Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C1COCC1>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:2]1
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -55 °C
Reaction time: 4 h

Procedure:
To a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (2.6 g, 10.0 mmol) in THF (30 mL) was slowly added LDA (6.7 mL, 12.0 mmol, 1.8 M solution in heptane/tetrahydrofuran/ethylbenzene) at −78° C. and the mixture was slowly warmed to −55° C. over 1 h. To this mixture, 1-bromo-3-methyl-2-butene (1.55 g, 10.5 mmol) was slowly added and the reaction was warmed to room temperature and stirred for 4 h. The mixture was quenched with saturated NH4Cl and extracted with diethyl ether, and the combined extracts were washed with brine, dried and concentrated. The product (2.75 g, 85%) was purified by CombiFlash eluted with hexane/ethyl acetate.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
691 mL of acetic anhydride are added to a solution cooled to 10° C. of 1200 g (6.976 mol, 1 eq) of 3-bromoaniline in 6 L of dichloromethane in the presence of 1.07 L (7.67 mol, 1.1 eq) of triethylamine and 25.6 g (0.209 mol, 0.03 eq) of 4-(dimethylamino)pyridine. The reaction medium is stirred at room temperature for 4 hours and then hydrolyzed with 850 mL of 1N hydrochloric acid solution, and the phases are separated by settling. The organic phase is washed with 0.5N hydrochloric acid solution and then with water, and the solvent is evaporated off. After recrystallization from diisopropyl ether/heptane, 1506.1 g of N-(3-bromophenyl)acetamide are obtained in solid form. Yield=100%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:17])[C:13](OC)=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]=[C:12]([F:17])[CH2:13][OH:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(F)=CC1(c2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
1-(4-Chlorophenyl)-1-(2-fluoro-2-(methoxycarbonyl)ethenyl)cyclopropane prepared as described In Example 1 (0.73 g) in dry diethyl ether (10 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.18 g) in dry diethyl ether at 0° C. Stirring was continued during 40 min, while the mixture warmed to room temperature. Water (20 ml) was added, and the mixture was extracted with diethyl ether (3×20 ml). The combined organic layers were washed with water (3×10 ml), dried and evaporated under reduced pressure. The residue was chromatographed on silica using diethyl ether/hexane (1:2) to yield 1-(4-chlorophenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl) cyclopropane (0.56 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:17][CH:16]=[C:15]([C:18](O)=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)=[C:5]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:4]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:18]([C:15]2[C:11]3[N:12]=[CH:13][N:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:21][CH2:22][CH2:23][O:24][CH3:25])[C:10]=3[NH:17][CH:16]=2)=[O:19])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)O)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A74) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=O)[C:20]=1[O:40][CH3:41]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:40][CH3:41]
Reactant: COc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure I-1, ethyl 4(diethoxyphosphoryl)-3-methyl-but-2E-enoate (233 mg, 0.87 mmol) and (2E)-3-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-146, 116 mg, 0.29 mmol) were reacted to give the title compound as a colorless oil after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane) and HPLC (normal phase, 1% ethyl acetate in hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][NH2:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][NH:25][C:32]([CH:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[O:33])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CN)c3)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(CNC(=O)C4CCOCC4)c3)cnc21
Reaction time: 16 h

Procedure:
6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), tetrahydro-pyran-4-carboxylic acid (57 mg, 0.44 mmol) and triethyl amine (0.12 mL, 0.88 mmol) are mixed in acetonitrile (3.0 mL). Then TBTU (113 mg, 0.35 mmol) is added and the mixture is stirred for 16 hrs. All the solvent is removed in vacuo and to the residue are added saturated NaHCO3 aqueous solution (5 mL), water (15 mL) and EtOAc (20 mL). The mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (2×15 mL). The organic layers are combined and concentrated to give the crude 6-(5-{[(Tetrahydro-pyran-4-carbonyl)-amino]-methyl}-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester which is used in the next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27]>>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:26]([OH:28])=[O:27])[CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Product: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)O)c3)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 6, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 3-carboxyphenylboronic acid was prepared the title compound as an off-white solid, MS (ESI−): m/z=434.3 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CCCCCC.C[CH2:20][O:21]C(C)=O>>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:20]=[O:21])[CH:10]=2)[CH2:6][O:7]1
Reactant: CC1(C)OCc2ccc(Br)cc21
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)OCc2ccc(C=O)cc21

Procedure:
The title compound is prepared in analogous manner as described for example 47a from 6-bromo-1,1-dimethyl-1,3-dihydro-isobenzofuran to yield a light yellow oil: TLC (hexane-EtOAc 1:1) Rf=0.50; HPLC RtA=1.43 min; 1H NMR (400 MHz, CDCl3): δ10.02 (s, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 5.11 (s, 2H), 1.53 (s, 9H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:14]([CH:22]([F:24])[F:23])[CH2:15]P(=O)(OC)OC)=[CH:9][CH:8]=1.[CH:32]([CH:34]1[O:39][C:38](C)(C)[O:37][CH:36]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:35]1)=O>O1CCCC1>[F:23][CH:22]([F:24])[C:14](=[C:13]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1)[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[CH:15]=[CH:32][CH:34]1[O:39][CH2:38][O:37][CH:36]([CH2:42][C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:35]1
Reactant: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(F)F)OC
Reactant: CC(C)(C)OC(=O)CC1CC(C=O)OC(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CC(C=CC(=C(c2ccc(F)cc2)c2ccc(F)cc2)C(F)F)OCO1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Butyl lithium (1.04 mL of 2.5M solution, 2.6 mmol) was added to a solution of dimethyl [3,3-bis(4-fluorophenyl)-2-difluoromethyl-2-propen-1-yl]phosphonate (1.0 g, 2.6 mmol) in 10 mL of tetrahydrofuran at -78° C. After stirring for 30 minutes, 1,1-dimethylethyl 6-formyl-2,2-dimethyl-1,3-dioxane-4-acetate (0.82 g, 3.2 mmol) was added and the mixture stirred for 64 hrs. at room temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with diethyl ether. The extracts were dried over magnesium sulfate and conentrated in vacuo. The residue was purified by chromatography on silica eluting with 5% ethyl acetate in hexane to give an oil. Crystallization from pentane gave 0.6 g of the title compound; m.p. =124°-125° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=O)[N:5]1[CH3:11].P(Cl)(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(Cl)(Cl)Cl>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]1[CH3:11]
Reactant: CN1CC(CCCl)N(C)C1=O
Reactant: Nc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CC(CCCl)N(C)C1=Nc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
To 8.0 g (0.045 mole) of 4-(2-chloroethyl)-1,3-dimethyl-2-oxo-imidazolidine was added 50 ml of phosphorus oxychloride, and the solution was refluxed for 18 hours, and concentrated in vacuo. The residue was dissolved in 25 ml of methylene chloride and added dropwise to 4.2 g (0.045 mole) of aniline stirring at room temperature. Stirring was continued for two hours. The solution was diluted with chloroform and washed with dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in isopropyl alcohol and treated with 5.2 g (0.045 mole) fumaric acid, and the resulting fumarate was recrystallized from isopropyl alcohol and weighed 9.0 g (50% yield); m.p. 109°-112° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:29])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])[CH3:31]
Reactant: CCOCCN
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC
Yield: 51.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (60.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), DPPA (85.0 mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 495; and 1H NMR (CD3OD, 400 MHz): δ 7.96 (1H, d), 7.77-7.75 (2H, m), 7.65 (1H, d), 7.43-7.41 (1H, m), 7.26-7.24 (1H, m), 4.27-4.26 (2H, q), 3.66-3.64 (2H, m), 3.59-3.55 (4H, m), 1.43-1.39 (3H, t), 1.23-1.20 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14]OS(C)(=O)=O)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:14][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1)[CH3:21]
Reactant: CS(=O)(=O)OCCC1(c2ccccc2)C=CCC=C1
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)CCC1(c2ccccc2)C=CCC=C1
Temperature: 150 °C

Procedure:
87 g. of methanesulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester are dissolved in 600 ml. of toluene. 95 ml. (about 3 equivalents) of diethylamine are added and then the mixture is heated at 150° C. in a pressure vessel for 16 hours. The workingup is carried out as described in the second part of Example 7. There is obtained crude N,N-diethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine which is dissolved in ether and converted with hydrogen chloride into the hydrochloride. After recrystallization from methylene chloride/ether, there is obtained the hydrochloride having the melting point of 134°-136° C.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)c([N+](=O)[O-])cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c(F)cc1[N+](=O)[O-]

Procedure:
To a solution of the crude 4-fluoro-5-methyl-2-nitrobenzoic acid (5 g) in MeOH (50 mL) was slowly added SOCl2 (3.5 mL, 48 mmol) dropwise and the resulting mixture was refluxed overnight. Then the solvent was removed to give crude methyl 4-fluoro-5-methyl-2-nitrobenzoate (5 g) as a white solid. It was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[C:19]1[NH:28][C:27](=[O:29])[C:26]2[C:21](=[C:22]([CH3:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:18])[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[C:19]1[NH:28][C:27](=[O:29])[C:26]2[C:21](=[C:22]([CH3:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)CN2CCOCC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(C(O)CN2CCOCC2)cc1-c1nc2c(C)cccc2c(=O)[nH]1
Reaction time: 18 h

Procedure:
2-(2-Ethoxy-5-morpholinoacetylphenyl)-8-methylquinazolin-4(3H)-one (Example 16; 0.2 g, 0.00049 mol) was suspended in stirred ethanol (30 ml) and the mixture treated with sodium borohydride (0.0018 g, 0.00049 mol). After 18 hours at room temperature, the solvent was evaporated under vacuum. The residue was suspended in saturated aqueous sodium carbonate solution (30 ml) and the suspension extracted with ethyl acetate (3×20 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum, then the residue crystallized from ethyl acetate-hexane to give the title compound as colorless plates (0.14 g, 70%), m.p. 145°-147° C. Found: C,67.28; H,6.46; N,10.14. C23H27 3O4 requires C,67.46; H,6.65; N,10.26%.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:43][CH3:44])=[C:35]([O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:36]=2)[N:31]=[CH:30][N:29]=1>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:28]3[C:37]4[C:32](=[CH:33][C:34]([O:43][CH3:44])=[C:35]([O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COCCOc1cc2c(Cl)ncnc2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COCCOc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (223 mg, 0.83 mmol) was treated with cesium carbonate (325 mg, 1.0 mmol) in anhydrous tetrahydrofuran (8 mL). The mixture was stirred at room temperature for 30 minutes. 4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (149 mg, 0.45 mmol) from Example 15A was added to the suspension and the mixture heated to 50° C. overnight. After cooling to room temperature the mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (ethyl acetate/dichloromethane 1:1) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (218 mg, 50%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H), 4.32 (bs, 2H), 4.00 (s, 3H), 3.77 (bs, 2H), 3.36 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 524 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:35](=[O:37])[SH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42](O)=[C:41](S(N2CCOCC2)(=O)=O)[CH:40]=1>>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][N:18]2[C:12]3=[N:11][C:10]([C:35]([S:36][CH:2]([CH:1]=[O:8])[CH2:3][C:42]4[CH:41]=[CH:40][C:39]([F:38])=[CH:44][CH:43]=4)=[O:37])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14](=[O:15])[N:13]3[CH:16]=[CH:17]2)[CH2:23][CH2:24]1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: O=S(=O)(c1cc(F)ccc1O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(C(=O)S)nc23)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(C(=O)SC(C=O)Cc4ccc(F)cc4)nc23)CC1

Procedure:
Adapted from the procedure of example 39 using the product of example 109 and the product of example 84
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]Br)=[CH:4][C:3]=2[O:2]1.[I-:17].[Na+]>CC(C)=O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][I:17])=[CH:4][C:3]=2[O:2]1
Reactant: BrCCC=CCCc1ccc2c(c1)OCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCC=CCCc1ccc2c(c1)OCO2

Procedure:
6-(3,4-Methylenedioxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 12.9 g. of 6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide (Preparation C2) and 7 g. of sodium iodide in 120 ml. of acetone, refluxed for three hours, affording 12.5 g. of product as an oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[Cl:16][C:10](=[O:12])[CH2:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)Cl)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-(diethoxyphosphoryl)acetic acid (0.1 mL, 0.622 mmol) in CH2Cl2 (1 mL) was added oxalyl dichloride (2 M in DCM) (0.622 mL, 1.244 mmol), followed by a drop of DMF. The reaction was stirred at rt for 2.5 h and concentrated in vacuo to yield the desired product as yellow oil. 1H NMR (500 MHz, CHLOROFORM-d) δ 4.24 (dq, J=8.4, 7.1 Hz, 4H), 3.55-3.47 (d, J=21.46 Hz, 2H), 1.42-1.38 (t, J=7.4 Hz, 6H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:23]
Reactant: O=C(O)c1ccccc1Br
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=C(c1ccccc1Br)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-bromobenzoic acid. MS (ESI) mass calcd. for C21H19BrN4O, 423.31; m/z found, 423.0, 425.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH3:12])[O:5][N:4]=1)[CH3:2].C([Li])CCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:5][N:4]=1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCc1noc(C)c1C(=O)NC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1noc(CC(O)c2ccccc2)c1C(=O)NC
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 58.5 g. (0.348 mole) of 3-ethyl-N,5-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6 M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of benzaldehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete, the mixture is stirred for 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and filtered to give 3-ethyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide, m.p. 135° to 137° C.