Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[F:23])=[O:6].[OH-].[NH4+:26]>C1COCC1>[F:23][C:9]1[CH:10]=[C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C

Procedure:
A solution of N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester (150 mg, 0.45 mmol) and ammonium hydroxide (2.0 mL) in THF (1.0 ml) in a sealed tube was heated at 55° C. for 6 h. After cooling to room temperature the mixture was evaporated and the title compound (60 mg, 42%) was purified by trituration from diethylether. MS: m/e=321.2 (M++H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=C[CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[N:29]1C=CC=C(OCC2CCCN2S(C2C=C3C(=CC=2)NC(=O)C3=O)(=O)=O)C=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:19][O:20][C:21]3[CH:26]=[N:29][CH:24]=[CH:23][CH:22]=3)(=[O:12])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28]
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc2C1=O
Product: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCCC3COc3cccnc3)ccc21
Yield: 55 %

Procedure:
1-Methyl-5-(2-(pyridin-3-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (21a) was prepared according to the same procedure for compound 11a, except using compound 20, and the crude product was purified with ethyl acetate to afford 55 mg (55%) of 21a as a yellow solid, mp 142.1-143.4° C. 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=2.7, 1H), 8.22 (dd, J=3.9 Hz, J=2.1 Hz, 1H), 8.08 (dd, J=8.4, J=2.1 Hz, 1H), 7.26 (s, 1H), 7.21 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 4.22 (m, 1H), 3.98 (m, 2H), 3.53 (m, 1H), 3.30 (s, 3H), 3.22 (m, 2H), 2.03 (m, 2H), 1.80 (m, 2H). LCMS m/e: 401.84 (M+H). Anal. Calcd for C19H19N3O5S: C, 56.85, H, 4.77; N, 10.47. Found: C, 56.48, H, 4.87; N, 10.19.
Reaction SMILES: CSC.B.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C@H:13]1[C:24](O)=[O:25])=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][C@H:13]1[CH2:24][OH:25])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 124.3 %

Procedure:
Borane-dimethyl sulfide (1.55 ml, 15.5 mmol) was added to a solution of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylic acid (2.39 g, 7.76 mmol) in THF (50 ml) under stirring at 0° C. The reaction mixture was stirred at the same temperature for 10 minutes and then at 50° C. for 2 hours. After cooling the reaction mixture to 0° C., water (30 ml) was added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 60 g), whereby from chloroform/methanol (50/1) eluate fractions, the title compound (2.83 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:10][Si:11]([CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([Cl:13])[Cl:12]
Reactant: ClCSc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](Cl)(Cl)CSc1ccccc1
Reaction time: 12 h
Yield: 36.7 %

Procedure:
As in Example 1, phenylthiomethyl chloride (3.31 g, 0.0209 mol), methyldichlorosilane (7.23 g, 0.0628 mol) and tetrabutylphosphonium chloride (0.615 g, 0.00209 mol) were put in a 50 mL stainless steel tube under nitrogen atmosphere. The reaction chamber was closed with a cover and the reaction was carried out at 120° C. for 12 hours. This reaction mixture was distilled under low pressure to give 1.82 g of methyl(phenylthiomethyl)dichlorosilane in 36.9% yield.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al].[H][H].[CH3:11][S:12]SC>>[CH3:11][S:12][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: Oc1ccccc1
Reactant: CSSC
Reactant: [H][H]
Agent: [Al]
Product: CSc1ccccc1O
Temperature: 170 °C
Yield: 40 %

Procedure:
A mixture of phenol (402 grams, 4.2 moles) and toluene (60 ml) was distilled to remove all toluene thereby yielding substantially anhydrous phenol. To the phenol, aluminum turnings (7.5 grams, 0.28 moles) were slowly added at 125° to 140° C. After cessation of hydrogen evolution, methyldisulfide (250 ml, 2.8 moles) was added and the resulting mixture was refluxed overnight at about 170° C. The mixture was then further heated at 170° to 185° C. for 3 hours. All volatile materials were then removed by vacuum evacuation at 20 mm Hg at 170° C. The unreacted phenol was removed by distillation through a 16"×1/2" heated column packed with glass helices. The residue, containing predominately the product ortho-(methylthio)-phenol, was distilled through a 7 cm Vigreax Column yielding 158 grams of the product (b.p. 115°-117° C. at 35 mm psig; 40.0 percent yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[N:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[C:42]([O:44][CH:45]([CH3:47])[CH3:46])[C:41]([NH2:48])=[CH:40][C:39]=2[CH3:49])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([NH:48][C:41]2[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[CH:43][C:38]([CH:35]3[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[CH2:37][CH2:36]3)=[C:39]([CH3:49])[CH:40]=2)=[N:3][C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])(=[O:11])[CH3:10]
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)c1c(Cl)nc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Solvent: CCO
Product: CC(=O)c1c(Cl)nc(Nc2cc(C)c(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC(C)C)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 130 °C

Procedure:
To a solution of 1-(2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)ethanone (113 mg, 0.29 mmol) in EtOH (2 mL) was added tert-butyl-4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate (203 mg, 0.58 mmol), and the reaction mixture was heated at 130° C. for 30 min The reaction was concentrated in vacuo, followed by purification by silica gel chromatography (EtOAC/Hexanes: 3/7) to afford Tert-butyl 4-(4-(5-acetyl-4-chloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-2-ylamino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate. MS (ES+): 700.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][NH:13][CH3:14])=[CH:5]2.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:20][C:19]=2[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][N:13]([CH3:14])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:21]1[CH:22]=[N:23][C:24]3[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=3[CH:20]=1)=[CH:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cc2cc(F)ccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc2cc(F)ccc2n1C)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of (5-fluoro-1-methyl-1H-indol-2-yl)-N-methylmethanamine (70 mg, 0.36 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (72 mg, 0.33 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol), diisopropylethylamine (191 uL, 1.1 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (72 mg, 0.36 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield title compound as a pale brown solid (97 mg, 76%): 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.40 (s, 1H), 8.08-8.18 (m, 1H), 7.91-8.08 (m, 1H), 7.52-7.68 (m, 1H), 7.37-7.52 (m, 1H), 7.13-7.36 (m, 2H), 6.42 (s, 1H), 4.86-5.06 (rotamers, 2s, 2H), 3.71 (s, 3H), 3.14 (m, 2H), 2.81-2.97 (m, 2H), 2.75 (s, 3H); MS (ESI) m/e 393 (C22H21FN4O2+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC=CC=2)(=O)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][C:25]#[CH:26])[CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][C:25]#[C:26][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:19][CH3:20])[CH3:22]
Reactant: C#CCN(CC)CC
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)CC#Cc1ccc(C#N)cc1OC

Procedure:
This product was prepared from benzene-sulfonic acid 4-cyano-2-methoxy-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 1:1; yield (90 mg, 74%); 1H NMR δ (CDCl3): 7.52 (d, J=8.35 Hz, 1H), 7.21 (d, J=8.21 Hz, 1H), 7.11 (s, 1H), 3.81 (s, 3H), 2.69 (t, J=7.22 Hz, 2H), 2.58 (t, J=7.21 Hz, 2H), 1.99 (p, J=7.11 Hz, 2H); LCMS m/z: 242.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].S(=O)(=O)(O)[OH:5].[CH2:9]([O:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#N)[CH:16]=[CH:17][CH:18]=1)[CH2:10][CH3:11]>O.CCOCC>[CH2:1]([O:3][C:20](=[O:5])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:9][CH2:10][CH3:11])[CH:14]=1)[CH3:2]
Reactant: CCO
Reactant: CCCOc1cccc(CC#N)c1
Reactant: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCCOc1cccc(CC(=O)OCC)c1

Procedure:
A mixture of ethanol (3.9 g), water (0.2 g), conc.sulphuric acid (3.9 g) and 3-propyloxyphenylacetonitrile (3.5 g; 20 mmol) was heated under reflux during 6 hours. After cooling, ether (20 ml) and water (20 ml) were added and the mixture was stirred. The phases were separated and the ethereal extract washed with 10% potassium bicarbonate (2×20 ml), dried over Na2SO4, filtered and evaporated to dryness to give a pale tan oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:17])[C:9](N1CCOCC1)=[O:10].[Mg].[Cl-].[NH4+].O.Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29]>O1CCCC1.C(Br)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:9](=[O:10])[C@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:17]
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In tetrahydrofuran (100 ml) were dissolved 1-bromo-2-fluorobenzene (5.6 ml), ethyl bromide (0.37 ml) and 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (11.3 g). To the mixture was added magnesium (turnings, 1.33 g). The mixture was stirred for 2 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (40 ml) and water (40 ml). The mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1) to give (2R)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (8.7 g) as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.[N+:26]([C:29]1[NH:30][CH:31]=[C:32]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[N:33]=1)([O-])=O.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[N:35]1([CH2:34][C:32]2[N:33]=[C:29]([NH:26][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[F:12])=[CH:14][CH:15]=3)=[O:24])[NH:30][CH:31]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=[N+]([O-])c1nc(CN2CCCC2)c[nH]1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(CN4CCCC4)c[nH]3)c3nccnc23)c1F
Temperature: 65 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 6 h at 65° C. and using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1). 2-Nitro-4-pyrrolidin-1-ylmethyl-1H-imidazole (Step 19.1) instead of 2-nitroimidazole was used in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 495.0 [M+H]+; tR=3.28 min (System 1); TLC: Rf=0.08 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]=O)[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH2:27][N:32]([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(C=O)CC3)c2-c2ccccc2)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CC1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarbaldehyde (Examples 14-17 General Procedure, Step A, 0.51 g) in dichloromethane (20 mL) is added sequentially a solution consisting of dimethylamine in tetrahydrofuran (2.0 M, 2 mL) followed by sodium triacetoxyborohydride (0.75 g.) The mixture is agitated overnight at room temperature under a nitrogen atmosphere. The mixture is diluted with dichloromethane (20 mL) and is washed twice with brine solution. The organic layer is separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography to afford the synthetic intermediate (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropylmethyl)-dimethyl-amine (0.251 g)
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7].ClC(Cl)(O[C:44](=[O:50])OC(Cl)(Cl)Cl)Cl.[N-:52]=[N+:53]=[N-:54].[Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[K+]>C(Cl)Cl.O.N1C=CC=CC=1>[CH3:39][Si:2]([CH3:38])([CH3:1])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([N:27]3[C:44](=[O:50])[NH:54][N:53]=[N:52]3)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(-n4nn[nH]c4=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 206.3 %

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (173 mg in 5 mL dry methylene chloride) at 0° C. was added triphosgene (36 mg) followed by 0.073 mL of pyridine and the mixture stirred for 2 hour at 0° C. At this time the reaction was quenched by the addition water, washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude isocyante. This was solvated in 2 mL methylene chloride and added by cannula to a freshly prepared solution of aluminum azide (0.6 mmols in 5 mL tetrahydrofuran) and the resulting mixture heated to reflux on an oil bath. After 20 hours, the mixture was added to 10 mL of an iced, 1M potassium tartarate solution and stirred for 20 minutes. This was then diluted with water and extracted with ethyl acetate. The organic portion was washed successively with 1 M potassium tartarate, saturated ammonium chloride, water and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (chloroform:10% acetic acid in methanol, 97:3) gave the title compound (160 mg).
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=O.[CH3:17][NH:18]N>C(O)C>[CH3:17][N:18]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=[N:2]1.[CH3:1][N:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:18]1
Reactant: CNN
Reactant: CN(C)C=CC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: Cn1ccc(-c2ccccc2[N+](=O)[O-])n1
Product: Cn1nccc1-c1ccccc1[N+](=O)[O-]

Procedure:
3-(Dimethylamino)-2′-nitroacrylophenone (3.0 g, 13.5 mmol) in absolute ethanol (25 mL) was treated with methylhydrazine (800 μL, 20 mmol) and heated to reflux for 5 hours. The solvent was distilled off, and the residue chromatographed on silica eluting with 2:1 hexane:ethyl acetate to provide 1-methyl-5-(2-nitrophenyl)pyrazole (1.9 g) and 1-methyl-3-(2-nitrophenyl)pyrazole (350 mg).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:32]=[CH:31][C:7]([C:8]([C:10]2[C:11]([CH3:30])=[C:12]([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1>CO.[Ni]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[C:11]([CH3:30])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: Cc1c(C=CCCCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Product: Cc1c(CCCCCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 63.9 %

Procedure:
Hydrogen was passed through a solution of 2.07 g of the acid of Step A in 60 ml of methanol in the presence of 3 g of Raney nickel for 2 hours and the mixture was then filtered. The filtrate was evaporated to dryness and the residue was crystallized from isopropyl ether to obtain 1.328 g of 12-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-dodecanoic acid melting at 79° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[CH:7]2)([O-:3])=[O:2].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH2:28]([N:29]([CH2:32][CH3:33])[CH2:30][CH2:31][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1)[CH3:27]
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cc3ccc(OC(F)(F)F)cc3)cc2c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Yield: 79.2 %

Procedure:
Compound 8 (77 mg, 0.229 mmol), 2-chloro-N,N-diethylethanamine hydrochloride (43.3 mg, 0.252 mmol), potassium carbonate (95 mg, 0.687 mmol) and anhydrous dimethylformamide (5 mL) were charged to a small, argon purged flask fitted with a magnetic stirbar and resulting solution heated in an oil bath at 65° C. for 2 hours. After cooling to room temperature the mixture was diluted with H2O and ethyl acetate, transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude solid. The crude product was purified via chromatography on silica gel (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) to yield compound 9 (79 mg, 79.2%) as a yellow solid. 1H NMR (DMSO-d6) δ 0.77 (t, 6H, J=7.1 Hz), 2.39 (q, 4H, J=7.2 Hz), 2.50 (m, 2H), 4.19 (t, 2H, J=6.5 Hz), 4.31 (s, 2H), 6.40 (s, 1H), 7.33-7.41 (m, 4H), 7.58 (d, 1H, J=9.1 Hz), 7.99 (dd, 1H, J=9.0, 2.2 Hz), 8.48 (d, 1H, J=2.3 Hz).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:25])[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([CH3:24])[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCC(=O)O)nc(C)c2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3,8-dimethyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (145 mg, 0.43 mmol), glycine (3.22 g, 43 mmol) and NaOMe solution (68 mL, 34 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 108 mg of the title compound as a white solid. MS: (+) m/z 382.08 (M+1).
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: COC(=O)c1ccccc1CN1CCN(c2nc(C)c(C(=O)NCc3ccccc3)s2)C1=O
Yield: 52 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with methyl 2-(bromomethyl)benzoate (prepared according to Dvornikovs, V., and Smithrud, D. B., J. Org. Chem., (2002), 67, 2160-2167) to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 52% yield: mp 130-133° C. (dichloromethane/hexanes): NMR (300 MHz, CDCl3) δ 7.97-7.94 (m, 1H), 7.51-7.27 (m, 8H), 5.95 (br s, 1H), 4.90 (s, 2H), 4.56 (d, J=5.6 Hz, 2H), 4.10-4.05 (m, 2H), 3.90 (s, 3H), 3.56-3.51 (m, 2H), 2.62 (s, 3H); MS (ES+) m/z 465.2 (M+1).