Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>O1CCCC1>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CNCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1ccc(CN(C)Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
1.71 g (0.01 mole) of N-methyl-1-naphthylmethylamine was dissolved in 30 ml of tetrahydrofuran, and 1.2 g (0.012 mole) of triethylamine was added. With stirring at room temperature, 1.85 g (0.011 mole) of p-isopropylbenzyl chloride was added, and the mixture was reacted at room temperature for 6 hours. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The residue was distributed between ether and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was collected. The organic layer was washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column and eluted with 4% ethyl acetate/n-hexane. The eluate was concentrated to give 2.82 g (yield 93%) of an oily substance.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([CH2:18]O)=[N:16][N:15]=[N:14]2)=[N:11][CH:12]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:18][C:17]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([F:21])([F:20])[F:5])=[CH:12][N:11]=2)[N:14]=[N:15][N:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-n2nnnc2CCl)nc1
Reaction time: 2 h
Yield: 27.8 %

Procedure:
Thionyl chloride (0.22 g, 1.85 mmol) was added at room temperature to a solution of {1-[5-(Trifluoromethyl)-2-pyridinyl]-1H-tetrazol-5-yl}methanol (Intermediate 58, 0.20 g, 0.82 mmol) in toluene, and the reaction mixture was stirred for 2 hr at reflux. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and washed with ice-water, saturated NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 mesh silica gel) eluting with 0-20% ethyl acetate/pet ether to give the title compound (60 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].CCOC(C)=O>OS(O)(=O)=O.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([Br:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(Br)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-3-methylbenzoic acid methyl ester (10.13 g, 44 mmol) was dissolved in a mixture of H2SO4 120 mL and TFA (15 mL) at room temperature. The solution was cooled on an ice bath and KNO3 (4.65 g, 46 mmol) was added portionwise over 30 min. The mixture was stirred at ambient temperature for 4 hours during which it warmed to rt. TLC analysis (after mini aqueous workup) showed total disappearance of starting material (30% EtOAc/Hex). The solution was poured onto ice and the aqueous slurry was extracted with EtOAc (3×150 mL). The organic layer was washed with 5% Na2CO3 (3×75 mL), NaHCO3 (3×50 mL), water (2×100 mL), brine (100 mL), then was dried over sodium sulfate. Concentration of the solution yielded a yellowish solid/gel substance (11.6 g) which was one spot by TLC. 1H NMR analysis shows two (major) products in ˜2:1 ratio, corresponding to the o- and m-nitrobenzoate derivatives. The material was carried onto the next step without further purification.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13].[F-].[Cs+].[CH3:16]B(O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[C:7]([F:8])[C:2]=1[CH3:16]
Reactant: NS(=O)(=O)c1cc(F)c(Br)c(F)c1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1c(F)cc(S(N)(=O)=O)cc1F
Temperature: 120 °C
Yield: 93.6 %

Procedure:
A mixture of 4-bromo-3,5-difluorobenzenesulfonamide (1.09 g, 4 mmol), CsF (1.34 g, 3 eq), methylboronic acid (494 mg, 2 equiv) and Pd(PPh3)4 (140 mg, 0.3 eq) in 1,2-dimethoxyethane (16 mL) was heated to 120° C. under microwave irradiation for 4 h. After cooling, solids were removed by filtration and washed with EtOAc. The filtrate was concentrated and then purified by column chromatography (silica, EtOAc-Hex, 1:4 to 4:1) to give 3,5-difluoro-4-methylbenzenesulfonamide (776 mg). 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 2H), 2.46 (s, 3H); GC-MS (ES) m/z 207 (M).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][NH:17][C:11]=3[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:4][CH:3]=1.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:31]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:32])[C:11]=3[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:6][CH:7]=1
Reactant: O=c1c2cn[nH]c2nc(-c2ccccc2F)n1-c1ccc(Br)cc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: O=C(N1CCOCC1)n1ncc2c(=O)n(-c3ccc(Br)cc3)c(-c3ccccc3F)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of 5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (20.0 mg, 0.052 mmol) in anhydrous pyridine (0.5 mL) is added 4-morpholinecarbonyl chloride (7.27 μL, 0.062 mmol). The mixture is stirred at room temperature for 2 h before removal of the solvent. The residue is purified by preparative LCMS followed by preparative TLC to provide the title compound (9.1 mg, 35% yield) as a white solid product; 1H NMR (CDCl3, 400 MHz) δ 8.91 (s, 1H), 7.42-7.28 (m, 4H), 7.11 (t, 1H), 7.02 (d, 2H), 6.88 (t, 1H), 4.15-3.84 (m, 8H); HPLC-MS calculated for C22H17BrFN5O3 (M+H+) 498.0. Found: 498.0.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=O)[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6][C@@H:5]1[OH:28])[CH3:2].Cl.[NH2:30][OH:31].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=[N:30][OH:31])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6][C@@H:5]1[OH:28])[CH3:2]
Reactant: NO
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@@]2(C)[C@H]3CCC23OCCO3)C[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=NO)C[C@@]2(C)[C@H]3CCC23OCCO3)C[C@@H]1O

Procedure:
2β-Ethoxy-17,17-ethylenedioxy-3α-hydroxy-5α-androstan-11-one (8.2 g) was added to hydroxylamine hydrochloride (15 g) in ethanol (500 ml) containing 44% sodium hydroxide solution (90 ml). After refluxing for 24 hours about half the solvent was evaporated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The washed and dried (Na2SO4) organic solution was evaporated in vacuo to afford a froth which on crystallization from ethyl acetate-petroleum ether afforded the title compound m.p. 136°-140°, [α]D +41.1°.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2CCC(C(=O)O)(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester (4.22 g, 10 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (71%). white solid mp 190° C. , MS: 420.4 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH3:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#N)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)C)ccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
4-t-Butyl-2-hydroxybenzonitrile (1.16 g) and potassium carbonate (376 mg) were dissolved in dimethylformamide (4 ml) and to the solution was added dropwise iodomethane (226 μl), followed by stirring at 50° C. for 2 hours. The resulting mixture was filtered to remove the remaining potassium carbonate and concentrated under reduced pressure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=10/1) to yield the compound 13-2a (167 mg, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].C(O)(=O)C>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(NC(=O)OCc2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NC1CC(O)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
N-(Benzyloxycarbonyl)-3-amino-1-cyclobutanone (3.51 g, 16.0 mmol) from Step A was dissolved in 100 mL of THF and the THF solution was cooled to -78° C. with stirring under a nitrogen atmosphere. To the solution was added 17.6 mL (17.6 mmol) of potassium tri-sec-butylborohydride (sold by Aldrich Chemical Company as a 1 M solution in THF under the registered trademark K-Selectride®) and stirring was continued for 10 minutes. The reaction mixture was allowed to warm to 0° C. and then quenched with 1.16 mL (1 equivalent) of glacial acetic acid. The reaction mixture was then filtered through Celite filter aid and concentrated in vacuo. The residue (3.1 g) was dissolved in ~10 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @5 psi with 250 mL of acetone:hexane (1:2 v/v), followed by 200 mL of acetone:hexane (1:1 v/v) to give 2.22 g (63% yield) of the title compound; MS DCI-NH3M/Z: 222 (M+H)+, 239 (M+NH4)+ ; 1H NMR (CD3OD) δ 1.81 (m, 2H), 2.62 (m, 2H), 3.60 (m, 1H), 3.90 (m, 1H), 5.09 (s, 2H), 7.25-7.40 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[Cl:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>>[Cl:22][C:23]1[S:27][C:26]([NH:28][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:19])=[N:25][CH:24]=1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ncc(Cl)s1
Product: CN1C(C(=O)Nc2ncc(Cl)s2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 34 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 5-chloro-2-thiazolamine with a yield of 34% of theory.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>CN(C)C=O>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccnc2)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 47.6 parts of 1H-imidazole, 33.6 parts of sodium hydride dispersion 50% and 750 parts of N,N-dimethylformamide was stirred at room temperature for 15 minutes. The resulting solution was added to 106 parts of 3,6-dichloropyridazine in 750 parts of N,N-dimethylformamide and the whole was further stirred for 2 days at room temperature. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from methanol. The product was filtered off, washed with petroleumether and dried, yielding 48.5 parts of 3-chloro-6-(1H-imidazol-1-yl)pyridazine; mp. 182.9° C. (compound 1).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(Nc3ccc(Cl)cc3)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-oxo-7-(4-chloroanilino)indoline (3.2 g.), sodium hydroxide (1.2 g.), dioxane (20 ml.) and water (40 ml.) was refluxed under heating for 118 hours with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in water and washed with ethyl acetate, adjusted to pH 2 to 3 with 5% sulfuric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with benzene to give 2-[2-amino-3-(4-chloroanilino)phenyl]acetic acid (2.7 g.). mp 190° to 192° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.P(Br)(Br)([Br:14])=O.[OH-].[Na+]>ClC(Cl)C>[Br:14][C:5]1[C:4]2[CH:9]=[CH:10][O:11][C:3]=2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=c1[nH]cc(Br)c2occc12
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Brc1ncc(Br)c2occc12
Temperature: 25 °C

Procedure:
Combine 7-bromo-5H-furo[3,2-c]pyridin-4-one (16.16 g, 75.5 mmol), dichloroethane (160 mL), and phosphorus oxybromide (100 g, 348.8 mmol) and heat at reflux for about 2 hours. Cool to room temperature and pour the reaction mixture into ice water (1 L). Adjust the pH to 8 with 5N NaOH, extract into dichloromethane, wash with brine, dry over magnesium sulfate, filter, and concentrate. Purification by flash chromatography, eluting with hexane:ethyl acetate gives the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Na+].[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:4][CH2:1][C:2]#[CH:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CCO
Reactant: BrCCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCCCCOCc1ccccc1
Temperature: 40 °C
Reaction time: 0.54 h
Yield: 124.1 %

Procedure:
To a 1:1 mixture of propargyl alcohol (100 mL, 1.72 mol) and anhydrous THF (100 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 14.0 g, 0.35 mol) under nitrogen, portionwise, over 30-35 min. An second reaction mixture was prepared in essentially the same manner. Both reaction mixtures were heated at 40° C. for 2 h and then cooled to room temperature. 4-Benzyloxy-1-bromobutane (90%, 35.0 g, 0.137 mol) was added to each reaction mixture. The resulting solutions were heated at 40° C. for 22 h and then quenched with water (˜5 mL), combined and concentrated in vacuo. The resulting crude product was then partitioned between dichloromethane (2×300 mL) and water (200 mL). The organic phases were removed, washed with saturated brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude title intermediate (67 g) as a yellow oil. This oil was then chromatographed on a silica gel column (˜8 kg, 230-400 mesh, flash under 10 psi nitrogen pressure) eluting with dichloromethane (Rf=0.45, dichloromethane). The appropriate fractions were combined and concentrated to give the title intermediate as a clear oil (37.2 g, 0.17 mol, 62% yield).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34]C(N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[OH:21][C:15]1([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:34]=[CH:35][C:30]([N:26]5[CH2:27][CH2:28][CH2:29][N:23]([CH3:22])[CH2:24][CH2:25]5)=[CH:31][CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Reactant: COC(=O)c1sc(C2(O)CCOCC2)cc1N=CN(C)C
Product: CN1CCCN(c2ccc(-n3cnc4cc(C5(O)CCOCC5)sc4c3=O)cc2)CC1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(4-hydroxytetrahydropyran-4-yl)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 440.57 (C23H28N4O3S) was obtained in this way; MS (EST): 441 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][N+:16]([O-])=O)[CH2:11][N+:12]([O-])=O)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:15][NH2:16])[CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])CC(C[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: NCC(CN)c1ccc(N)cc1

Procedure:
A mixture of 1-nitro-4-[2-nitro-1-(nitromethyl)ethyl]benzene (742 mg, 0.45 mmol) and 148 mg platinum (IV) oxide in 40 mL MeOH was reacted under 60 PSI hydrogen on the Pan apparatus. After 24 hours the mixture was filtered and rinsed with MeOH. The MeOH solution was acidified to pH=0 using concentrated HCl and then evaporated to give a quantitative yield of the title compound. 1H NMR (D2O) δ: 7.55-7.60 (m, 2H), 7.48-7.54 (m, 2H), 3.26-3.51 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:54][N:55]1[CH2:59][CH2:58][CH2:57][C@@H:56]1[CH:60]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:60]/[C@H:56]4[CH2:57][CH2:58][CH2:59][N:55]4[CH3:54])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCC[C@@H]1C=O
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCOC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 8d (200 mg, 0.37 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (740 μL, 0.74 mmol) was added dropwise. After stirring for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (84 mg, 0.74 mmol) was added to the reaction solution. The reaction mixture was stirred for another 1 hour, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 8 (100 mg, yield 54.2%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:8](=O)[CH:9]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])[C:10]([O:12]CC)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32]([NH2:34])=[NH:33]>C(N(CCCC)CCCC)CCC>[CH:1]1([C:8]2[N:34]=[C:32]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][N:26]=3)[N:33]=[C:10]([OH:12])[C:9]=2[C:15]2[C:16]([F:23])=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C(=O)C1CCCCCC1)c1c(F)cc(F)cc1F
Reactant: N=C(N)c1cnccn1
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc(-c2cnccn2)nc(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate (649 mg, 1.9 mmol) and 2-pyrazinecarboxamidine hydrochloride (452 mg, 2.85 mmol) in 1.5 mL of tributylamine is stirred under nitrogen atmosphere at 160° C. for 4 h. The mixture is cooled to room temperature and the excess of tributylamine is decanted off. The residue is washed with hexanes and chromatographed over silica gel, eluting with 10% methanol in ethyl acetate. Concentration provides 6-cycloheptyl-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidin-4-ol as a light yellow solid. MS: m/z 401.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([F:20])[C:18]=2[Cl:19])[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 49.7 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (0.059 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.041 g, 0.090 mmol, 49.6% yield) as a white solid. The mother liquor was concentrated to small volume, diluted with IPA, stirred for 30 minutes, and filtered to give a second batch of 4-chloro-N-({4-chloro-3-[(2-chloro-5-cyano-3-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.011 g, 0.024 mmol, 13.31% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.25 (t, J=5.56 Hz, 1H), 7.88-7.99 (m, 1H), 7.78 (s, 1H), 7.37-7.57 (m, 2H), 7.30 (s, 1H), 4.55 (d, J=5.49 Hz, 2H). LC-MS (ES−) m/z 455.10, 457.03 [M−1]. LC-MS (ES+) m/z 456.99, 459.87 [M+H].