Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][CH2:15][CH:16]([C:19]([O:21]C)=[O:20])[CH2:17][CH2:18][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][CH2:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][CH2:18][C:12]=3[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCc2onc(-c3ccc(OC)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2noc3c2CCC(C(=O)O)CC3)cc1
Temperature: 20 °C
Reaction time: 66 h
Yield: 67.8 %

Procedure:
1.7 g (0.00565 mol) of methyl 5,6,7,8-tetrahydro-3-(4-methoxyphenyl)-4H-cyclohept[d]isoxazole-6-carboxylate were dissolved in 20 ml of methanol. 1 g of potassium hydroxide in 3 ml of water was added and the mixture was stirred at 20° C. for 66 hours. The methanol was removed by evaporation and an excess of water was added. The mixture was acidified with dilute hydrochloric acid and the resulting precipitate was filtered off, washed with water and dried. Crystallization from ethyl acetate/hexane gave 1.1 g of 5,6,7,8-tetrahydro-3-(4-methoxyphenyl)-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 147°-148° C.
Reaction SMILES: [F:1][C:2]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]1.FC(F)(F)C([O-])=O.[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH3+:37].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[O:27]=[C:28]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]1[CH2:34][CH2:35][CH2:36][NH:37][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:2]2([F:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3]2)=[CH:19][CH:18]=1
Reactant: [NH3+]CCCN1C(=O)C=CC1=O
Reactant: O=C(O)c1ccc(CC2(F)C#CCCCCC2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C=CC1=O)c1ccc(CC2(F)C#CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
TEA (0.508 mL, 3.65 mmol) was added to a solution of cyclooctyne 3b (0.200 g, 0.768 mmol), amine 13 (0.235 g, 0.875 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (HATU, 0.305 g, 0.802 mmol), and 1-hydroxybenzotriazole (HOBT, 0.123 g, 0.802 mmol) in CH2Cl2 (3 mL) at rt. The reaction was stirred for 15 min at rt, quenched with H2O (10 mL), and diluted with CH2Cl2 (50 mL). The organic layer was washed with 1 N HCl (3×50 mL), saturated NaHCO3 (3×50 mL), and brine (2×25 mL) and dried over MgSO4. Chromatography of the crude product (2:1 to 1:1 hexanes/EtOAc) yielded the desired product as a white solid (0.198 g, 65%, Rf=0.30 in 1:1 hexanes/EtOAc), mp 122.0-124.0° C. (dec). IR: 3413, 2931, 2854, 2222, 1705, 1640 cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.39 (m, 1H), 1.74 (m, 2H), 1.81-2.06 (m, 6H), 2.14-2.32 (m, 3H), 3.05 (d, 1H, J=2.8 Hz), 3.09 (s, 1H), 3.40 (q, 2H, J=6.4 Hz), 3.67 (t, 2H, J=6.0 Hz), 6.75 (s, 2H), 6.93 (m, 1H), 7.41 (d, 2H, J=8.0 Hz), 7.81 (d, 2H, J=8.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 20.5, 26.0, 28.1, 29.4, 34.0, 34.8, 36.2, 44.6 (d, J=25.0 Hz), 47.8 (d, J=24.0 Hz), 90.7 (d, J=32.0 Hz), 95.3 (d, J=174.0 Hz), 104.5 (d, J=10.0 Hz), 126.7, 130.5, 132.9, 134.2, 139.6, 167.1, 171.1. 19F NMR (CDCl3, 376 MHz): δ −139.0 (m). FAB-HRMS: Calcd. for C23H26N2O3F+[M+H]+: 397.1927. found: 397.1920.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:27][CH3:28].[Li+].[OH-]>>[CH2:30]([O:29][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:27][CH3:28])[C:3]([OH:32])=[O:2])[CH3:31]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1CC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1CC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-[2-ethyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as colorless liquid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:33]O>>[CH3:33][O:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Nc2nccc(-c3ccnc(NCCCO)c3)n2)c1
Temperature: 25 °C

Procedure:
2.0 g (5.4 mmol) of N-[3-carboxy-phenyl]-4-(2-(3-hydroxy-propyl-amino)-4-pyridyl)-2-pyrimidineamine and 0.28 ml (5.4 mmol) of conc. sulfuric acid are boiled under RF in 150 ml of methanol for 24 h. After cooling to RT, the reaction mixture is concentrated to half the volume, diluted with 100 ml of ethyl acetate and extracted twice with 50 ml of buffer (pH 7) each time. The organic phase is dried (Na2SO4) and concentrated. Crystallisation (methylene chloride/methanol) gives N-[3-methoxycarbonylphenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine; m.p. 162°-163°, FAB-MS: 380 (M+ +H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:7]1
Reactant: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-butyl 2-methyl-4-(4-phenylphthalazin-1-yl)piperazine-1-carboxylate (2.05 g, 5.07 mmol) was dissolved in dichloromethane (75 mL). Trifluoroacetic acid (15 mL) was added and the reaction stirred at rt for 1.5 hours. The reaction was added to saturated NaHCO3 (150 mL) and neutralized by the portion wise addition of solid NaHCO3. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a pale yellow foam. MS (M+H)+=305.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:12]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnc(OC)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OC)c(N)c1
Yield: 92.7 %

Procedure:
A solution of methyl 6-methoxy-5-nitronicotinate (5.4 g) in ethyl acetate (120 mL) is hydrogenated using 5% palladium on carbon (1 g) as catalyst. When hydrogen uptake ceased the mixture is filtered through a pad of diatomaceous earth and the filtrate evaporated. The residue is triturated with n-pentane and methyl t-butyl ether to give methyl 5-amino-6-methoxynicotinoate (4.3 g) as a light-brown solid, m.p. 108–9° C. [Elemental analysis:—C, 52.99; H, 5.49; N, 15.25%. calculated:—C, 52.74; H, 5.53; N, 15.38%.]
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)[CH2:30][N:29]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:28][CH:27]2[CH2:51]OS(C)(=O)=O)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH:27]([CH2:51][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:28][N:29]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:30][CH:31]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:24][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Cn2cncn2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A solution of 22 mg (0.32 mmol) of 1,2,4-triazole in 5 ml of DMF was cooled to 0° C. and treated with 15 mg (0.29 mmol) of sodium hydride (50% dispersion in refined oil). Subsequently, the mixture was left to warm to room temperature and was stirred for a further 1 hour. 70 mg (0.105 mmol) of tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methane-sulphonyloxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate were added to this solution. The reaction mixture was heated to 100° C. for 24 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was partitioned between water and methylene chloride and the organic phase was separated, dried over sodium sulphate and evaporated. For purification, the crude product (70 mg) was chromatographed on silica gel using a 98:2 mixture of methylene chloride and methanol as the eluent. There were obtained 52 mg (77% of theory) of tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-[1,2,4]triazol-1-ylmethyl-piperidine-1-carboxylate as a colourless solid; MS: 663 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:8](F)=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].[CH2:16]([O:23][C:24]([C:26]1[CH:32]=[CH:31][C:29]([O-:30])=[CH:28][CH:27]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[K+].[K]>CN(C)C=O>[CH2:16]([O:23][C:24]([C:26]1[CH:27]=[CH:28][C:29]([O:30][C:8]2[C:7]([F:10])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=2[C:2]([F:1])([F:15])[F:14])=[CH:31][CH:32]=1)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)c1ccc([O-])cc1
Reactant: Fc1c(F)c(F)c(C(F)(F)F)c(F)c1F
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(F)c(F)c2C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
35.4 g of octafluorotoluene (0.15 mol) are dissolved in 400 ml of dimethylformamide, the solution is cooled to 0° C. using a cryostat, and a solution of 40 g of potassium 4-benzyloxycarbonylphenoxide (0.15 mol) in 300 ml of dimethylformamide is then added drop wise over the course of 2 hours. After 24 hours at 0° C., the potassium salt has reacted. The dimethylformamide is then removed in a rotary evaporator, the residue is taken up in a little tetrahydrofuran, and the solution is filtered through a silica-gel column. The clear solution obtained is evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then stirred in n-hexane, filtered off through a fluted filter and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([O:16][CH3:21])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2

Procedure:
4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid, 25.5 g, synthesized according to the method of D.E. Aultz, et al. [J. Med. Chem., 20, 456 (1977)] and 0.9 g of p-toluenesulfonic acid monohydrate were heated under reflux for 3 hours in 600 ml of methanol. The solvent was distilled off under reduced pressure and the resulting residue was extracted with 500 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate= 3:1) to give 24.9 g of methyl 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate as light yellow solids.
Reaction SMILES: [C:1]1([C:11]2[CH:23]=[C:14]3[NH:15][CH:16]=[C:17](C(O)=O)[C:18](=[O:19])[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CS(C)=O.[Cl-].[Na+]>O>[C:1]1([C:11]2[CH:23]=[C:14]3[NH:15][CH:16]=[CH:17][C:18](=[O:19])[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c[nH]c2cc(-c3cccc4ccccc34)nn2c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc[nH]c2cc(-c3cccc4ccccc34)nn12
Yield: 86.5 %

Procedure:
2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid (2.00 g, 6.55 mmol) is stirred in dimethyl sulfoxide (5.06 mL, 71.2 mol) in a 350 mL sealed reaction vessel. Sodium chloride (0.545 g, 9.33 mol) is dissolved in water (2.26 mL) and added to the reaction mixture. The reaction is heated at 150° C. for 3 days during which time an additional 8 mL of DMSO is added along with 15 mL of additional water. The resulting precipitate is collected in a Buchner funnel to provide 2-(naphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.48 g, 87%). LCMS: (AA) M+1 262.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.C([N-]C(C)C)(C)C>C1COCC1.CN(C=O)C>[C:1]([NH2:15])(=[O:12])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(C)[N-]C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc(C(=O)O)c1
Temperature: 20 °C
Reaction time: 13.5 h
Yield: 80 %

Procedure:
These compounds are preferably prepared as set forth as follows. An ester, preferably the monomethyl ester of isophthalic acid or methyl 5-methyl-1,3-isophthalate is dissolved in a THF/DMF mixture. 1,1′-Carbonyldiimidazole is added at 20-25 degrees C. The diisopropyl amide is added. After 3-24 hr of stirring at 20 degrees C. to the reflux temperature of the solvent, the reaction mixture is partitioned between saturated aqueous ammonium chloride and a water immiscible organic solvent such as ethyl acetate. The aqueous layer is separated and extracted twice more with the organic solvent (ethyl acetate). The solvent removed and the residue thus obtained is basified to yield the isophthalic amide (IIa) in 80% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCN(C(=O)OC(C)(C)C)n1cccc1

Procedure:
Prepared according to the N-alkylation condition used in Example 1 step b) from starting materials pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 1-iodobutane (2.0 eq.) and sodium hydride (1.3 eq.). 1H NMR (CDCl3, δ in ppm): 6.60 (m, 2H), 6.10 (m, 2H), 3.64 (t, 2H, J=7.0 Hz), 1.42 (s, 9H), 1.55-1.26 (m, 4H), 0.92 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl>CN(C=O)C.C1COCC1>[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29][N:9]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:6]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106 %

Procedure:
The diester 1 from Step (a) (23 g, MW 240, 0.096 mol) was dissolved in 300 ml DMF. Potassium t-butoxide (100 ml of a 1M solution in dry THF) was added through a syringe. The solution was stirred for 15 min at 25° C. [2-(trimethylsilyl)ethoxy]methyl chloride (SEM-chloride, 18.6 ml, 1.1 eq, MW 166, d 0.94) was added and a precipitate instantly formed. The reaction was stirred for 90 min at 25° C. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic extract was dried over K2CO3 and concentrated. By TLC (SiO2, MeOH-CHCl3 /1-10) a single major spot was observed. This crude product (38 g, 106% yield) was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7](Cl)=[O:8].[CH3:23][N:24]([CH3:37])[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH2:32][CH2:31]2)(=[O:27])=[O:26]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7]([N:33]1[C:34]2[C:30](=[CH:29][C:28]([S:25]([N:24]([CH3:37])[CH3:23])(=[O:26])=[O:27])=[CH:36][CH:35]=2)[CH2:31][CH2:32]1)=[O:8]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Cl)c2)c1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CCN2
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CCN2C(=O)COc1cc(Cl)cc(Oc2cc(Cl)cc(C#N)c2)c1

Procedure:
41 mg (0.115 mmol) of [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetyl chloride (5-4) and 26 mg (0.115 mmol) of N,N-dimethylindoline-5-sulfonamide (23-1) were refluxed in benzene. When the reaction was complete the benzene was evaporated off and the residue was purified on a silica column eluted with EtOAc:hexanes (3:97 to 1:1). Recovered the desired compound 23-2. HRMS: measured 546.0665; theoretical 546.0652. 1H NMR (CDCl3): 2.70 (s, 6H), 3.35 (t, 2H), 4.23 (t, 2H), 4.78 (bs, 2H), 6.59 (t, 1H), 6.68 (t, 1H), 6.83 (m, 1H), 7.15 (m, 1H), 7.24 (m, 1H), 7.39 (m, 1H), 7.63 (bs, 1H), 7.66 (bd, 1H), 8.34 (bd, 1H).
Reaction SMILES: [C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[C:7]([N+:20]([O-:22])=[O:21])[C:6]([F:9])=[CH:5][C:4]=1[C:10]1([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 161.8 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate (21.5 g, 81 mmol) in 10 mL of concentrated sulfuric acid was added drop-wise to ice cold mixture of concentrated sulfuric acid (120 mL) and KNO3 (8.2 g, 81 mmol) at 0° C. After addition, the reaction mixture was stirred for 15 min while warming to ambient temperature, poured onto crushed ice, extracted with ethyl acetate (120 mL×3). The organic layer was washed with brine, dried over MgSO4, and evaporated under vacuum. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)-5-nitrophenyl methyl carbonate as a yellow oil (40.8 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=6.8 Hz, 1H), 7.34 (d, J=13.2 Hz, 1H), 3.97 (s, 1H), 2.02-1.96 (m, 2H), 1.73-1.45 (m, 8H), 1.39 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:14]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17].S(=O)(=O)(O)O>O>[C:19]1([C:16](=[O:18])[CH2:17][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCC(C)(C)C
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CCCCCC(=O)CC(=O)c1ccccc1
Temperature: 150 °C
Yield: 70.4 %

Procedure:
Sodium hydride (200 g, 5 mol, 60% dispersion in mineral oil) was placed in a 5-liter four-neck round-bottomed flask equipped with a mechanical stirrer, a condenser and a thermometer under a nitrogen atmosphere. To the sodium hydride was added xylenes (600 g, 5.65 mol) and methyl neo-decanoate (1163 g, 6.25 mol) in a dropping funnel at ambient temperature, while carefully watching the pot temperature and nitrogen gas flow. The resulting slurry was heated to 150° C. while vigorously stirring (300 rpm or so) under a nitrogen atmosphere, and acetophenone (301 g, 2.5 mol) was introduced in portions over 3h maintaining the same temperature. After completion of the addition, the mixture was stirred an additional 30 min. The mixture was then cooled to ambient temperature, and treated with cold water (100 mL) and then cold aqueous sulfuric acid (2 liter of 125 g H2SO4 per liter) keeping the temperature below 30° C. After transfer of the solution into a 5-liter separatory funnel, aqueous phase was separated and the remaining organic layer washed with water (800 mL×3) followed by brine (NaCl saturated, 500 mL). Most of low boiling components (mostly xylenes) were removed by a rotary evaporator (80° C. at 10-20 mbar). Distillation using a 15-cm Vigreux distill column in vacuo gave 1-phenyl-3-neononyl-1,3-propanedione (481 g, 1.76 mol) in 61% yield, after combining the fractions distilled at 185-196° C. at 1.5-2 mmHg.
Reaction SMILES: Cl.[CH:2]1[C:7]2[S:8][C:9]3[NH:10][C:11]4[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=4[N:13]=[C:14]([NH2:16])[C:15]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][C@H:25]1[CH2:30]N[CH2:28][CH2:27][NH:26]1>>[CH3:21][O:22][CH2:23][CH2:24][C@@H:25]1[NH:26][CH2:27][CH2:28][N:16]([C:14]2[C:15]3[C:6]4[CH:5]=[CH:4][CH:3]=[CH:2][C:7]=4[S:8][C:9]=3[NH:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:30]1
Reactant: NC1=Nc2ccccc2Nc2sc3ccccc3c21
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc4ccccc4c32)CCN1
Temperature: 115 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
Following the method of Example 380, using 11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.40 g, 1.3 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (0.38 g, 2.7 mmol), stirring at 115° C. for 24 hours, wash the separated organic layer with 0.1 N NaOH (2×), and extract the combined aqueous layers with ethyl acetate. Combine the organics and wash them with a saturated solution of sodium chloride (3×), and then dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of 5% 2M ammonia in methanol, in dichloromethane (in dichloromethane) to give the title compound (0.075 g). Mass spectrum (APCI+, m/e): 393 (M+1).