Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:31]=[C:32]([CH2:35][N:7]([CH3:6])[CH:8]([CH3:9])[CH3:4])[S:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
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+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 4.8 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg). The reaction mixture was heated to 150° C. for 20 minutes in microwave. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and N-methyl-2-propanamine (50 mg) were added. The mixture was heated at 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (12 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[NH:9]2)[C:3]=1[CH3:19].C(=O)(OC(C)(C)C)[O:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[C:3]=1[CH3:19]
Reactant: Cc1c(Br)ccnc1C1CC[C@]2(CCN(C)C2=O)N1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1c(Br)ccnc1[C@H]1CC[C@]2(CCN(C)C2=O)N1C(=O)OC(C)(C)C
Yield: 62.4 %

Procedure:
To a solution of (5R)-2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 10) (554.4 mg, 0.8500 mmol) in DCM (2 mL) was added and tert-butoxycarbonyl tert-butyl carbonate (373.2 mg, 1.71 mmol) the reaction was then stirred at room temperature for 3 days. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc in isohexane from 0% to 100%. A slower running material was isolated tert-butyl (2R,5R)-2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D98) (225.1 mg, 0.5305 mmol, 62% yield) as a colourless oil; M/Z: 423.8, 425.9 [M+H]+.
Reaction SMILES: CN1C2C(=CC=CC=2)C=C1CNC.[CH3:14][NH:15][C:16]([C:18]1[N:19](C)[C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=2)=O.CNC(C1N(C)C2C(C=1)=CC=CC=2)=O>>[F:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH2:16][NH:15][CH3:14])=[CH:26]2
Reactant: CNC(=O)c1cc2cc(F)ccc2n1C
Agent: CNC(=O)c1cc2ccccc2n1C
Agent: CNCc1cc2ccccc2n1C
Product: CNCc1cc2cc(F)ccc2[nH]1
Yield: 78 %

Procedure:
According to the procedure of Preparation 1 (c), except substituting N,1-dimethyl-5-fluoro-1H-indole-2-carboxamide for the N,1-dimethyl-1H-indole-2-carboxamide, the title compound (1.5 g, 78%) was prepared as a white solid: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.17 (t, 1H), 6.97 (br, 2H), 6.77 (d, 1H), 5.39 (s, 2H), 3.68 (m, 4H), 3.31 (m, 2H), 3.22 (m, 2H), 2.27 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=401.1, found=401.1.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].[CH:33]12[O:39][CH:38]1[CH2:37][CH2:36][N:35]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]2>C(OCC)(=O)C>[C:43]([O:42][C:40]([N:35]1[CH2:36][CH2:37][CH:38]([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:21]([O:23][CH3:24])=[O:22])[C@@H:10]([CH3:25])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH:33]([OH:39])[CH2:34]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4O)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (200 mg, 0.59 mmol) and N,N-dimethylformamide (10 mL). Sodium hydride (47 mg, 1.96 mmol) was added and the mixture stirred at room temperature for 30 minutes. tert-Butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (995 mg, 4.99 mmol) was added, and the resulting solution stirred overnight at 80° C. in an oil bath. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (50 mL), washed with water (3×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford methyl (2S)-6-(1-[1-[(tert-butoxy)carbonyl]-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (250 mg, 78%) as yellow oil. MS (ESI, pos. ion) m/z 541 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH:7][C@@H:8]([CH3:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[NH:21]([C:49]([O:51][CH2:52][CH:53]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:59]2[C:54]1=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[C@H:22]([C:46](O)=[O:47])[CH2:23][C:24](=[O:45])[NH:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:8]([CH3:16])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[C:46](=[O:47])[C@@H:22]([NH:21][C:49](=[O:50])[O:51][CH2:52][CH:53]2[C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:59]3[C:54]2=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:23][C:24](=[O:45])[NH:25][C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(OCC)[C@H](C)NCc1csc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-(benzo[b]thiophen-3-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-6) 13.2 g (45 mmol) and Fmoc-Asn(Trt)-OH 35.1 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=30:1 to 5:1 to give the title compound 22.0 g, (yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1C=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.I([O-])(=O)(=O)=[O:22].[Na+]>[Ru](=O)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[CH:12]=[N:13][N:14]=[CH:7]2)=[C:4]([CH:3]=1)[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)cc1nncn12
Agent: O=[Ru]=O
Agent: [Na+]
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1

Procedure:
In the manner given in Example 3, 7-chloro-5-phenyl-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH2:15])=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(N2C(=O)c3ccccc3C2=O)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cc(N2C(=O)c3ccccc3C2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Methoxyacetyl chloride (0.65 ml) was added dropwise to a solution of N-(2-chloro-4-fluoro-5-aminophenyl)phthalimide (1.39 g) and triethylamine (1.16 ml) in dry methylene chloride (45 ml) and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulphate, filtered and evaporated to dryness to yield N-[2-chloro-4-fluoro-5-(2-methoxyacetamido)phenyl]phthalimide as a solid (1.72 g, 99%); NMR (CDCl3): 3.53 (s, 3H), 4.04 (s, 2H), 7.37 (d, 1H), 7.81 (m, 2H), 7.98 (m, 2H), 8.57 (d, 1H), 8.62 (broads s, 1H); m/s: [M−H]− 361, 363.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]#[N:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([C:2]2[C:7]([CH2:8][CH3:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=2)[C:23]#[N:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CCc1c(Cl)nc(OC)nc1OC
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1c(OC)nc(OC)nc1C(C#N)c1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a stirred mixture of 4-Chloro-5-ethyl-2,6-dimethoxy-pyrimidine (1.42 g, 7 mmol) and (3,5-Dichloro-phenyl)-acetonitrile (1.3 g, 7 mmol) in anhydrous DMF (14 ml) at 0° C. (ice bath) under nitrogen atmosphere, was portionwise added 60% sodium hydride (616 mg, 15.44 mmol). After stirring for 1 hr., the mixture was further stirred at room temperature for 18 hr. The mixture was then neutralized with aqueous saturated ammonium chloride solution and the crude product was extracted with ethyl acetate and purified by silica gel column chromatography (eluent, EA:hexanes (1:10)) to afford 2.1 g (85%) of the title compound as a white solid. m.p. 121-122° C.; 1H NMR (200 MHz, CDCl3) δ 1.03 (3H, t, J=7.4 Hz), 2.03-2.57 (2H, m), 3.98 (6H, s), 5.23 (1H, s), 7.33 (3H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]2[CH2:10][CH2:11][O:12][C:13](=[O:14])[CH:7]2[CH2:6]1.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([OH:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28].C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([O:40][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH:8]5[CH2:10][CH2:11][O:12][C:13](=[O:14])[CH:7]5[CH2:6]4)[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C1OCCC2CN(CCCCl)CC12
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCOC(=O)C2C1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
To a solution of 2-(3-chloropropyl)hexahydropyrano[3,4-c]pyrrol-4(2H)-one (0.19 g) in DMF (8 mL) was added K2CO3 (3.0 eq), 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.25 g) and tetrabutylammonium iodide (0.1 eq). The reaction mixture was heated at 90° C. for 20 h, and then treated with CH2Cl2 (100 mL). The mixture was washed with water (100 mL×3) and brine (100 mL), and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (113 mg, 19.62%), HPLC: 95.64%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 502.0 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.06-2.12 (m, 4H), 2.35 (d, J=2.92 Hz, 1H), 2.51-2.58 (m, 3H), 2.76-2.79 (m, 2H), 2.97-3.02 (m, 1H), 3.49-3.50 (m, 1H), 3.52 (s, 1H), 4.00 (s, 3H), 4.18 (d, J=1.80 Hz, 1H), 4.21-4.24 (m, 1H), 4.35-4.40 (m, 1H), 7.13 (t, J=8.80 Hz, 1H), 7.24 (d, J=9.48 Hz, 1H), 7.41 (s, 1H), 7.68 (m, 1H), 7.95-7.98 (m, 1H), 8.28 (s, 1H), 8.63 (s, 1H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][N:46]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reactant: NOCc1ccccc1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOCc3ccccc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-benzylhydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Br:10])N.N([O-])=[O:12].[Na+]>O.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:7]=[CH:8][C:9]=1[Br:10]
Reactant: COc1cc(N)ccc1Br
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(O)ccc1Br
Reaction time: 3 h
Yield: 69.9 %

Procedure:
3-Methoxy-4-bromoaniline (D1) (10.0 g, 49 mmoles) in water (60 ml) and concentrated sulphuric acid (30 ml) was treated with a solution of sodium nitrite (3.4 g, 49 mmoles) in water (15 ml) dropwise keeping the temperature below 5° C. The resulting slurry was then added slowly to a mixture of water (60 ml) and concentrated sulphuric acid (30 ml) at 80° C. and stirred at this temperature for 3 hrs. The mixture was cooled and extracted with dichloromethane (2×200 ml). The organics were then extracted with 2N sodium hydroxide solutions (2×100 ml). The aqueous was washed with more dichloromethane (2×200 ml) then acidified to pH 1. Extraction with dichloromethane, drying (Na2SO4) and evaporation to dryness gave the title compound (D8) (6.95 g, 69%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:21]1[N:26]=[C:25]([OH:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>C(O)C>[N+:28]([C:24]1[C:25](=[O:27])[NH:26][C:21]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[N:22][CH:23]=1)([O-:30])=[O:29]
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: O=c1[nH]c(NCCCOc2cccc(CN3CCCCC3)c2)ncc1[N+](=O)[O-]

Procedure:
A solution of 3-(3-piperidinomethylphenoxy)propylamine (8.20 g; 33.0 mmoles) and 2-methylthio-5-nitro-4-hydroxypyrimidine (6.20 g; 32.5 mmoles) [prepared according to the procedure described in U.S. Pat. No. 4,241,056] in 35 ml of ethanol was stirred at reflux temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, and the residue was placed on 250 g of silica gel (230-400 mesh) and chromatographed by flash chromatography using a gradient elution of methanol-methylene chloride. The appropriate fractions were combined and evaporated, and the product was recrystallized from tetrahydrofuran to give the title compound, mp 161°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:12]
Reactant: O=C(O)Cc1cc(Br)ccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(Br)ccc1F
Temperature: 64 °C

Procedure:
To a solution of 5-bromo-2-fluorophenylacetic acid (5 g) in MeOH (200 mL) is added concentrated sulfuric acid (2 mL) and the solution is heated at 64° C. for 16 hours. The solution is evaporated in vacuo and the residue is taken up in EtOAc and washed with 10% sodium bicarbonate, brine and dried over sodium sulfate. The solution is filtered and evaporated in vacuo to afford (5-bromo-2-fluoro-phenyl)-acetic acid methyl ester (5.1 g). 1H NMR (300 MHz, CDCl3) □7.3-7.5 (m, 2H); 6.9 (m, 1H); 3.9 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.CCOC(C)=O>[N:11]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccccc1

Procedure:
To the desired bromo-acetophenone (from last step, 1.0 equivalents), in DMF (10 mL) was added NaN3 (0.24 g, 3.0 equiv). The resulting mixture was then stirred in DMF for 1 hour. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (2×50). The solvent removed in vacuo and the product was purified by silica gel column chromatography using the Combi-Flash system (Hex:EtOAc) to give the azido-acetophenone product as a white solid in 99% (0.44 g) yield. TLC (4:1, Hex/EtOAc), Rf=0.4.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][C@@H:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[C:13]1([C@@H:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 69.6 %

Procedure:
106 mg of (S)-4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 91 mg of 2-(Trifluoromethyl)phenyl boronic acid, 18 mg of tetrakis(triphenylphosphine)palladium(0), 1.1 mL of 2M sodium carbonate solution, 2.9 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 10 to 40% ethyl acetate/hexanes gradient. The product fractions were pooled and concentrated to afford 88.3 mg of product. ES MS (+) m/z 398.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.I[CH2:19][CH3:20].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH:17]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccncc2)c1Cl
Reactant: CCI
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2cccc(S(C)(=O)=O)c2Cl)CC1

Procedure:
Preparation according to preparation 6: 4-[2-chloro-3-(methylsulfonyl)phenyl]-pyridine (1.77 g, 6.6 mmol), 1-iodoethane (5 ml), ethanol (40 ml), sodium borohydride (2.2 g, 58 mmol). Yield: 0.6 g. MS m/z (rel. intensity, 70 eV) 300 (M+, 24), 299 (M+, 71), 298 (33), 284 (bp), 110 (74).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][O:16][CH2:18][CH2:19][O:20][CH3:21])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Reactant: COCCBr
Product: COCCOCc1cc(C(=O)OC)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxymethylbenzoate (6.0 g) was reacted analogously to O5.043 with 1-bromo-2-methoxyethane to give methyl 3-tert-butyl-5-(2-methoxyethoxymethyl)benzoate. The latter was then converted to the title compound analogously to the sequence O4.043 to O2.043. 508 mg of the title compound were obtained.