Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[S:31][CH:30]=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1.C([Li])CCC.[S:37]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38]1>O1CCCC1>[Cl:1][C:2]1[C:3]([C:27]2[S:31][C:30]([C:39]3([OH:42])[CH2:40][CH2:41][S:37][CH2:38]3)=[N:29][CH:28]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:19])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cncs4)c(Cl)cnc32)cc1
Reactant: O=C1CCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cnc(C5(O)CCSC5)s4)c(Cl)cnc32)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 144A (0.095 g, 0.202 mmol) in tetrahydrofuran (2.5 mL) was cooled to −78° C. and treated with n-butyllithium (2.45 M in hexanes, 0.173 mL, 0.424 mmol) dropwise over 5 minutes. The reaction was stirred at −78° C. for 20 minutes, and dihydrothiophen-3(2H)-one (0.033 mL, 0.384 mmol) was added. The reaction was stirred 60 minutes at −78° C. and was quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was allowed to warm to ambient temperature and was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with 1% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 572.3 [M+H]+.
Reaction SMILES: N1C=CN=C1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1COCC1.O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][CH:9]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
Imidazole (1.80 g, 26.1 mmol) and p-methoxyphenol (1.62 g, 13.05 mmol) were suspended in THF (30 mL) and placed under nitrogen. Tert-butyldimethylsilyl chloride (2.23 g, 14.36 mmol) was added and the mixture was stirred for 15 hours at room temperature. The thick white mixture was diluted with water (50 mL) and extracted with ether (3×15 mL). The organic solvent was removed under reduced pressure to give the product as a clear liquid (2.33 g, 75%). Characterization matched literature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:14]=[CH:15]N(C)C)=[S:13])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br)[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][C:25]([C:24](=[O:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[CH2:20][CH3:21])=[CH:15][N:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Reactant: CCc1ccccc1C(=O)CBr
Product: CCc1ccccc1C(=O)c1cnc(NCCCNC(=O)OC(C)(C)C)s1

Procedure:
The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 2-ethyl phenacylbromide according to the procedure described for Example 25. MS (m/e): 389.9 (MH+, 100%).
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)=[O:8])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[O:6][CH:5]=2)=[O:8])=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: COc1ccc(NC(=O)c2coc(Br)c2)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2coc(-c3ccncc3)c2)cc1N1CCN(C)CC1
Yield: 18 %

Procedure:
5-bromo-N-[4-methoxy-3-(4-methyl- 1-piperazinyl)phenyl]furan-3-carboxamide (0.16 g;0.41 mmol) was stirred with 4-pyridylboronic acid (0.050 g;0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g;5 mol %) and anhydrous sodium carbonate (0.047 g;0.45 mmol) in water (8 ml) and DME (8 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml ) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a orange oil which was triturated with hexane/Et2O. The solid that formed was collected by filtration and dried in vacuo to yield the title compound as a tan solid (0.029 g;18%), mp=103°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[N:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:15]=[N:16][CH:17]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cncc(Br)c1
Product: O=Cc1ccc(Oc2cncc(Br)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 5-bromopyridin-3-ol.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[C:15]2[CH:14]=[N:13][C:12]([S:16][CH3:17])=[N:11][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:23])[CH:7]=1>CN(C=O)C>[N:1]([C:6]1[C:15]2[CH:14]=[N:13][C:12]([S:16][CH3:17])=[N:11][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:23])[CH:7]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ncc2c(Br)cc(=O)n(C3CCCC3)c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(N=[N+]=[N-])cc(=O)n(C3CCCC3)c2n1
Temperature: 90 °C
Yield: 57.1 %

Procedure:
Sodium azide (543 mg, 8.35 mmol) was added to a mixture of 5-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.42 g, 4.17 mmol) in DMF (17 mL) at RT and the reaction mixture was heated to 90° C. in a microwave reactor for 30 min. The resulting mixture was then cooled to RT and quenched with water (70 mL). The solid that formed was collected by filtration, dried under reduced pressure, dissolved in THF and adsorbed onto silica gel. This material was purified by flash chromatography (from 10 to >25% EtOAc/hexanes in 20 min) to afford 0.720 g (57% yield) of 5-azido-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid. MS=303 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.[NH3:24]>CCO>[NH2:24][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N)ncnc32)CC1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (4A-1; 0.050 g, 0.148 mmol) in saturated NH3 in EtOH (1 mL) was heated to 80° C. for 30 min. in the microwave. The mixture was cooled, concentrated, and dried in vacuo. Used without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.93 (s, 1H), 5.60 (bs, 2H), 4.84-4.95 (m, 1H), 4.29 (bs, 2H), 2.95 (bs, 2H), 2.13-2.28 (m, 2H), 1.92-2.03 (m, 2H). LRMS m/z (M+H) Calcd: 319.1, found: 319.1.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:20])[CH3:18])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:30]([O:32]C)=O)[CH2:5]1)=[N+:2]=[N-:3].[Li+].[OH-].[C@H:36]1([NH2:46])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1>>[N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:29])[C@@H:10]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:20])[C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:18])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:6]([C:30](=[O:32])[NH:46][C@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][CH2:38][CH2:37]2)[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Reactant: N[C@@H]1CCCc2ccccc21
Agent: [Li+]
Agent: [OH-]
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound of Example 2 was treated with LiOH using the general procedure C to hydrolyze the methyl ester. The resulting acid was coupled to (R)-tetrahydro-1-naphthylamine using the general procedure D to prepare the title compound of Example 3. 1H NMR (CDCl3): consistent with proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH2:43][CH3:44])=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH2:43][CH3:44])=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K35) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous red substance (184 mg, 44%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[N:6][CH:7]=1.[H-].[Na+].IC.[C:20]([O-])(O)=O.[Na+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([CH3:20])[C:9]2=[O:15])=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC1(C)CN(c2ncc(I)cn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ncc(I)cn2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
(55 mg, 173 μmol) 1-(5-Iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 122, step 1) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (9 mg, 225 μmol, 1.3 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (13 μl, 200 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min without cooling bath. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (31 mg, 54% yield) was obtained as a white solid, MS: m/e=333.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.CC1C([O:44]CC(F)(F)F)=CC=NC=1CSC1NC2C=CC=CC=2N=1>>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:44])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Yield: 78 %

Procedure:
The experiment described in example 2 was repeated using 52.2 g 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl]methyl]thio]-1H-benzimidazole as substrate instead of Lansoprazole sulfide. 42.3 g of crystallized Pantoprazole are isolated after crystallization and drying (yield 78%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:8][O:9][CH3:10])[NH:5][C:6]=1I.[O-]S([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([CH2:8][O:9][CH3:10])=[N:5][CH:6]=1
Reactant: COCc1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCc1ncc(I)[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 4,5-diiodo-2-(methoxymethyl)-1H-imidazole (compound 230.3, 2 g, 5.50 mmol) in ethanol (40 mL). A solution of Na2SO3 (5.9 g, 46.83 mmol) in water (80 mL) was added to the reaction. The reaction mixture was stirred overnight at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was extracted with 3×20 mL of dichloromethane and the organic layers combined and concentrated under reduced pressure. This resulted in 1 g (76%) of the title compounds as yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6][C@@H:5]2[C:7]([Br:11])([Br:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13].C(N(CC)CC)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[CH3:1][C:2]1([CH3:15])[S:6][C@@H:5]2[C:7]([Br:11])([Br:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([O:14][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:13]
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a solution of 54 g. (0.165 mole) of 6,6-dibromopenicillanic acid in 350 ml. of N,N-dimethylacetamide was added 22.9 ml. (0.165 mole) of triethylamine and the solution was stirred for 40 minutes. Benzyl bromide (19.6 ml., 0.165 mole) was added and the resulting mixture was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was filtered off, and the filtrate was added to 1,500 ml. of ice-water, adjusted to pH 2. The mixture was extracted with ether, and the extracts were washed successively with saturated sodium bicarbonate, water and brine. The dried (MgSO4) ether solution was evaporated in vacuo to give an off-white solid, which was recrystallized from isopropanol. This afforded 70.0 g. (95% yield) of the title compound m.p. 75°-76° C. The IR spectrum (KBr disc) showed absorptions at 1795 and 1740 cm-1. The NMR spectrum (CDC13) showed absorptions at 1.53 (s,3H), 1.58 (s,3H), 4.50 (s,1H), 5.13 (s,2H), 5.72 (s,1H) and 7.37 (s,5H)ppm.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH:10]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:11][C:12](=O)[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:7][CH:8]=1.[NH2:39][NH2:40].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CCO>[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:9]2[N:39]=[N:40][C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)=[CH:11][C:10]=2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccncc3)c(-c3cccc(C(F)(F)F)c3)nn2)CC1
Reaction time: 4 h
Yield: 73.5 %

Procedure:
Under Ar, a solution of 13 (2.2 g, 4.2 mmol) in EtOH (50 mL) was treated with hydrazine (306 mg, 9.6 mmol). After 4 h, the reaction was concentrated to dryness and the residue was partitioned between water-EtOAc (3×). The EtOAc extracts were backwashed with brine, dried, filtered and concentrated to dryness. The residue was dissolved in toluene (60 mL) and 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.0 g, 4.5 mmol) was added. After 0.5 h, the reaction was chromatographed on a Still column (60 mm) and the product eluted with 90-100% EtOAc-hexanes to yield 1.6 g of 15.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH3:27]>CN(C=O)C>[CH2:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1)[CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 75 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a mixture of tert-butyl 7-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.2 g, 8 mmol) in anhydrous DMF (20 ml) was added potassium carbonate (2.43 g, 17 mmol) followed by propyl iodide (4.42 g, 26 mmol). The mixture was stirred at 75° C. for 16 hours, then evaporated under reduced pressure. The residue was taken up with EtOAc (50 ml) and washed with water and brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure to afford the titled compound as a solid (2.2 g, 88%) used in the next step without further purification. TLC—Chloroform/methanol (9/1): Rf=0.75. 1H-NMR (CDCl3, 400 MHz) δ 1.04 (3H, t), 1.50 (9H, s), 1.81 (2H, m), 2.76 (2H, m), 3.62 (2H, m), 3.91 (2H, m), 4.54 (2H, s), 6.65 (1H, s), 6.74 (1H, d), 7.04 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.Cl.[C:28]([O:32][NH2:33])([CH3:31])([CH3:30])[CH3:29].Cl>N1C=CC=CC=1>[C:28]([O:32][N:33]=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=2[Cl:26])=[CH:9][CH:10]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=Cc1ccc(CCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)ON=Cc1ccc(CCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
To a mixture of 0.43 g of 4-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)benzaldehyde and 5 ml of pyridine was added 0.15 g of O-tert-butylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.38 g (yield, 75%) of 4-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyl)benzaldehyde O-tert-butyloxime, nD25.5 1.5673.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)([CH2:13][CH2:14][O:15][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCO)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.43 g, 0.97 mmol), triethylamine (3.3 mL, 2.4 mmol), and anhydrous dichloromethane (30 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.082 mL, 1.06 mmol) at such a rate that the temperature of the reaction mixture does not rise above 2° C. Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract 3 times with 1M hydrochloric acid solution and 2 times with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.48 (silica gel, 20/1 ethyl acetate/methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C-:17]#[N:18].[Na+]>CN(C)C=O.[Cl-].[Na+]>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14][C:17]#[N:18])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of (5-bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (prepared according to WO 02/070494, 1.00 g, 3.470 mmol) in N,N-dimethylformamide (6.9 mL) was treated with sodium cyanide (350.7 mg, 6.940 mmol). The reaction mixture was stirred at 40° C. for 1 h. The reaction was diluted with a saturated aqueous sodium chloride solution (100 mL) and then extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/7 ethyl acetate/hexanes) afforded (5-cyanomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (807.6 mg, 99%) as a light yellow solid: mp 162–164° C.; EI-HRMS m/e calcd for C11H14N4O2 (M+) 234.1117, found 234.1120.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:8]=[C:7]2[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1.[O-]CC.[Na+].[CH:50]([C:52]1[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=1)=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:50]/[C:52]1[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=1)[N:8]=[C:7]2[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1
Reactant: Cn1ccnc1C=O
Reactant: COc1ccc(-c2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(/C=C/c3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl)quinazolin-2-yl]methyltriphenylphosphonium chloride (9.1 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.394 g) and ethanol (100 ml)). Then a solution of 2-formyl-1-methylimidazole (1.7 g) in ethanol (10 ml) was added dropwise. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/methanol (20/1, v/v) gave (E)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[2-(1-methylimidazol-2-yl)vinyl]quinazoline (5.1 g, 82%) which was then recrystallized from ethanol-chloroform.