Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[H-].[Na+].I[CH3:14]>C1COCC1.O>[CH3:14][O:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCc1cccs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCCc1cccs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 4-thiophen-2-yl-butan-1-ol (4.55 g, 29.09 mmol) in 20 ml of THF was carefully added to a stirred suspension of oil-free sodium hydride (1.05 g, 43.75 mmol) in 15 ml of THF. When the addition was complete, the mixture was heated to 50° C. and stirring continued for 1 hour. Iodomethane (2.7 ml, 43.75 mmol) was then added and the turbid solution was stirred at 50° C. for another 2 hours. After cooling, a few drops of water were added and the mixture was partitioned between 1N-HCl and ether. The organic layer was washed with saturated sodium bicarbonate solution and brine. Drying over sodium sulfate and careful evaporation (product is volatile) gave a pale yellow oil. Yield: 4.45 g (90%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=[O:10])[O:9][CH2:8][CH2:7]1>>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:8][CH2:7][C:6]([OH:10])=[O:9]
Reactant: OCCCBr
Reactant: O=C1CCO1
Product: O=C(O)CCOCCCBr
Temperature: 80 °C
Yield: 63.6 %

Procedure:
To a flask was added 3-bromopropanol (25 mL, 0.28 mol) and β-propiolactone (5.0 mL, 0.07 mol) and the resulting mixture was heated to 80° C. for 14 h. The reaction mixture was then cooled to room temperature and the excess 3-bromopropanol was removed under reduced pressure. The crude product was dissolved in dichloromethane (300 mL) and extracted with 1 N sodium hydroxide (300 mL). The aqueous layer was then acidified to pH 2 and extracted with dichloromethane (300 mL). The organic layer was then washed with water (200 mL), brine (200 mL), dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to give 9.4 g of the title intermediate, which was used without further purification (64% yield).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[K+]>C(O)C.O>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:15][CH:17]1[CH2:18][O:19]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(O)c1
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)c1cccc(OCC2CO2)c1

Procedure:
19.4 g. (0.1 mole) 3-(1-hydroxyhexyl)-phenol and 28.6 g. epichlorohydrin are dissolved in 25 ml. ethanol and heated to the boil. A solution of 6.6 g. potassium hydroxide in 3 ml. water and 25 ml. ethanol is then added dropwise thereto in the course of 15 minutes. The reaction mixture is boiled under reflux for 2 hours, the solvent is then distilled off and the residue is taken up in water. Extraction is carried out with ethyl acetate, the ethyl acetate phase is washed twice with aqueous sodium hydroxide solution and water, dried and evaporated to give 22.4 g. (89% of theory) of the title compound in the form of an oil.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[CH2:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45](=[O:75])[NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:61]=[C:60]5[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:70])[CH3:69])[C:64]([O:66]C)=[O:65])[C:59]5=[O:62])=[CH:55][CH:54]=4)=[C:49]([C:71]([F:74])([F:73])[F:72])[CH:48]=3)=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>>[CH2:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45](=[O:75])[NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:61]=[C:60]5[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:70])[CH3:69])[C:64]([OH:66])=[O:65])[C:59]5=[O:62])=[CH:55][CH:54]=4)=[C:49]([C:71]([F:72])([F:73])[F:74])[CH:48]=3)=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)cc3C(F)(F)F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)cc3C(F)(F)F)cc2C1=O
Yield: 97 %

Procedure:
The compound of example 420 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 419.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:7]2=[O:24])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[CH3:31][Si:32](C(O)C)([CH3:34])[CH3:33]>CCOCC.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:4]1(=[O:25])[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:32]([CH3:34])([CH3:33])[CH3:31])=[O:20])[C:7]2=[O:24])[C:1](=[O:30])[C:2]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:3]12
Reactant: CC(O)[Si](C)(C)C
Reactant: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOCC
Product: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1

Procedure:
(R)-Dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester is heated in trimethylsilylethanol in the presence of titanium (IV) ethoxide. Upon completion of the reaction, the reaction mixture is diluted with ether, washed with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated in vacuo. The residue is purified chromatographically on silica gel to yield (R)-dihydro-5-phthalimido-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([OH:12])=[CH:9][CH:8]=[CH:7]2.[CH3:13][O:14]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:12][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=1
Reactant: COC(Cl)Cl
Reactant: Cc1cccc2cccc(O)c12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cccc2c(C=O)ccc(O)c12
Reaction time: 0.17 h

Procedure:
101.9 g of 8-methyl-1-naphthol was dissolved in 815 ml of dichloromethane, in which 141.6 ml of titanium tetrachloride was gradually dropped under ice-cooling conditions. Thereafter, 93.7 ml of dichloromethyl methyl ether was gradually dropped under ice-cooling conditions. After agitation for 10 minutes, 200 ml of water was gently dropped under ice-cooling conditions. The reaction solution was extracted with ethyl acetate and the resultant organic phase was washed with water. After drying with anhydrous magnesium sulfate, the solvent was distilled off and the resultant crystals were washed with chloroform to obtain 80 g of the captioned compound as brown crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cccnc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(C3C(=O)Nc4ncccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
A solution of 7-azaoxindole (284 mg, 2.1 mmol), (prepared as described for the starting material in Example 2), in THF (10 mn) was added to a suspension of sodium hydride (112 mg, 2.8 mmol, prewashed with petroleum ether) in THF (6 ml). After stirring for 20 minutes at ambient temperature, a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (238 mg, 0.7 mmol) in a mixture of THF (3 ml) and DMF (1 ml) was added. After stirring for 1 hour at 65° C., the volatiles were removed by evaporation. The residue was partitioned between water and ether. The aqueous layer was separated and adjusted to pH7 with 2M hydrochloric acid. After evaporation of water, the precipitate was triturated with ether, collected by filtration, washed with ether, and dried under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (9515 followed by 90110). After evaporation of the solvent, the residue was suspended in methylene chloride/methanol (1/1) and 3M hydrogen chloride in ether was added. After removal of the solvent by evaporation, the solid was collected by filtration, washed with ether and dried under vacuum to give 4-(7-azaoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 51%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=2)O1.[NH2:24][C:25]1[C:26]([C:34]#[N:35])=[N:27][C:28](Cl)=[CH:29][C:30]=1[NH:31][CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:24][C:25]1[C:26]([C:34]#[N:35])=[N:27][C:28]([C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:10]=2)=[CH:29][C:30]=1[NH:31][CH3:32]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CC1(C)OB(c2ccc(OCCO)c(C(F)(F)F)c2)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cc(-c2ccc(OCCO)c(C(F)(F)F)c2)nc(C#N)c1N
Yield: 146.1 %

Procedure:
2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)ethanol (7.1 g), 3-amino-6-chloro-4-(methylamino)picolinonitrile (21.38 mmol, 3.90 g), potassium phosphate, tribasic (13.61 g), tricyclohexylphosohine (0.719 g), and tris(dibenzylideneacetone)dipalladium(0) (0.979 g) were dissolved in Dioxane (100 ml) and Water (40.0 ml) and stirred under nitrogen at 100° C. for 3 hrs. The mixture was diluted with ethyl acetate and filtered through celite. Filtrate was washed with water (300 ml), organic layer extracted and concentrated in vacuo to give crude 3-amino-6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (11 g). 1H NMR (MeOH) δ: 8.07 (s, 1H), 8.00 (d, 1H), 7.70 (m, 1H), 7.42 (m, 1H), 7.25 (m, 1H), 4.20 (t, 2.5), 3.93 (t, 2.5), 3.66 (s, 1.5), 2.98 (s, 3.5). MS m/z 353 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]([CH2:26][CH3:27])[C:8]([N:10]1[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH3:2].[CH3:29][O:30][CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:29][O:30][CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36]([O:25][C@@H:23]2[CH2:24][N:10]([C:8]([N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH2:26][CH3:27])=[O:9])[C@H:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:22]2)=[CH:35][CH:34]=1
Reactant: COC=Cc1ccc(O)cc1
Reactant: CCOC(=O)CCN(CC)C(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2ccc(C=COC)cc2)C[C@H]1C(=O)OCc1ccccc1

Procedure:
Equimolar amounts of (trans)-1-[[(3-ethoxy-3-oxopropyl)ethylamino]carbonyl]-4-hydroxy-L-proline, phenylmethyl ester and 4-(2-methoxyethenyl)phenol are reacted in the presence of triphenylphosphine and diethylazodicarboxylate to give (cis)-4-[4-(2-methoxyethenyl)phenoxy]-1-[[(3-ethoxy-3-oxopropyl)ethylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C=CCCCCCCCC>>[C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCC=CC(=O)O
Product: CCCCCCCCC=CCCCCCCCCCC(=O)O

Procedure:
14-eicosenoic acid; 2-undecenoic acid;
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([O:24][CH3:25])[C:16]([CH2:26][CH3:27])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:29].[Cl-].[NH4+]>CN(C=O)C.O>[C:3]1([S:9]([CH:12]([C:13]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([O:24][CH3:25])[C:16]([CH2:26][CH3:27])=[CH:15][CH:14]=2)[CH3:29])(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(CC)c1OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(C)S(=O)(=O)c2ccccc2)ccc(CC)c1OC

Procedure:
Sodium hydride (60% oil dispersion, 0.009 g) was added to a stirred and cooled solution of ethyl 6-(benzenesulphonylmethyl)-3-ethyl-2-methoxybenzoate (Intermediate 20, 0.075 g) in DMF (1 ml) at 0° C. under an atmosphere of nitrogen. After stirring for 15 minutes iodomethane (0.014 ml) was added and the resultant mixture was stirred at room temperature for 1 hour. Ammonium chloride (saturated aqueous solution) was added followed by water and the mixture was extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give ethyl 6-(1-benzenesulphonylethyl)-3-ethyl-2-methoxybenzoate (0.063 g) as a colourless oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C1COCC1.[H-].[Na+].Cl[C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([NH:25][S:26](=[O:38])(=[O:37])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47]>CN(C=O)C>[CH2:1]([O:4][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[N:16]=[C:15]([NH:25][S:26](=[O:37])(=[O:38])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:14]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:46][CH3:47])[CH:2]=[CH2:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2ccncc2)nc(NS(=O)(=O)Nc2ccc(C(C)C)cc2)c1Oc1ccccc1OC
Temperature: 80 °C

Procedure:
To a mixture of allyl alcohol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silicagel with EtOAc/Hex=3:2 to give 4-i-propyl-phenyl sulfamic acid-[6-allyloxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (10 mg). tR=5.36 min, (LC); [M+H]+=548.46 (ES+).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][C:11]=1[O:24][CH:25]([CH3:27])[CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CCOC(C)=O.CCO>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[O:24][CH:25]([CH3:27])[CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(O)ccc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 10% palladium on carbon (0.543 g, 0.510 mmol) in a solution of 4-(benzyloxy)-2-isopropoxyphenyl benzoate (3.70 g, 10.21 mmol) in EtOAc (25 mL) and EtOH (5 mL) was shaken in a Parr shaker under H2 (45 psi) at 25° C. for 3 days. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 25% EtOAc in hexanes over 4536 mL) to afford 4-hydroxy-2-isopropoxyphenyl benzoate. Rf=0.28 (20% EtOAc in hexanes). LCMS calc.=295.10; found=295.07 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 8.22 (d, j=7.8 Hz, 2 H); 7.64 (t, J=7.4 Hz, 1 H); 7.51 (t, J=7.7 Hz, 2 H); 6.94 (d,J=8.6 Hz, 1 H); 6.49 (d, J=2.7 Hz, 1 H); 6.35 (dd, J=8.6, 2.7 Hz, 1 H); 4.39 (p, J=6.1 Hz, 1 H); 1.22 (d, J=6.1 Hz, 6 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[F:33])(C)(C)C.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].N1CCCC(=O)C2C=CC=CC1=2.Cl.O1CCOCC1>>[ClH:32].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[F:33]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1)C2
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C1CCCNc2ccccc21
Solvent: C1COCCO1
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Yield: 100 %

Procedure:
[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester from Example E102.1 (503 mg, 1.03 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (440 mg, 100%).
Reaction SMILES: Cl[C:2](=[N:11][OH:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:13]([O:15][P:16]([C:21]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH2:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:25]([O:24][P:23]([C:21]1([P:16](=[O:20])([O:15][CH2:13][CH3:14])[O:17][CH2:18][CH3:19])[O:12][N:11]=[C:2]([C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:22]1)(=[O:30])[O:27][CH2:28][CH3:29])[CH3:26]
Reactant: O=C(C(Cl)=NO)c1ccccc1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)c2ccccc2)=NO1
Reaction time: 20 h

Procedure:
A solution of 2-chloro-2-oximino-1-phenylethanone (I, PREPARATION 8, 0.92 g) and ethenylidene bisphosphonic acid tetraethyl ester (II, PREPARATION 1, 1.50 g) in methylene chloride (5 ml) are treated with triethylamine (1.0 ml) and stirred for 20 hrs. The reaction is diluted with ethyl acetate, washed with water, hydrochloric acid (1N) and saturated sodium bicarbonate, dried with magnesium sulfate and concentrated under reduced pressure. Two reactions of identical size are chromatographed over a silica gel column eluting with ethyl acetate. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 8.11, 8.54, 7.40, 4.23, 3.90 and 1.28 δ.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[NH:18][C:17]2[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28](=[O:42])[N:29]([CH3:41])[CH2:30][C:31]3[N:32]([CH3:40])[C:33]4[C:38]([CH:39]=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:24]=[N:25][C:16]1=2)=O)(C)(C)C>C(Cl)Cl>[CH3:41][N:29]([CH2:30][C:31]1[N:32]([CH3:40])[C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28](=[O:42])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[N:25][C:16]2[NH:15][CH2:20][C:19](=[O:21])[NH:18][C:17]=2[CH:22]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)NC(=O)CN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)NC(=O)CN2
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (E)-7-{2-[methyl-(1-methyl-1H-indol-2-ylmethyl)-carbamoyl]-vinyl}-2-oxo-2,3-dihydro-1H-pyrido[2,3-b]pyrazine-4-carboxylic acid tert-butyl ester in CH2Cl2 (1 mL) at 10° C. After stirring 1 hr, volatiles were removed in vacuo and the resulting residue was dissolved in EtOAc (2 mL). Upon addition of dilute NaOH, a precipitate formed. The solid was collected by filtration, washed with water (100 mL), MeOH (50 mL), EtOAc (50 mL) and CH2Cl2 (50 mL) to afford the title compound (170 mg). 1H NMR (300 MHz, DMSO-d6) δ 10.42 and 10.33 (rotamers, 2s, br, 1H), 7.90 (m, 1H), 7.45 (m, 3H), 7.22 (m, 1H), 7.12 (m, 1H), 6.83 (d, J=15.4 Hz, 1H), 6.42 and 6.17 (rotamers, 2s, 1H), 4.98 and 4.84 (rotamers, 2s, 2H), 3.99 and 3.95 (rotamers, 2s, 2H), 3.72 and 3.68 (rotamers, 2s, 3H), 3.07 and 3.00 (rotamers, 2s, 3H). MS (ESI) m/e: 376 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: C1CCNCC1
Product: O=C(NC(CCN1CCCCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and piperidine, the title compound was obtained in 99.5% purity by HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][C:30]1[O:34][C:33](B(O)O)=[CH:32][CH:31]=1.CC(C)([O-])C.[K+]>COCCOC.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>[Cl:28][C:4]1[CH:3]=[C:2]([C:33]2[O:34][C:30]([CH3:29])=[CH:31][CH:32]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:26][CH3:27])(=[O:10])=[O:9]
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccc(B(O)O)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)cc1Cl
Temperature: 100 °C

Procedure:
To a mixture of 4-bromo-2-chloro-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E104) (220 mg, 0.45 mmol), (5-methyl-2-furanyl)boronic acid (113 mg, 0.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) in DME (3 ml) was added potassium tert-butoxide (454 mg, 4.10 mmol) in water (1 ml), and the reaction heated in the microwave (set at high absorbance) at 100° C. for 30 minutes. The reaction was poured on to the SCX column eluting first with methanol and then 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo. The product was purified by mass directed autoprep HPLC, the relevant fractions collected and solvent evaporated in vacuo. The product was triturated in ether to give the title compound (E306). MS (ES+) m/e 490/492 [M+H]+.