Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:12]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(N(CC)CC)C>O>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:8]([N:7]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)[CH3:6])[S:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(N(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(C)c2nc(-c3ccc(N)cc3)cs2)cc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (1.20 L, 10.0 v/w) was added to ethyl 4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)amino)benzoate (123 g, 0.321 mol) obtained in Example 3(2). With stirring at room temperature, sodium hydrosulfite (80% purity, 210 g, 0.963 mol) was added. After stirring at room temperature for 10 min., distilled water (123 ml, 1.0 v/w) was added carefully. After stirring at 100° C. for 1.5 hr., triethylamine (223 ml, 1.61 mol) was added at 80° C., and the mixture was cooled to room temperature with water. After stirring at room temperature for 1 hr., distilled water (1.1 L, 9.0 v/w) was added. After stirring at room temperature for 30 min., the mixture was extracted twice with ethyl acetate (1.20 L) and the organic layer was washed successively with distilled water (400 ml) and saturated brine (400 ml), and dried over magnesium sulfate (60 g). The magnesium sulfate was filtered off, the solvent was evaporated, the residue was boiled with toluene and dried in vacuo to give the title compound (67.0 g, yield 63.0%) as a yellow to orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[N+:19]([C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br)([O-:21])=[O:20].COC(=O)C(C1CCN(C(OC(C)(C)C)=O)CC1)CC1C=CC=CC=1[N+]([O-])=O>>[CH3:1][O:2][C:3](=[O:18])[CH:4]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)C(Cc1ccccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Product: COC(=O)C(Cc1ccccc1[N+](=O)[O-])N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 51 %

Procedure:
tert-Butyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (1.0 g, 3.9 mmol) and 2-nitrobenzylbromide (1.0 g, 4.6 mmol) were reacted in a manner analogous to the preparation of tert-butyl 4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperidine-1-carboxylate. Title compound was obtained as amber oil in 51% yield. MS m/e (M+H)+=394.4.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][C:13]2([CH2:17][OH:18])[CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[F:1][C:2]([F:19])([F:20])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][CH2:12][C:13]2([CH2:17][O:18][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: OCC1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCC1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1

Procedure:
In analogy to the procedure described in example 1G], {1-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-cyclobutyl}-methanol and methanesulfonyl chloride gave the title compound as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[CH2:20][C:19]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33](=[O:42])[NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1I)([CH3:31])([CH3:30])[CH3:29].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:40]2[CH:39]=[N:38][CH:37]=[CH:36][C:35]=2[NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:42])[CH2:20][C:19]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccncc1C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Reaction time: 5 h
Yield: 50.9 %

Procedure:
A solution containing 2-(2-oxo-4-prop-2-ynyl-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.27 mmol), EXAMPLE 812, (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (87 mg, 0.27 mmol), EXAMPLE 69, Part B, Et3N (110 mg, 1.08 mmol), (Ph3P)4PdCl2 (10 mg, 0.013 mmol), and CuI (1 mg, 0.008 mmol) in anhydrous DMF (5 mL) is stired at ambient temperature. After 5 h, the reaction mixture is diluted with EtOAc (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH CH2Cl2) to provide 77 mg (51%) of the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3, ˜2:1 mixture of rotamers) major rotamer: δ1.53 (s, 9H), 1.69 (s, 9H), 2.98 (m, 2H), 3.49 (s, 2H), 3.56 (m, 2H), 3.78 (s, 2H), 4.98 (s, 2H), 6.43 (s, 1H), 7.89 (m, 1H), 8.09 (m, 2H), 8.34 (m, 1H), 8.41 (m, 1H), 8.75 (m, 1H) ppm; MS (ISP loop): m/z 561 (M+H).
Reaction SMILES: OCC1CCN(C(OC(C)(C)C)=O)C1.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH:22]1[CH2:27][CH2:26][CH:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)(=[O:38])=[O:37])[CH2:24][CH2:23]1>>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH:22]1[CH2:23][CH2:24][CH:26]([CH2:25][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)(=[O:37])=[O:38])[CH2:27]1
Reactant: O=S(=O)(Nc1ccccc1OC1CCNCC1)c1ccccn1
Agent: CC(C)(C)OC(=O)N1CCC(CO)C1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OCC1CCNC1)c1ccccn1
Yield: 39 %

Procedure:
Intermediate 6b (solid) is prepared using tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate instead of tert-butyl 4-hydroxypiperidine-1-carboxylate using the procedure described for 6a (yield: 39% over the 4 steps).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:33]2[CH2:35][CH2:34]2)[N:5]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[N:8]=1.[Cl:36][C:37]1[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=[CH:39][C:38]=1[NH:52][S:53]([CH2:56][CH2:57][CH3:58])(=[O:55])=[O:54].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:36][C:37]1[C:38]([NH:52][S:53]([CH2:56][CH2:57][CH3:58])(=[O:55])=[O:54])=[CH:39][CH:40]=[CH:41][C:42]=1[C:2]1[N:3]=[C:4]([CH:33]2[CH2:35][CH2:34]2)[N:5]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[N:8]=1
Reactant: CCCS(=O)(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1Cl
Reactant: C[C@@H](CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)n(COCC[Si](C)(C)C)c2-c2ccnc(NC[C@H](C)NC(=O)OC(C)(C)C)n2)c1Cl
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a mixture of (S)-tert-butyl 1-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (I-1a, 256 mg, 0.45 mmol), N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide (SM-10, 292 mg, 0.81 mmol), aqueous 2.0 M Na2CO3 solution in DME (4 mL) was added PdCl2(dppf).DCM. The reaction vial was sealed and irradiated at 120° C. for 10 minutes in a microwave reactor. LCMS indicated complete conversion and the reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with water, brine, dried (Na2SO4), and concentrated to furnish a dark red oil. Purification by flash chromatography (SiO2, 50-100% EtOAc in heptane) provided (S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (4A-1: 116 mg, 0.14 mmol) as a yellow oil: LCMS (m/z) 720.3, (MH+), tR=1.03 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[NH:27]1[CH:26]=[C:25]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Reactant: CC1(C)OB(c2cn[nH]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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc(-c3cn[nH]c3)c2)c(F)c1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a solution of 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.0 g, 12.6 mmol, from Example A2) in a solvent comprised of toluene/ethanol/water (4:4:1, 50 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (3.17 g, 16.4 mmol), sodium carbonate (4.01 g, 37.8 mmol) and tetrakis(triphenylphosphine)palladium (0.73 g, 0.63 mmol). The headspace was evacuated and back-filled with nitrogen (3×) and then the reaction mixture was heated to 100° C. overnight. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give 4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluoroaniline (2.66 g, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.03 (brs, 1H), 8.28-8.31 (m, 2H), 7.99 (s, 1H), 7.24 (s, 1H), 6.95-7.00 (m, 1H), 6.39-6.50 (m, 3H), 5.43 (brs, 2H); MS (ESI): m/z 271.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:23](=[O:25])[CH3:24])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-p-Chlorophenyl-2-(1,2,4-triazol-1-yl)-ethanol (2.24 g) and triethylamine (1.1 g) in dry diethyl ether (50 ml) were treated with acetyl chloride (0.8 g) in dry diethyl ether (5 ml) and the mixture was stirred for 3 hours at room temperature to give a white solid which was filtered off and washed with ether. The solvent was removed from the filtrate to give a brown oil. The oil was distilled to give the title compound as a semi-solid which could not be purified further.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Br)cc4)nc23)ccn1
Yield: 43.4 %

Procedure:
Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (94 mg, 43%). MS (ISP) 433.3 [(M+H)+]; mp 226° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[CH2:32]([O:39][CH2:40][CH2:41][NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:32]([O:39][CH2:40][CH2:41][NH:42][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: NCCOCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(NCCOCc2ccccc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 6, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 2-benzyloxy-ethylamine, [rac]-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, palladium(II) acetate and cesium carbonate in toluene at reflux to give the title compound as yellow oil. MS: 567.4 (MH+).
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].[Cl:7][C:8]1[CH:17]=[C:16]([Cl:18])[C:15]2[C:10](=[C:11]([O:21]C)[CH:12]=[CH:13][C:14]=2[O:19]C)[N:9]=1>CC#N.O>[Cl:7][C:8]1[CH:17]=[C:16]([Cl:18])[C:15]2[C:14](=[O:19])[CH:13]=[CH:12][C:11](=[O:21])[C:10]=2[N:9]=1
Reactant: COc1ccc(OC)c2c(Cl)cc(Cl)nc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=CC(=O)c2c(Cl)cc(Cl)nc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
Cerium ammonium nitrate (CAN 21.4 g, 39.03 mmol) is added portionwise to a solution of 2,4-dichloro-5,8-dimethoxyquinoline (2.85 g, 11.04 mmol) in a CH3CN/H2O mixture (150 ml/75 ml). The reaction mixture is stirred at ambient temperature for 40 min. The acetonitrile is subsequently evaporated and 50 ml of water and 200 ml of a saturated NaHCO3 solution are added. The aqueous phase is extracted with CH2Cl2 (5 times 200 ml). After drying over MgSO4, the solvent is evaporated on a rotary evaporator to give the expected compound in the form of a brown powder (1.9 g).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[CH:8][CH:7]=1.[OH-].[Na+]>CO.[Pd]>[NH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH2:5][CH2:4][C:3]([OH:17])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(N)c2ccccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(CCC(=O)O)c2ccccc12
Yield: 101.4 %

Procedure:
A solution of 3-(4-amino-naphthalen-1-yl)-acrylic acid methyl ester (2.5 g, 11.0 mmol) and 10% Pd—C (320 mg) in methanol (100 mL) under an atmosphere of H2 for 18 hours then filtered. To the filtrate was added 19M NaOH (3 mL), and the resulting mixture heated to reflux for 30 minutes. The mixture was concentrated under reduced pressure taken up in water (10 mL) and the pH adjust to 4 with 12M HCl. The mixture was extracted with ethyl acetate (3×20 mL), then the combined ethyl acetate layers were washed with brine (1×10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to provide the titled compound (2.4 g, 100%).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[C:9](B(O)O)=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1>C(Cl)Cl>[Cl:3][C:4]1[C:9]([OH:1])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1
Reactant: OB(O)c1ccc(Cl)nc1Cl
Reactant: OO
Solvent: ClCCl
Product: Oc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
H2O2 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6-dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2Cl2 (30 mL) at 0° C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S2O3 aqueous (50 mL) and adjusted to pH<7 with 1N HCl. The mixture was extracted with EtOAc (40 mL×3). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H-NMR (CDCl3, 400 MHz) δ 7.30 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.70 (br, 1H). MS (M+H)+: 164/166/168.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]1[C:12]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:4]1C=CC=CC=1.[NH4+].C(=O)([O-])[O-:25].[K+].[K+].C1(=O)OCCO1>CO.[Pd]>[CH3:22][N:20]([CH3:21])[CH2:19][CH2:18][O:17][C:12]1[C:11]([O:10][CH2:3][CH2:4][OH:25])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CN(C)CCOc1ncccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: N#N
Agent: [K+]
Solvent: O=C1OCCO1
Solvent: CO
Product: CN(C)CCOc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a N2-flushed solution of 2-{[3-(benzyloxy)pyridin-2-yl]oxy}-N,N-dimethylethanamine (from Step 2; 8.4 g, 31.1 mmol) in MeOH (100 mL) was added 10% Pd/C (0.8 g) followed by ammonium fornate (6.3 g, 100 mmol). The mixture was stirred at 50° C. under an atmosphere of nitrogen for 2 h. The reaction was filtered through Celite® and the solvent was removed under reduced pressure to yield a semi-crystalline material that was used without further purification in the next synthetic step. The crude product was dissolved in dry DMF (50 mL), potassium carbonate (6.0 g, 43 mmol) was added and the mixture was heated at 150° C. for 20 minutes. Ethylene carbonate (4.1 g, 46 mmol) was added and the heating was continued for another 1.5 h. Solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a column of silica using CHCl3/MeOH/NH4OH (95:5:0.2) as eluent to give 3.28 g (31%) of the title product as a light brown oil. HRMS m/z calcd for C11H18N2O3 (M)+ 226.1317. found 226.1323.
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:18](=[O:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.O>CN(C)C=O>[CH3:21][C:22]1[N:26]([CH2:5][CH:6]2[C:18](=[O:19])[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]([CH3:20])[C:9]=3[CH2:8][CH2:7]2)[CH:25]=[CH:24][N:23]=1
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 6 h
Yield: 97 %

Procedure:
3-[(Dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (10 g, 34 mmol) and 2-methylimidazole (16.8 g, 205 mmol, 6.0 eq.) were suspended in mixture of water (75 ml) and dimethyl formamide (37.5 ml). The reaction mixture was heated to reflux (102–103° C.) and stirred for a further 6 hours at this temperature. The reaction mixture was cooled to 5–10° C. and stirred for half an hour at this temperature. The precipitated crude ondansetron base was filtered and washed with cold water (3×90 ml) and dried under vacuum at 60° C. to give ondansetron base (9.68 g, 96.4% yield) in 98.9% HPLC purity.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][NH2:15])([CH3:13])([CH3:12])[CH3:11].C(NNC(C)(C)C)(=O)C(C)(C)C>O>[C:1]([NH:15][NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)NNC(=O)C(C)(C)C
Solvent: O
Product: CC(C)(C)NNC(=O)c1ccccc1

Procedure:
1-benzoyl-2-tert.-butylhydrazine was prepared in 71% yeild by adding benzoyl chloride to a basic solution of t-butylhydrazine in water. The procedure was the same as that for preparing 1-pivaloyl-2-tert.-butylhydrazine in Example XIX A. The product has a melting range of 94-95° C. and its infra-red spectrum was consistent with that of the proposed structure.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCCCC1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(CC1(C(=O)O)CCCCCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a cold solution of formic acid (40.2 mL, 1.04 mol) in dichloromethane (150 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (15.2 mL, 160 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cycloheptanecarboxylic acid from Preparation 37 (16.1 mmol theoretical) in dichloromethane (150 mL) was added. The reaction was stirred at 0° C. for 3 h and was concentrated in vacuo. Water (150 mL) was added and the mixture was extracted with dichloromethane (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. Purification by preparative, reverse-phase HPLC provided the title compound (2.56 g, 52%). MH+306.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1)[CH3:2].C(N(CC)CC)C.C(Cl)[Cl:19]>CCOC(C)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:10][Cl:19])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C)[n+]([O-])c1
Reactant: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1ccc(CCl)nc1
Temperature: 20 °C

Procedure:
To a solution of 5-ethyl-2-methyl-pyridine-1-oxide (427 mg, 3.11 mmol, example 45c) in CH2Cl2 (2 mL) is added a solution (0.2 mL) of phosphorous (v) trichloride oxide (327 μL) in CH2Cl2 (2 mL). Added simultaneously the remaining phosphorous (v) trichloride oxide solution and a solution of triethylamine (488 μL) in CH2Cl2 (2 mL) at such a rate as to maintain a reflux. After the addition is complete, let reaction mixture cool to 20° C. and diluted with EtOAc. The organic layer is washed with sat. NaHCO3 soln., brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to provide the title compound. MS (ESI) 156 (M+H)+.