Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:10][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)(C)c1cc(Br)cc(C=O)c1O
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCOc1c(C=O)cc(Br)cc1C(C)(C)C
Temperature: 20 °C
Yield: 106.7 %

Procedure:
A mixture of 5-bromo-3-(tert-butyl)-2-hydroxybenzaldehyde (4.74 g, 18.42 mmol) and anhydrous potassium carbonate (2.83 g, 20.45 mmol) in anhydrous DMF (20.0 mL) was stirred under nitrogen in a water bath (20° C.) to give an orange-yellow suspension. After stirring for 20 min, 2-methoxyethoxymethyl chloride (2.40 mL, 21.19 mmol, technical grade) was added drop wise (20 min) to above suspension while maintaining an internal temperature of 20° C. The reaction mixture was stirred at room temperature for 3 h to give a canary yellow suspension. The reaction mixture was poured into ice-water (150 mL) and stirred at room temperature to give a yellow oily liquid, no solid formation was observed. After 30 min of stirring, the reaction mixture was extracted with dichloromethane (2×75 mL). The organic layer was removed, washed with water (1×50 mL) and dried over anhydrous magnesium sulfate, filtered and evaporated in-vacuo to give a pale yellow viscous liquid (6.7832 g). No purification was necessary and the crude product (purity >97%) was used directly in the next Step #3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.OS(O)(=O)=O.[I:24](O)(=O)(=O)=O.II>C(O)(=O)C>[Cl:1][C:2]1[C:3]([I:24])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(I)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a stirred solution of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.0 g, 3.87 mmol) in acetic Acid (25 mL) was added H2SO4 (0.206 mL, 3.87 mmol) followed by periodic acid (0.881 g, 3.87 mmol). The mixture was then heated to 80° C. for 20 min. I2 (0.294 g, 1.160 mmol) was then added at 80° C. and stirred for 120 min. After cooling to ambient temperature, the acetic acid was removed under reduced pressure. The residue was neutralized with 70 mL of saturated aqueous sodium bicarbonate solution. The solid so obtained was collected by vacuum filtration and air dried to afford 8-chloro-9-iodo-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.3 g, 3.21 mmol, 83% yield) as a brown solid. LC/MS (ESI) m/e 385.1 [(M+H)+, calcd for C14H11ClIN2O 384.9]; LC/MS retention time (method E): tR=1.09 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (s, 1H) 8.69 (d, J=5.58 Hz, 1H) 8.36 (d, J=5.52 Hz, 1H) 7.76 (s, 1H) 3.63 (s, 3H) 3.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:10]([OH:12])=O)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:48]([O:50][C:51]([C:53]1([NH2:62])[CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54]1)=[O:52])[CH3:49]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:48]([O:50][C:51]([C:53]1([NH:62][C:10]([C:7]2[S:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH3:9])=[O:12])[CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54]1)=[O:52])[CH3:49]
Reactant: Cc1c(C(=O)O)sc2ccc(Cl)cc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2sc3ccc(Cl)cc3c2C)Cc2ccccc2C1
Yield: 53.4 %

Procedure:
To a 40 mL vial containing a stirring bar, 5-chloro3-methyl-benzo[b]thiophene-2-carboxylic acid ([50451-84-8], 0.81 g, 3.53 mmol) is charged with dry DCM (10 mL). Stirring is initiated. HBTU (1.34 g, 3.54 mmol) and the DIPEA (1.4 mL, 8.0 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (0.725 g, 3.53 mmol) is added. The reaction is allowed to stir for 240 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (80 mL) and transferred to a reparatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.26 g of a off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 20% EtOAc in heptanes over 3 column volumes followed by a step gradient to 30% and then 50% and then 70% EtOAc for 2 column volumes each with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 22 through 60 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.78 g.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[F:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[F:14]
Reactant: Cc1noc2c(F)c(F)c(CO)cc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1noc2c(F)c(F)c(C=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of (6,7-difluoro-3-methyl-1,2-benzisoxazol-5-yl)methanol (Intermediate 334, 200 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added NMO (235 mg, 2.0 mmol) followed TPAP (35 mg, 0.1 mmol) and mixture stirred for 2 hours at room temperature. The reaction mixture filtered thorough silica gel bed and washed with EtOAc. The organic phase was concentrated under reduced pressure to give product as a yellow solid. Yield: 150 mg (76%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[N:6][CH:7]=1.C([Li])CCC.[CH2:22]([S:24]SCC)[CH3:23]>O1CCCC1>[CH2:22]([S:24][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:23]
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Reactant: CCSSCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCSc1ccc(N)nc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (4 g, 12.7 mmol, J. Am. Chem. Soc. 1997, 119, 5499-5511) in tetrahydrofuran (40 mL) was added n-butyllithium at −78° C. under nitrogen. After 2 h, diethyl disulfide (1.7 mL, 12.7 mmol) was added and the mixture was stirred at −78° C. for 3 h. The temperature was gradually raised to room temperature over 2 h. The mixture was poured into ice aqueous sodium hydrogencarbonate. The organic layer was separated and extracted with 2 N hydrochloric acid. The aqueous layer was separated and basified and the mixture was extracted with ethyl acetate (50 mL×4). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 as eluent) to afford the title compound (1.23 g, 63%) as a pale brown solid.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.Cl[CH2:15][C:16]1[C:21]([CH2:22]Cl)=[CH:20][CH:19]=[CH:18][N:17]=1>C(O)C>[CH2:11]([O:10][C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][C:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:22]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1cccnc1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)Cc2cccnc2C1
Temperature: 25 °C

Procedure:
Sodium metal (0.345 g, 15.0 mmol) is dissolved in ethanol (20 ml) and diethyl malonate (0.713 g, 4.70 mmol) is added, followed by a suspension of 2,3-bis(chloromethyl)pyridine hydrochloride (Org. Process Res. Dev., 2002, 6, 938; 1.0 g, 4.70 mmol) in ethanol (15 ml) over 5 minutes. The reaction is heated to reflux for 5 hours, cooled to ambient temperature and filtered. The filtrate is evaporated, taken into water and extracted with ethyl acetate. The combined organic phases are washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash column chromatography (3:1-2:1 isohexanes-EtOAc gradient) to afford 5,7-dihydro-[1]pyrindine-6,6-dicarboxylic acid diethyl ester, MH+264.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:40][O:41][CH2:42][CH3:43])[C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[N:3]([CH2:40][O:41][CH2:42][CH3:43])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: CCOCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCOCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 1.2 g of bis(pivaloyloxymethyl) 1,4-dihydro-2,6-dimethyl-1-ethoxymethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate obtained in Example 14, and 200 mg of Lipase B was added thereto, followed by stirring at room temperature for 4 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 840 mg (yield: 83%) of (S)-1,4-dihydro-2,6-dimethylethoxymethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([F:13])[CH:5]=1>O.[Fe]>[Br:3][C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([F:13])[CH:5]=1)[NH2:10]
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cc(F)cc(Br)c1
Temperature: 90 °C
Yield: 58.4 %

Procedure:
A suspension of 29.0 g of iron powder and 20.0 g of ammonium chloride in 50 ml of water was heated to 90° C. with vigorous stirring. To this was added 24.0 g of 1-bromo-3-fluoro-5-nitrobenzene portionwise. The mixture was refluxed for 4 hours, cooled to room temperature and filtered to remove insoluble matter. The insoluble matter and the filtrate were extracted, respectively, with ethyl acetate. Both extracts were combined together and evaporated in vacuo to give 12.1 g of the title compound. Vacuum distillation of a portion thereof gave an analytical sample boiling at 103.0°-105.0° C. /7 mm Hg.
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[CH3:9][NH:10][NH2:11]>C(O)C>[IH:1].[CH3:9][N:10]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:11]
Reactant: CNN
Reactant: CSC1=NCCN1
Agent: I
Solvent: CCO
Product: CN(N)C1=NCCN1
Temperature: -10 °C

Procedure:
A solution of 48.8 g. of 2-methylthio-2-imidazoline hydroiodide and 10.0 g. of methylhydrazine in 200 ml. of ethanol is heated at reflux for several hours, clarified and then cooled at -10° C. The precipitate is collected, washed with diethyl ether and dried, giving 2-(1-methylhydrazino)imidazoline hydroiodide.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[C:48]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[C:47]([F:56])[C:46]([O:57][CH2:58][CH3:59])=[C:45]([CH:60]=[O:61])[CH:44]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([C:43]2[C:48]([C:49]3[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=3)=[C:47]([F:56])[C:46]([O:57][CH2:58][CH3:59])=[C:45]([CH:60]=[O:61])[CH:44]=2)[CH2:3][CH2:2]1
Reactant: CCOc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Cyclopropylboronic acid (1.79 g), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (854 mg), tris(dibenzylideneacetone)dipalladium (0) (953 mg) and 2M aqueous sodium carbonate solution (15.6 mL) were added to a solution of 6-bromo-3-ethoxy-2,4′-difluorobiphenyl-4-carbaldehyde (3.55 g) in toluene (35 mL) at room temperature. The mixture was stirred at 100° C. under argon atmosphere for 16 hours. The mixture was quenched with water at room temperature and filtrated through celite. The filtrate was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.99 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[CH2:14]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C@H:22]2[CH2:21][CH2:20][C@H:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]2)[CH:3]=1
Reactant: CCCCCC1CCC(=O)CC1
Reactant: Fc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2cccc(F)c2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
1-Bromo-3-fluorobenzene (s1) (60.0 g) and THF (1,000 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M in n-hexane; 218 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 4-Pentylcyclohexanone (s2) (57.7 g) dissolved in THF (150 ml) was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a vessel containing an aqueous solution of ammonium chloride (500 ml) and ethyl acetate (500 ml), and mixed with them. The mixture was allowed to stand and separate into organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure. p-Toluenesulfonic acid (2.4 g) and toluene (250 ml) were added to the residue, and the mixture was heated to reflux for 2 hours, while distilled water was removed. After the reaction mixture had been cooled to 30° C., water (500 ml) and toluene (900 ml) were added and mixed with it. The mixture was allowed to stand and separate into two layers of organic and aqueous layers, and the latter was extracted. The separated organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by fractionation using column chromatography with heptane as an eluent and silica gel as a stationary phase powder, and dried. The product was dissolved in toluene (150 ml) and Solmix A-11 (150 ml), to which Pd/C (0.8 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The resulting residue was purified by fractionation using column chromatography with heptane as an eluent and silica gel as a stationary phase powder, and by recrystallization from Solmix A-11, and then dried to give 1-fluoro-3-(trans-4-pentyl cyclohexyl)benzene (s3) (58.4 g). The yield based on the compound (s1) was 68.6%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8](O)[N:7]=[CH:6][N:5]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[CH3:1][O:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([Cl:14])[N:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1ncnc(O)c1C
Agent: [Na+]
Agent: [OH-]
Product: COCc1ncnc(Cl)c1C
Temperature: 0 °C

Procedure:
4-Methoxymethyl-5-methyl-6-hydroxypyrimidine (38.40 g) was stirred with phosphorus oxychloride (275 ml) at room temperature for 24 hours. The mixture was stripped, ice/water added and the pH raised to 11.5 (NaOH). The solution was extracted with chloroform, extracts dried (MgSO4) and stripped to give 4-methoxymethyl-5-methyl-6-chloropyrimidine, 38.23 g, as an oil, which solidified on cooling to 5° (m.p. 37°-38°). It was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[C:22]1([CH:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH2:31]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:30][CH2:31][S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SCCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 43 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 4,4-diphenylbutyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 43%.
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:25]=[C:24]([CH3:26])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:23])=[C:13]([CH:22]=2)[C:14]([N:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])=[C:6]([CH3:27])[CH:5]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>>[CH:18]1([N:16]([CH3:17])[C:14](=[O:15])[C:13]2[CH:22]=[C:9]([O:8][C:7]3[C:6]([CH3:27])=[CH:5][C:4]([NH:3][C:1]4[NH:30][N:29]=[N:28][N:2]=4)=[CH:25][C:24]=3[CH3:26])[CH:10]=[CH:11][C:12]=2[OH:23])[CH2:21][CH2:20][CH2:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(NC#N)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(Nc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Temperature: 165 °C

Procedure:
N-Cyclobutyl-5-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide was prepared from 5-(4-cyanoamino-2,6-dimethyl-phenoxy)-N-cyclobutyl-2-hydroxy-N-methyl-benzamide according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (1.2 equiv) and ammonium chloride (10 equiv) were used, and the reaction was heated to 165° C. for 5 hours. After the reaction had been acidified, the aqueous mixture was washed with ethyl acetate (3×10 ml). The combined organic extracts were extracted with aqueous 1N HCl (3×50 ml), and brine (50 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane 15:1.5:83.5) to afford the title product of Example 6. MS (APCI+) Calc.: 408.5, Found: 409.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH2:15])[CH:8]=2)[CH2:5][NH:4][C:3]1=[O:16].[CH2:17]1[CH:21]2[CH2:22][C:23](=O)[CH:19]([CH2:20]2)[CH2:18]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.CCOCC.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH:15][CH:18]3[CH2:17][CH:21]4[CH2:20][CH:19]3[CH2:23][CH2:22]4)[CH:8]=2)[CH2:5][NH:4][C:3]1=[O:16]
Reactant: O=C1CC2CCC1C2
Reactant: COc1ccc(C2CNC(=O)N2C)cc1N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(C2CNC(=O)N2C)cc1NC1CC2CCC1C2
Temperature: 5 °C
Yield: 10.1 %

Procedure:
The aniline of Example 51 (3.07 g, 17.95 mmol) is dissolved in 60 ml of glacial acetic acid and to this is added norcamphor (2.37 g, 21.54 mmol). The reaction is cooled to 5° C. and to it is added sodium cyanoborohydride (1.36 g, 21.54 mmol). The reaction is poured onto ice and is pH adjusted to 7 with 1 normal NaOH solution. The aqueous is extracted with methylene chloride dried over MgSO4, filtered and concentrated in vacuo to afford a brown oil which is flashed on SiO2 with ethyl acetate as the eluent. The appropriate fractions are combined and concentrated in vacuo to yield a white paste which is tritarted with ether to yield 0.57 g (10%) of the product as a white crystalline solid. MP=171°-174° C.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[CH3:23][C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH:22]=[CH:21][N:20]=1
Reactant: Cc1cc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)ccn1
Agent: Cl
Product: Cc1cc(-c2ccc3c(c2)CNC3)ccn1

Procedure:
Prepared in analogy to Example A3(e) from 5-(2-Methyl-pyridin-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 211.0 ([M+H]+, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:13])[NH:9][CH:10]([CH3:12])[CH3:11])=[O:5].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29](=N)OCC>C(O)C.C(OCC)(=O)C>[OH:22][CH2:21][C@H:20]([CH3:23])[CH2:19][O:18][C:15]1[CH:14]=[C:3]2[C:2](=[CH:17][CH:16]=1)[N:1]=[C:29]([C:28]1[CH:34]=[CH:35][CH:36]=[C:26]([O:25][CH3:24])[CH:27]=1)[N:6]([CH2:7][C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:13])[C:4]2=[O:5]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(OC[C@@H](C)CO)ccc1N
Reactant: CCOC(=N)c1cccc(OC)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nc3ccc(OC[C@@H](C)CO)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of crude (S)-(+)-2-amino-5-(3-hydroxy-2-methylpropoxy)-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE VII.1) (223 mg, 0.70 mmol) (prepared in Procedure VIII) and ethyl 3-methoxybenzimidate*HCl (INTERMEDIATE III.2) (449 mg, 2.08 mmol) in anhydrous ethanol (5 mL) was heated to 80° C. in a tightly capped scintillation vial for 16 h. This was then cooled and concentrated in vacuo. The crude residue was partitioned between dichloromethane/2-propanol (3:1, v/v) and water and the aqueous extracted with further dichloromethane/2-propanol (3:1, v/v). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The crude solid thus obtained was suspended in cold ethyl acetate and collected by filtration affording (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (145 mg, 0.33 mmol, 43% from 2-amino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]benzoic acid) as a light brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:8]2([C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])[CH2:7][CH2:6][CH2:5][NH:4]1.[CH3:20]OC(OC)N(C)C>ClCCl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]3([CH2:7][CH2:6][CH2:5][N:4]4[CH:20]=[N:1][CH2:2][CH:3]34)[C:9](=[O:19])[NH:10]2)=[CH:15][CH:14]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc2c(c1)NC(=O)C21CCCNC1CN
Solvent: ClCCl
Product: COc1ccc2c(c1)NC(=O)C21CCCN2C=NCC21
Temperature: 25 °C

Procedure:
A solution of 31 mmol of 2′-(aminomethyl)-6-methoxyspiro[indole-3,3′-piperidin]-2(1H)-one and 31 mmol of N,N-dimethyl formamide dimethylacetal in 50 ml of dichloromethane is heated to reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.