Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:15][C:14]([F:17])([F:16])[CH2:13][NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)NCC(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Slurry 1-benzoyl-3-(2,2,2-trifluoroethyl)-thiourea (5.5 g, 21.2 mmol) and potassium carbonate (11.7 g, 84.7 mmol) in methanol (180 mL) and water (40 mL). Stir the mixture at room temperature for 16 h. Concentrate the solution in vacuo to a paste. Triturate with hot water (20 mL, 60° C.), filter off the solids, wash with water (20 mL, 25° C.) and hexane (excess). Collect the solids, slurry in EtOAc and concentrate in vacuo twice to remove residual water. Dry the material in a vacuum oven at 45° C. for 16 h to obtain the desired intermediate as an off-white solid (2.2 g, 66%). MS (ES+) m/z: 159.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: COc1cccc(O)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methoxy-phenol to give [1-(3-methoxy-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 333(MH+).
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(-c2cc(C(Cl)C3CCCCC3)c(C)o2)nn1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)nn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A mixture of 3-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-6-methylpyridazine (107 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (175 mg), sodium carbonate (74 mg) and sodium iodide (210 mg) in N,N-dimethylacetamide (5 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (30% ethyl acetate/hexane to 100% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.3 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (56 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=2)[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+].O>C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([N:6]2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:14]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:27])=[CH:29][CH:30]=1)([OH:36])=[O:35]
Reactant: COC(=O)c1ccc(-n2c(C(=O)OC)c(-c3cc(OC)c(OC)c(OC)c3)c3ccccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To the compound obtained in Example 20 (1.51 g) are added methanol (150 ml) and 1M aqueous sodium hydroxide solution (3 ml), and the mixture is stirred at 60° C. overnight. To the reaction solution is further added 1M aqueous sodium hydroxide solution (1.5 ml) which is divided to two portions, and the mixture is refluxed for 12 hours. The reaction mixture is allowed to stand for cooling, and thereto are added water and ethyl acetate. The aqueous layer is separated, and acidified with hydrochloric acid, and further extracted with ethyl acetate. The ethyl acetate layers are combined, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 2-(4-carboxyphenyl)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (245 mg) as listed in Table 4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-].[K+].Cl[CH2:29][C:30]1[C:31]([CH3:36])=[N:32][O:33][C:34]=1[CH3:35]>C(#N)C>[CH3:36][C:31]1[C:30]([CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=3)(=[O:9])=[O:10])=[CH:4][CH:3]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: Cc1noc(C)c1CCl
Reactant: CC(C)CN(c1nccc(C(F)(F)F)n1)S(=O)(=O)c1ccc(O)cc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2nccc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 121.9 %

Procedure:
To a suspension of 4-hydroxy-N-(2-methylpropyl)-N-[4-(trifluoromethyl)-2-pyrimidinyl]benzenesulfonamide (31 mg, 0.083 mmol) and potassium fluoride on alumina (30 mg, 0.207 mmol) in acetonitrile (0.5 mL) stirred under nitrogen at room temperature was added a solution of 4-(chloromethyl)-3,5-dimethylisoxazole (12 mg, 0.083 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was filtered to remove the potassium fluoride on alumina and the filtrate evaporated. The sample was purified by mass directed autoprep (TFA modifier). The solvent was evaporated under a stream of nitrogen and then freeze-dried from water/dioxane to give the title compound (49 mg). LCMS (2 min, formic) Rt 1.35 min, m/z (ES+) 485 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: COc1cccc(N)c1OC
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1OC

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 2,3-dimethoxyaniline (69 μl, 0.486 mmol) similar to Example 11 and isolated as a white solid (169 mg). 1H NMR (CDCl3): 8.85–8.82 (m, 1H), 8.48 (d, J=7.8 Hz, 1H), 7.87–7.82 (m, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.40–7.35 (m, 2H), 7.10 (t, J=8.4 Hz, 1H), 6.73 (d, J=1.5 Hz, 1H), 7.00 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[O:11]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]=[C:10]=[O:11]
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(C)c1N
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N=C=O
Yield: 76 %

Procedure:
7 g (0.05 mole) of 2,6-dimethyl aniline dissolved in 20 ml of toluene are added dropwise to a 20% solution of phosgene in toluene (1.5 equivalents) maintained at 0° in an ice bath. The mixture is then heated at reflux for 3 h. The mixture is concentrated and the residue is distilled under vacuum. B.p.=100°/13 mm Hg. Yield: 76%.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH:10]([OH:13])([CH3:12])[CH3:11]>C([O-])(O)=O.[Na+]>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([O:13][CH:10]([CH3:12])[CH3:11])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Br)cnc1OC(C)C
Reaction time: 24 h

Procedure:
To a solution of potassium tert. butylate (1.26 g, 11.3 mmol) in isopropanol (30 mL), 2,5-dibromo-3-picoline (2.89 g, 11.3 mmol) is added. The mixture is stirred at 80° C. for 15 h before another portion of potassium tert.-butylate (2.53 g, 27.5 mmol) is added. Stirring is continued at 80° C. for 24 h before the mixture is diluted with sat. aq. NaHCO3-solution. The mixture is extracted with ether, the org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 5-bromo-2-isopropoxy-3-methyl-pyridine (1.24 g) as a colourless oil; LC-MS: tR=1.06 min; [M+1]+=230.00; 1H NMR (CDCl3): δ1.35 (d, J=6.3 Hz, 6H), 2.16 (s, 3H), 5.27 (hept, J=6.3 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.CO.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)C1CCN(c2ccc(OC)cn2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCC(C(=O)O)CC2)nc1
Reaction time: 3 h
Yield: 39.7 %

Procedure:
To a solution of 5′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (0.17 g, 0.64 mmol) in 5 mL of THF/MeOH/H2O (1/1/1) was added LiOH.H2O (54 mg, 1.28 mmol). After 3 hours, the reaction was concentrated under vacuo, taken up in EtOAc, washed with aq. NH4Cl. The organic phase was dried over Na2SO4, and concentrated under vacuo to yield 60 mg (39%) of the title product as a light brown solid. ES-MS m/e: 235.1 (M−H+).
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.[NH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[Br:49])[C:37]1=[O:50].O>CN(C=O)C.C(OCC)(=O)C>[Br:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[CH:38]1[CH2:39][CH2:40][CH2:41][N:36]([NH:35][C:32](=[O:34])/[CH:31]=[CH:30]/[C:20]2[CH:21]=[CH:22][C:23]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:18]([O:17][CH3:16])[CH:19]=2)[C:37]1=[O:50]
Reactant: NN1CCCC(c2ccc(F)cc2Br)C1=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3ccc(F)cc3Br)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
BOPCl (1.48 g) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (1.0 g), 1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one (1.15 g) and TEA (1.1 mL) in DMF (20 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 953 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15][C:16]#[N:17])(=O)OCC)C.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23](=O)[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1>C1COCC1>[CH3:18][C:19]1([CH3:28])[CH2:24][C:23](=[CH:15][C:16]#[N:17])[CH2:22][C:21]([CH3:27])([CH3:26])[NH:20]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=CC#N)CC(C)(C)N1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
Potassium tert-butoxide (9.40 g, 83.7 mmol) is suspended in THF (175 mL), then cooled to 0° C. Cyanomethyl-phosphonic acid diethyl ester (16.0 g, 90.2 mmol) is added over five minutes. After stirring for 20 minutes, 2,2,6,6-tetramethylpiperidin-4-one (10.0 g, 64.4 mmol) dissolved in THF (50 mL) is added to the reaction mixture at −78° C. After the addition is complete the cold bath is removed. The reaction is stirred overnight, then enough water is added to dissolve any suspended salts. The organic layer is separated and the aqueous layer is extracted with EtOAc. The organic layers are combined, concentrated, then the residue is chromatographed on silica gel, eluting with 0-3% 2M NH3/MeOH in dichloromethane to give 3.77 g of (2,2,6,6-tetramethylpiperidin-4-ylidene)-acetonitrile (33% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[OH:11][C:12]1[CH:24]=[CH:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH:13]=1>>[CH:13]1[C:14]2[NH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]=2[CH:23]=[CH:24][C:12]=1[O:11][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCCCBr
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Product: CCOC(=O)CCCCOc1ccc2c(c1)[nH]c1ccccc12
Yield: 34.3 %

Procedure:
In a manner analogous to that of example 6(a), ethyl 5-bromo-pentanoate (685 mg, 3.28 mmol) was reacted with 2-hydroxycarbazole (600 mg, 3.28 mmol) to give ethyl 5-(9H-carbazol-2-yloxy)-pentanoate (350 mg, 34%) as a colorless solid. MS (MH+)310.
Reaction SMILES: IC.Br[CH2:4]C1OC(C(F)(F)F)=CC=1.[OH:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]2[C:23]3([CH2:42][O:43][C:17]=2[CH:16]=1)[C:31]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:25]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:24]3=[O:41].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH3:4][O:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]2[C:23]3([CH2:42][O:43][C:17]=2[CH:16]=1)[C:31]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:25]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:24]3=[O:41]
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C#N)cc43)c3ccccc32)cc1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Solvent: CI
Product: COc1ccc(CN2C(=O)C3(COc4cc(OC)c(C#N)cc43)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using iodomethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (62%): mp 207-208° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.27-7.20 (m, 3H), 7.10-6.99 (m, 2H), 6.90-6.83 (m, 4H), 6.56 (s, 1H), 5.07-4.74 (m, 4H), 3.90 (s, 3H), 3.78 (s, 3H); MS (ES+) m/z 412.9 (M+1).
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56].[BH3-]C#N.[Na+]>>[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: CC(C)(C)CN
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 63.7 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2-dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.7 mg of the title compound (34%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[CH2:9].[Na].C1(C=CC(O)=CC=1)O>O>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:9][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Cc1ccccn1
Reactant: C=Cc1ccccn1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: O
Product: c1ccc(CCCc2ccccn2)nc1
Yield: 18.9 %

Procedure:
To a flask were added 93 g of 2-picoline, 21 g of 2-vinylpyridine, 1 g of sodium and a trace of hydroquinone. The mixture was heated to 130 C under nitrogen for 2 hours. After cooling to 22 C, 200 ml of water were added and the mixture was extracted with 150 ml diethyl ether. After washing the diethyl ether layer twice with 100 ml of water, and twice with 50 ml of 10% sodium sulfite, the solvent was removed and the product was purified by vacuum distillation to give 7.5 g of a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][N:12]([CH2:23][OH:24])[C:13](=[O:22])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:8]3[NH:7][C:6]=2[CH:25]=1.[C:26](Cl)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][N:12]([CH2:23][O:24][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:13](=[O:22])[C:14]([C:15]4[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=4)=[C:8]3[NH:7][C:6]=2[CH:25]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Reaction time: 0.58 h
Yield: 78 %

Procedure:
To 1.0 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (2.6 mmol.) in 15 ml. of pyridine at 0° C. was added dropwise 0.9 ml. of hexadecanoyl chloride (3.9 mmol.). After stirring for 35 minutes, the mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in the formation of a yellow precipitate. The precipitate was collected, washed with water and air-dried, then purified using flash chromatography on silica gel, employing a mixture of 2% ethyl acetate: 98% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(1-oxohexadecyloxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a pale yellow crystalline solid (1.25 g; 78% yield) having the structural formula, ##STR21## a melting point in the range of 120°-122° C. and the following elemental analysis:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:33]([CH2:34][OH:35])[CH2:32][CH2:31][C@:22]32[O:26][CH2:25][C:24]([Sn](C)(C)C)=[CH:23]3)=[CH:17][CH:16]=1.N>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C@@H:33]([CH2:34][OH:35])[CH2:32][CH2:31][C@@:22]32[O:26][CH2:25][C:24]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH:11]([CH3:13])[CH3:12])=[CH:23]3)=[CH:17][CH:16]=1
Reactant: C[Sn](C)(C)C1=C[C@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)OC1
Reactant: CC(C)Oc1ccc(C#N)cc1Br
Agent: N
Product: CC(C)Oc1ccc(C#N)cc1C1=C[C@@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)OC1

Procedure:
The title compound was prepared following the procedure described in Example 6, Step F(d) using 3-bromo-4-isopropoxybenzonitrile and (5R,6S,7S)-6-(4-fluorophenyl)-3-(trimethylstannyl)-1-oxaspiro[4.4]non-3-ene-7-methanol as substrates for the cross-coupling reaction. 400 MHz 1H NMR (CD3OD): δ 1.28 (s, 3H), 1.31 (s, 3H), 1.70 (m, 1H), 2.18 (m, 2H), 2.72 (m, 1H), 2.82 (d, 1H), 3.37 (dd, 1H), 3.55 (dd, 1H), 4.05 (dd, 1H), 4.67 (dd, 1H), 4.70 (m, 1H), 6.35 (m, 1H), 6.92 (t, 2H), 7.07 (d, 1H), 7.30 (m, 2H), 7.38 (d, 1H), 7.52 (dd, 1H); Mass spec (NH3 /CI): 408 (M+1); 425 (M+NH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:19])[C:17]=1[OH:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[O:6].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[C:20]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([Cl:1])[C:17]([O:18][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][CH:17]=[CH:2][CH:3]=2)=[C:16]([Cl:19])[CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccccc1O)c1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1OC(=O)c1ccccc1)c1cc(Cl)c(OC(=O)c2ccccc2)c(Cl)c1
Yield: 88.2 %

Procedure:
3,5-Dichloro-2',4-dihydroxybenzanilide (1 g.) was dissolved in dry pyridine (15 ml.) in the cold at 0°-5° C. and to it was added dropwise benzoyl chloride (1.2 ml.). With gently stirring reaction was continued for several hours. The solution was then poured into ice-cold water and acidified with 1 N hydrochloric acid to pH 2, yielding oily material which was extracted by ethyl acetate. The ethyl acetate solution was washed with 1 N hydrochloric acid and 5% sodium bicarbonate solution in that order and dried with anhydrous sodium sulfate, followed by removal of the solvent by evaporation. The residue was subjected to recrystallization from ether and petroleum ether mixture to give white crystals (1.5 g.) of 2',4-dibenzoyloxy-3,5-dichlorobenzanilide. Yield: 88.2%. Melting point: 157°-160° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30]C4C=CC=CC=4)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])[CH3:2]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:37])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(CCc4ccccc4)c3)oc2C)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(CC)c3)oc2C)cc1

Procedure:
2-Methyl-2-(4-{2-[5-methyl-2-(3-phenethylphenyl)oxazol-4-yl]ethoxy}phenoxy)-propionic acid ethyl ester Rf=0.36 in 1:4 EtOAc:hexanes; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.79 (d, 1H), 7.32-7.20 (m, 3H), 7.19-7.13 (m, 4H), 6.80-6.72 (m, 4H), 4.23-4.16 (m, 4H), 2.94-2.86 (m, 6H), 2.34 (s, 3H), 1.43 (s, 6H), 1.24-1.19 (m, 6H); MS (EI) 536.2 (M+Na)+, 514.2 (M+H)+.