperature for 15 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column (ethyl acetate:ethanol=10:1) to obtain the title compound as a pale yellow oil (2.5 g, 61%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: O=Cc1ccccc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2C=O)cc1
Temperature: 50 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and 4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylamine were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper(I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. Purification of the crude compound by column chromatography (SilicaGel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) afforded of 2-(4-methoxy phenylethynyl)benzaldehyde (2.1 g, 89%).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:12]>N1C=CC=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:12]=1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1cccnc1S
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ncccc12
Temperature: 135 °C
Yield: 1.3 %

Procedure:
A mixture of 2-mercaptonicotinic acid (5.00 g, 32.2 mmol), 2-cyanopyridine (3.39 g, 32.5 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 72 hrs as described in Example 9. The mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The resultant product was recrystallized from ethanol to give the titled compound (0.10 g, 1%).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])=[O:19]
Reactant: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 93.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 194 (0.30 g, 0.83 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 195 (0.21 g, 95%) as a colorless foam.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Cl[CH:19]([OH:21])[CH3:20]>CS(C)=O>[OH:21][CH2:19][CH2:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(O)Cl
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(C=O)c(OCCO)c1

Procedure:
2.5 g of 2-hydroxy-4-methoxybenzaldehyde, 6.8 g of K2CO3, 3.3 ml of chloroethanol and 33 ml of DMSO were heated for 8 hrs. to 80° C. Extraction with ethyl acetate and chromatography on silica gel with methylene chloride-acetone gave 2.1 g of 2-(2-hydroxy-ethoxy)-4-methoxy-benzaldehyde, m.p. 94° C., MS: 196 (M)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>O1CCOCC1.CCO>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:13]2[N:12]=[C:11]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([I:1])[C:10]=4[N:9]=[N:8]3)[CH:16]=[CH:15][N:14]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)c1nccc(-n2nnc3c(I)cccc32)n1
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Temperature: 110 °C
Reaction time: 4 h
Yield: 139.3 %

Procedure:
A mixture of 4-iodo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-benzotriazole (2.0 g) and 4-amino-cyclohexanecarboxylic acid ethyl ester (1.8 g) in 1,4-dioxane (25 mL) was stirred at 110° C. for 4 h. The solvent was removed in vacuo to provide an oil, which was taken up in EtOH and heated in a water bath until a light orange solid formed. The solid was filtered, washed with Et2O, and dried to provide 4-[4-(4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester (3.56 g, 93%) as a light orange powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Cl>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[O:38][CH3:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2cc(O)c3ccccc3c2)C1
Reactant: COc1ccccc1CCl
Product: COc1ccccc1COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCO)cc2)cc2ccccc12

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(4-hydroxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-methoxybenzyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-[4-(2-methoxy-benzyloxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil; MS: 652 (M+K)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:20]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.08 (s, 1H), 7.85 (dd, J=7.1, 2.2 Hz, 1H), 7.65 (m, 2H), 7.57 (dd, J=5.0, 1.0 Hz, 1H), 7.52 (m, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.01 (m, 2H), 4.11 (d, J=15.4 Hz, 1H), 3.95 (d, J=15.4 Hz, 1H), 2.41 (m, 2H), 0.78 (t, J=7.0 Hz, 3H); MS (ES) m/z 400 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: O
Solvent: CN(C)C=O
Product: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 82.3 %

Procedure:
A mixture of 4-bromo-2-fluoropyridine (100 mg, 0.57 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (117 mg, 0.57 mmol) and TEA (115 mg, 1.14 mmol) in DMF (5 mL) was stirred at 120° C. under microwave heating for 1 h. Water was added to the mixture which was extracted with DCM. The combined organic layers were concentrated to give the desired compound as a colorless oil (170 mg, Yield 82%) and used directly in the next step. LCMS (m/z): 362.08, 364.08 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
N-(4-Nitrobenzyl)methanesulfonamide (881 mg, 3.83 mmol) was dissolved in methanol/tetrahydrofuran (1:1, 35 mL). 10% Pd/C (264 mg, 3 eq) was added to it. The resulting mixture was stirred at room temperature for overnight under H2. TLC showed complete consumption of starting material. The mixture was filtered through celite bed and the filterate was concentrated under reduced pressure. The crude was purified by column chromatography to give N-(4-aminobenzyl)methanesulfonamide (352 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][B:30]([CH2:32][CH3:33])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]1>>[CH2:32]([B:30]1[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:27][C@@H:26]([CH2:25][CH2:24][N:23]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:31]1)[CH3:33]
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CCB1O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)C)O1
Product: CCB1O[C@H](CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)C[C@H](CC(=O)OC(C)(C)C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-ethyl-1,3,2-dioxaborinan-4-yl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][CH2:25][CH2:24][CH2:23]2.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[C:7]([C:8]([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:19])=[C:29]([F:30])[CH:28]=3)[CH2:23][CH2:24][CH2:25]2)=[O:10])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)c(Cl)c1
Reactant: Fc1cc2c(cc1F)NCCC2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: O=C(c1cccnc1Oc1ccc(F)c(Cl)c1)N1CCCc2cc(F)c(F)cc21
Temperature: 60 °C
Yield: 9.4 %

Procedure:
To a solution of 2-(3-chloro-4-fluoro-phenoxy)-nicotinic acid (32.1 mg, 0.12 mmol, 1.0 equiv; Example 77, Step 1) in dichloromethane (1 mL) was added 6,7-difluoro-1,2,3,4-tetrahydro-quinoline (24.4 mg, 0.14 mmol, 1.2 equiv; [CAS RN 953717-64-1]), tri-n-butylamine (111.2 mg, 143 μL, 0.60 mmol, 5.0 equiv; [CAS RN 102-82-9]) and 2-chloro-1-methylpyridinium iodide (36.8 mg, 0.14 mmol, 1.2 equiv; [CAS RN 14338-32-0]). The reaction mixture was heated by microwave irradiation to 60° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.7 mg (9%) of the title compound. MS (ISP): 419.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].S(O)(C)(=O)=O.C1C(=O)N([Br:23])C(=O)C1>>[Br:23][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(F)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CS(=O)(=O)O
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 50 °C
Reaction time: 33 h

Procedure:
To a 3 L 3 Neck round bottomed flask equipped with overhead stirrer was charged 2-fluoro-6-methyl-benzonitrile (191.8 g., 1419 mmol) and MsOH (563 mL, 8516 mmol). NBS (265 g., 1490 mmol) was added portionwise to this stirred solution over 30 minutes, and the mixture was stirred at 50° C. for 33 hours. The reaction was poured into 1 L of ice, diluted with 700 mL 30% EtOAc/Hexanes, and agitated. The aqueous layer was cut, and the organics washed 2× with 1N NaOH and with water. The organics were dried over MgSO4, concentrated, then stored in a −10° C. freezer overnight. Precipitate formed over this time, and was filtered and washed with 5% EtOAc/Hexanes, providing a first crop of product. A second crop of precipitate provided additional 3-Bromo-6-fluoro-2-methyl-benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (5.0 g, 32 mmol) and 4-fluorobenzyl bromide (6.3 g, 33 mmol) in acetone (50 mL) containing potassium carbonate (5.3 g, 38 mmol) was heated under reflux for 2 h. After cooling to room temperature the mixture was filtered and evaporated to leave the title compound (7.3 g, 86%) as a light yellow solid. MS: m/e=265.1 (M++H).