Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:25]1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: ICC1CCC(OC2CCCCO2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid methyl ester (prepared as in Example 1, 1.42 g, 6.48 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16.15 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. A solution of 2-(3-iodomethyl-cyclopentyloxy)-tetrahydropyran (2.21 g, 7.13 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was then added. The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). This mixture was poured into water (100 mL) and extracted with methylene chloride 3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-[3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (2.12 g, 81.6%) as a clear oil: EI-HRMS m/e calcd for C20H26Cl2O4 (M+Na)+ 423.1106. found 423.1093.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:18][C:19]1[CH:25]=[C:24]([C:26]([F:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])[CH:23]=[C:22]([CH3:36])[C:20]=1[NH2:21].N1C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([NH:21][C:20]1[C:22]([CH3:36])=[CH:23][C:24]([C:26]([F:35])([C:27]([F:28])([F:29])[F:30])[C:31]([F:32])([F:33])[F:34])=[CH:25][C:19]=1[CH3:18])=[O:7]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(F)c(N)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
3-Amino-2,4,5-trifluoro-benzoic acid (commerically available) (12.5 g, 65.50 mmol) was heated with thionyl chloride (110 ml) at 90° C. for 2 hours under a nitrogen atmosphere. The excess thionyl chloride was removed in vacuo. To a solution of the residue (13.37 g, 52.30 mmol) in dichloromethane (218 ml) under a nitrogen atmosphere was added a solution of 2,6-dimethyl-4-(heptafluoroprop-2-yl)aniline (prepared according to EP 1,006,102) (15.12 g, 52.30 mmol) in pyridine (4.2 ml, 52.30 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then extracted with aqueous hydrochloric acid (1M). The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with aqueous sodium hydrogen carbonate (1M), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give 3-amino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2,4,5-trifluoro-benzamide (18.4 g, 76% yield). 1H-NMR (400 MHz, CDCl3): 2.35 (6H, s), 4.07 (2H, bs), 7.3-7.35 (1H, m), 7.36 (2H, s), 7.83 (1H, d) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2.C(O)(C(F)(F)F)=O>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:22]([CH3:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Reactant: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: CNCCOc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.69 mmol) was suspended in DMA (10 ml) and N-methylethanolamine (56 μl, 0.69 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 20 minutes at ambient temperature, and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 103, preparation of starting materials, 100 mg, 0.28 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 110° C. for 1 hour, then at 125° C. for 14 hours. The mixture was cooled to ambient temperature, and acidified with TFA. The mixture was concentrated in vacuo, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in H2O. The appropriate fractions were evaporated to a volume such that all of the acetonitrile had been removed. The resulting aqueous solution was basified with concentrated aqueous ammonia, and extracted with DCM (4×20 ml). The combined extracts were filtered through a silicone-treated filter paper, and concentrated in vacuo to give 5-[2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine as a yellow solid (40 mg, 34%); NMR Spectrum (CDCl3, 400 MHz) 2.20 (s, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.12 (t, 2H), 4.25 (t, 2H), 6.80 (d, 1H), 6.83 (d, 1H), 7.00 (d, 1H), 7.04 (dd, 1H), 7.39 (d, 1H), 7.55 (dd, 1H), 7.61 (dd, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.56 (s, 1H), 10.26 (s, 1H); Mass spectrum MH+ 416.0
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:23][NH:24][CH3:25].[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:24]([CH3:25])[CH3:23])=[O:7]
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N(C)C)c1I

Procedure:
The acid chloride (16.23 g.) prepared from 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and thionyl chloride was interacted with 60 ml. of dimethylamine (40% in water), 20 ml. of 35% aqueous sodium hydroxide and 30 ml. of water. The product was isolated and recrystallized from isopropyl alcohol to give 3-amino-2,4,6-triiodo-5-(N-methylacetamido)N,N-dimethylbenzamide as a pale yellow solid, m.p. 235°-240° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.ClCCl.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[OH:26])[CH:21]=[O:22]>O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:10][O:11][CH3:12])[CH:21]=[O:22]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 11 h

Procedure:
N,N-diisopropylethylamine (23.7 ml) and chloromethyl methyl ether (7.76 ml) were added to a dichloromethane (130 ml) solution of 3-fluoro-4-hydroxybenzaldehyde (13 g) under cooling on ice, and the obtained mixture was stirred at room temperature for 11 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 7:3), so as to obtain the title compound (17.4 g).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](N1C=CN=C1)=[O:25])[CH2:4][CH3:5])[CH3:2].C[Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH:24]=[O:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)n1ccnc1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C=O

Procedure:
The title compound was prepared by reacting [4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone with methylmagnesium bromide/ethyl ether in methylene chloride. 1H NMR(CDCl3) d 9.7(d,1H), 6.88(s,2H), 6.10(s,1H), 3.32(m,1H), 2.73(s,3H), 2.31(s,3H), 2.10(s,3H), 2.09(s,6H), 1.5-1.7(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:16][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1cc(Br)cc(Br)c1
Solvent: O
Product: CC(C)NS(=O)(=O)c1cc(Br)cc(Br)c1
Reaction time: 2 h

Procedure:
3.0 G. of 3,5-dibromobenzenesulfonylchloride is added to a solution of 17.7 g. of isopropylamine in 25 ml. of water at room temperature. A complete solution results which is stirred for two hours and poured onto 250 ml. of water. The precipitate is filtered, washed with water, and dried affording 3,5-dibromo-N-isopropylbenzenesulfonamide, m.p. 105° to 107° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[ClH:41]>O1CCCC1>[Cl:41][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[C:15]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:16]=1
Reactant: Cl
Reactant: COc1ccc(C(=O)Cl)cc1OCCCCCCCCCCCc1ccccc1
Reactant: Nc1cc(Cl)ncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OCCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a magnetically stirred suspension of 60% sodium hydride (60% in mineral oil) (0.53 grams) in anhydrous tetrahydrofuran (20 ml) at 0° C. is added a solution of 4-amino-2,5-dichloropyridine (0.90 grams) in anhydrous tetrahydrofuran (20 ml). After stirring for 30 minutes at room temperature the reaction mixture is cooled to 0° C. and treated with a solution of 4-methoxy-3-(11-phenylundecyloxy)benzoyl chloride (2.30 grams) in tetrahydrofuran (20 ml). After stirring at room temperature for 16 hours the reaction mixture is poured into 50 ml of 1N hydrochloric acid and extracted with ethyl acetate. The combined organics are washed with 1N hydrochloric acid, water and brine and then dried over sodium sulfate and concentrated under reduced pressure. The resulting yellow solid is purified by column chromatography on a silica gel column using a ratio of 9:1 mixture of methylene chloride and ethyl acetate as eluent to give 1.9 grams of an off-white solid. MP 114-5° C.; MS m/z 543, 545; Anal. calcd for C30H36Cl2N2O3 : C, 66.29; H, 6.68; N, 5.15. Found: C, 6646; H, 6.61; N, 5.08
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([O:20][CH3:21])[C:9]([CH3:19])=[C:10]([O:17][CH3:18])[C:11]=2[CH2:15][CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:23]1([N:29]2[C:33]([SH:34])=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[C:23]1([N:29]2[C:33]([S:34][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([O:20][CH3:21])[C:9]([CH3:19])=[C:10]([O:17][CH3:18])[C:11]=4[CH2:15][CH3:16])[S:4]3(=[O:6])=[O:5])=[N:32][N:31]=[N:30]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CCl)S2(=O)=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCc1c(OC)c(C)c(OC)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 76 %

Procedure:
By the method of Example 44 condensation of 2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.17 g) and 1-phenyltetrazol-5-thiol sodium salt (0.084 g) in dimethylformamide (4 mL) and purification of the product by flash column chromatography on silica gel using hexane-ethyl acetate (75:25) as eluant afforded 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, 0.15 g, 76% yield, mp 44°-46° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH2:21]>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C@@H:20]([NH:21][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH3:19]
Reactant: C[C@H](N)c1ccccn1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: C[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1ccccn1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and (αS)-α-methyl-2-pyridinemethanamine hydrochloride (1:1) (100.0 mg, 0.64 mmol) as starting materials, and isolated (15 mg, 13.03%) as off white solid, LC-MS (UV peak area, ESI) 97.58%, 339.0 (M+H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([CH3:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[C:30]([CH3:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Reactant: NCCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.Br[CH2:32][CH3:33]>>[CH2:32]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=3)=[CH:12][N:11]=2)=[C:2]([F:1])[C:7]=1[F:8])[CH3:33]
Reactant: CCBr
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCC)c(F)c3F)nc2)cn1
Yield: 51 %

Procedure:
The etherification of 2.8 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine using 3.0 mmol of 1-bromoethane is carried out analogously to the procedure indicated for Example 3. Corresponding purification gives 0.62 g (51%) of colorless crystals, X 111 SC 122.5 SA 185 I.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:4]12[CH2:5][CH:1]([CH:2]=[CH:3]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]2=1
Reactant: O=S(=O)(Oc1ncccc1CC1CC=CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C1=CC2CC1Cc1cccnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
Trifluoro-methanesulfonic acid 3-cyclopent-3-enylmethyl-pyridin-2-yl ester (3.1 g, 10.1 mmol) was stirred in DMF (20 mL) and degassed (3 N2/vacuum cycles) then treated under a N2 atmosphere with triethylamine (1.52 g, 15 mmol), 1,3-bis(diphenylphosphino)propane (334 mg, 0.80 mmol) and palladium acetate (72 mg, 0.32 mmol). After 20 min. the mixture was warmed to 100° C. under nitrogen for 18 h, at which time the reaction was deemed 90% complete. Additional triethylamine (1 mL, 7.2 mmol) was added and the mixture brought to 110° C. for 6 h at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled and poured into 50% saturated aqueous NaCl solution (75 mL) then extracted with EtOAc (4×30 mL). The combined organic layer was washed with H2O (2×50 mL), saturated aqueous NaHCO3 solution (50 mL), saturated aqueous NaCl solution (50 mL), dried over Na2SO4, filtered and concentrated to an oil, 2.3 g. Of this material 1.89 g was chromatographed on silica gel eluting with 20% EtOAc/hexanes to provide an oil (1.07 g, 77%). (TLC 20% EtOAc/hexanes Rf 0.21); 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J=4.9, 0.7 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 6.92 (dd, J=7.5, 4.9 Hz, 1H), 6.21 (dd, J=5.5, 2.9 Hz, 1H), 5.73 (dd, J=5.5, 2.6 Hz, 1H), 3.43 (m, 1H), 2.86 (m, 2H), 2.40 (d, J=16.2 Hz, 1H), 2.21 (m, 1H), 1.80 (d, J=10.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.0, 145.0, 138.2, 138.0, 131.7, 130.1, 121.6, 47.3, 39.5, 37.9, 29.7; APCl MS m/z 158.1 (M)+.
Reaction SMILES: ClC1[CH:7]=[CH:6][C:5]([OH:8])=C(F)C=1.[Cl:10][C:11]1[C:16]([CH:17]=O)=[C:15]([F:19])[C:14]([O:20][CH2:21][CH3:22])=[CH:13][CH:12]=1.ClC1C(C=C)=C(F)[C:27]([O:33]CC)=[CH:26]C=1.C=CC1C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClC(Cl)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:27]([O:33][C:5]([C@@H:6]1[CH2:7][C@@H:17]1[C:16]1[C:11]([Cl:10])=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH3:22])[C:15]=1[F:19])=[O:8])[CH3:26]
Reactant: Oc1ccc(Cl)cc1F
Reactant: CCOc1ccc(Cl)c(C=O)c1F
Reactant: C=Cc1c(Cl)ccc(OCC)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CC(Cl)Cl
Solvent: C=Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1c(Cl)ccc(OCC)c1F
Reaction time: 1 h
Yield: 10 %

Procedure:
The titled compound was obtained starting from 4-chloro-2-fluorophenol which was converted to 6-chloro-3-ethoxy-2-fluorobenzaldehyde according to procedure in Example 362 of WO 93/03022. This aldehyde was converted to 6-chloro-3-ethoxy-2-fluorostyrene according to procedure in Example 375 of WO 93/03022. Styrene (30.7 g, 153 mmole) was dissolved in dichloroethane (400 mL) and CuJ (50 mg) and Pd(OAc)2 (50 mg) added. The temperature of this solution was raised to reflux and diethyl azodicarboxylate (32.2 mL, 306 mmole) in 100 mL of dichloroethane was dropped into it during a period of 2 hrs. The reflux was continued for 1 hr. The reaction mixture was evaporated and the residue purified by chromatography on silica gel column EtOAc/Hexane 2:98-5:95 as eluent to give 4.36 g (10%) of pure (+,-)-cis-2-(6-chloro-3-ethoxy-2-fluorophenyl)-cyclopropylcarboxylic acid ethyl ester which was then hydrolyzed in KOH (2.56 g)--EtOH/H2O (45 mL/5mL) at 100° C. for 24 hrs. The reaction mixture was extracted twice with hexane, made acidic with conc. HCl and extracted with diethyl ether which was dried over Na2SO4 and evaporated to give 3.87 g (98%) of pure acid.
Reaction SMILES: [C:1]([C@H:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].[C:22]([BH3-])#[N:23].[Na+].ClC1[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=[C:29]([Cl:37])[N:28]=1.CCN(C(C)C)C(C)C>CO>[Cl:37][C:29]1[N:28]=[C:22]([NH:23][CH:1]([C@H:4]2[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH3:2])[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=1
Reactant: [BH3-]C#N
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: CC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(Nc1nc(Cl)cc2nccnc12)[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A mixture of (S)-tert-butyl 2-acetylmorpholine-4-carboxylate (2.29 g, 10.0 mmol), ammonium acetate (7.70 g, 100 mmol), sodium cyanoborohydride (0.94 g, 15.0 mmol), and 5 angstrom molecular sieves (10 g) in methanol (50 mL) was stirred at room temperature under nitrogen for 16 hours. The sieves were removed by filtration and the filtrate was concentrated. A solution of 1 N NaOH was added until the pH reached 12. The mixture was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, filtered and concentrated. The resulting light yellow oil (2.17 g) was dissolved in THF (40 mL) and 5,7-dichloropyrido[3,4-b]pyrazine (2.00 g, 10.0 mmol) and DIPEA (1.94 g, 15.0 mmol) were added. The mixture was heated to reflux for 48 hours. The volatile components were evaporated and the residue was extracted with ethyl acetate. Ethyl acetate was washed with brine and dried. The solvent was removed in vacuo. The crude residue was purified by silica-gel chromatography eluting with Hexane-50% EtOAc/Hexane (gradient) then C18 column to afford the subtitled compound as brown oil 450 mg. MS (m/z): 394 (M+H)+
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.O>C(Cl)(Cl)Cl>[C:18]1(=[O:23])[N:8]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Br:2])=[CH:4][CH:5]=2)[C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a suspension of 10 g (44.94 mmol) of 4-bromobenzylamine hydrochloride in 200 ml of chloroform was added 12.5 ml (89.62 mmol) of triethylamine, followed by the addition of 8.99 g (60.67 mmol) of phthalic anhydride. The mixture was stirred at room temperature for 10 minutes to give a homogeneous solution, which was then heated at 75° C. for three hours. The reaction mixture was then evaporated to remove the chloroform and the residue was suspended in 400 ml of toluene followed by adding 700 mg of p-toluenesulfonic acid monohydrate. The resulting mixture was briefly refluxed at 140° C., and additional 3 ml of triethylamine was added to form a homogeneous solution. The solution was refluxed at 140° C. for 2 hours; and the water formed was collected through a Dean-Stark trap apparatus. The solution was then cooled to room temperature, washed with 3% sodium hydroxide (2×200 ml), water (1×200 ml), brine (1×200 ml), and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 12.07 g (85% yield) of 4-phthalimidomethyl bromobenzene as a white solid. Rf: 0.6 (silica gel, ethyl acetate:hexane=1:2). 1H NMR (CDCl3): δ ppm 4.79 (2H, s), 7.31, 7.44 (2H each, AA'BB'), 7.73, 7.84 (2H each, m).