Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([N:32]([CH3:34])[CH3:33])=[N:30][CH:31]=2)[CH:21]=1)(=O)C>>[CH3:33][N:32]([CH3:34])[C:29]1[N:28]=[CH:27][C:26]([C:22]2[CH:21]=[C:20]([NH:19][C:5]3[CH:6]=[CH:7][C:8]([N:10]4[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH:25]=[CH:24][CH:23]=2)=[CH:31][N:30]=1
Reactant: CC(=O)Nc1cccc(-c2cnc(N(C)C)nc2)c1
Reactant: O=[N+]([O-])c1cc(-n2cccc2)ccc1F
Product: CN(C)c1ncc(-c2cccc(Nc3ccc(-n4cccc4)cc3[N+](=O)[O-])c2)cn1
Yield: 20 %

Procedure:
N-(3-(2-(Dimethylamino)pyrimid-5-yl)phenyl)-2-nitro-4-(1-pyrrolyl)aniline (3f) was prepared analogously from 1a and 2i. Yield: 20%. Mp 166-168° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]3[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][CH:14]3O)=[O:11])=[CH:8][C:7]=2[F:26])[CH2:3][CH2:2]1.C(N(CC)CC)C.O>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]3[O:11][C:22]4[CH2:21][C:16]5([O:20][CH2:19][CH2:18][O:17]5)[CH2:15][CH2:14][C:13]=4[N:12]=3)=[CH:8][C:7]=2[F:26])[CH2:2][CH2:3]1
Reactant: O=C(NC1CCC2(CC1O)OCCO2)c1ccc(OCC2CC2)c(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluoro-N-(7-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzamide (4.53 g) in dimethyl sulfoxide (40 mL) were added triethylamine (5.18 mL) and sulfur trioxide-pyridine complex (5.92 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (30 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (4.66 g), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.18 g).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH:6]1([NH2:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[S:27][CH2:26][CH2:25][NH:24]1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[S:27][CH2:26][CH2:25][N:24]1[CH2:2][C:3]([NH:16][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: NC1CCCc2ccccc21
Reactant: COc1ccc(CC2NCCSc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3SCCN2CC(=O)NC2CCCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with rac-1,2,3,4-tetrahydro-naphthalen-1-ylamine and 9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[C:5]([SH:10])[CH:4]=1.Br[CH2:12]Br>CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[S:10]1[C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[N:8]=[CH:7][C:6]=2[O:9][CH2:12]1
Reactant: BrCBr
Reactant: OCc1cc(S)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1cc2c(cn1)OCS2
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of 6-(hydroxymethyl)-4-mercapto-3-pyridinol (500 mg, 3.2 mmol) in anhydrous DMF, potassium carbonate was added. The reaction mixture was stirred for 10 minutes and dibromomethane (0.44 mL, 6.4 mmol) was added. The reaction mixture was stirred at 70° C. for 18 hours under an argon atmosphere. DMF was removed in vacuo and the residue was partitioned between 5% MeOH in dichloromethane and water. The aqueous layer was extracted several times with 5% methanol in dichloromethane. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 3-5% methanol in dichloromethane to afford the product as a solid (381 mg, 70%); MS (+ve ion electrospray) m/z 170 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 91 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)2-n-hexyloxyiminoacetate (syn isomer, 29.1 g.), methanol (97.2 ml.), 2 N aqueous solution of sodium hydroxide (97.2 ml.) and tetrahydrofuran (50 ml.) were treated in a similar manner to that of Example F-(4) to give 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 24.0 g.), mp. 174° C. (dec.).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:27][C:28]1([CH2:36][NH2:37])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>O1CCCC1>[OH2:3].[OH:27][C:28]1([CH2:36][NH:37][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1.[OH:27][C:28]1([CH2:36][NH:37][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1
Reactant: NCC1(O)CN2CCC1CC2
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC2(O)CN3CCC2CC3)cc1
Product: O
Reaction time: 0.75 h
Yield: 105.9 %

Procedure:
A solution/suspension of 4-[(methanesufonyl)amino]benzoic acid (1.62 g, 7.5 mmol) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.38 g, 8.5 mmol), stirred for 45 minutes, and degassed under a stream of nitrogen over 15 minutes. A solution of 3-hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethanamine (1.56 g, 10 mmol) in anhydrous tetrahydrofuran (6 mL) was added, and the mixture soon became cloudy. After 18 hours at room temperature and 90 minutes at 50° C. the mixture was concentrated in vacuo and the residue was triturated from acetonitrile. The foamy solid thus obtained was filtered through alumina (eluted with 1:1 methanol/tetrahydrofuran) and the filtrate was concentrated in vacuo and recrystallized from 2-propanol/ether to afford 1.92 g (71%) of the title compound as a hygroscopic voluminous colorless solid (water soluble); mp 123°-125° C. (foam).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[CH3:36][O:37][CH2:38][C:39](O)=O>>[CH3:36][O:37][CH2:38][C:39]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COCC(=O)O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Product: COCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 178, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and methoxyacetic acid were reacted to give 161. LCMS: M+H−=535.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.13 (d, 1H), 7.71 (d, 1H), 7.32 (m, 2H), 5.08 (s, 2H), 4.26 (s, br, 4H), 4.02 (s, 1H), 3.83 (s, 3H), 3.78 (m, 4H), 3.73 (s, 2H), 3.27 (s, 3H), 2.90 (m, 2H), 2.00 (m, 2H), 1.65 (m, 2H), 1.22 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.[CH2:27]([O:34][NH:35][C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[C:38](Cl)[N:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O1C2C=CC(N)=CC=2OCC1>>[CH2:27]([O:34][NH:35][C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[C:38]([NH:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)[N:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1NOCc1ccccc1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)c1cnc(Nc2ccc3c(c2)OCCO3)nc1NOCc1ccccc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-benzyloxy-2-chloro-5-ethoxycarbonyl-4-pyrimidineamine and 1,4-benzodioxan-6-amine were reacted to yield N4-benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.49-7.44 (m, 3H), 7.39-7.34 (m, 4H), 7.30-7.22 (m, 1H), 6.67 (d, 1H, J=8.4 Hz), 4.98 (s, 2H), 4.23-4.17 (m, 6H), 1.26 (t, 3H, J=7.2 Hz); LCMS: ret. time: 26.14 min.; purity: 95%; MS (m/e): 423 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]23[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]3)[CH:5]=[CH:6][C:7]=1[F:8].C(O)C.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C@:9]23[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]3)=[CH:3][C:2]=1[C:35]1[CH:36]=[N:31][CH:32]=[N:33][CH:34]=1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)c(Br)c3)C[C@H](O)C[C@H]2CS1)c1ccccc1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(NC1=N[C@@]2(c3ccc(F)c(-c4cncnc4)c3)C[C@H](O)C[C@H]2CS1)c1ccccc1
Temperature: 97 °C
Yield: 79 %

Procedure:
A solution of N-((4aR,6R,7aS)-7a-(3-bromo-4-fluorophenyl)-6-hydroxy-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.588 g, 1.31 mmol) in a mixture of 1,2-dimethoxyethane (8 mL), ethanol (4 mL) and water (4 mL) is purged with nitrogen and is heated to 97° C. Pyrimidine-5-boronic acid (0.810 g, 6.54 mmol), cesium carbonate (2.56 g, 7.84 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.184 g, 0.261 mmol) is added in a single portion and the reaction is heated at 97° C. for 30 minutes. The reaction is cooled, diluted with water and is extracted twice with ethyl acetate. The organic layer is dried over sodium sulfate and the crude product is purified by silica gel chromatography with a linear gradient of 0% to 40% ethyl acetate in dichloromethane over 20 minutes to give the title compound (0.464 g, 79%). ES/MS m/e: 449 (M+1).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[O:10]=[CH:11][C:12](=[CH2:14])[CH3:13].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:10][CH:11]=[C:12]([CH3:13])[CH2:14][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1)(=[O:17])[CH3:16]
Reactant: c1ccc2c(c1)OCO2
Reactant: C=C(C)C=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
reacting 1,2-methylenedioxybenzene, methacrolein and acetic anhydride with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene; and
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=2[CH2:11]O)[CH2:3][CH2:2]1.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH2:11][C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCc1c(F)cccc1C1CC1
Solvent: ClCCl
Product: Fc1cccc(C2CC2)c1CCl
Yield: 54.1 %

Procedure:
(2-Cyclopropyl-6-fluorophenyl)-methanol (4, 5.56 g, 34 mmol) was dissolved in dichloromethane (100 mL) and thionyl chloride (2.49 mL, 34 mmol) was added. The mixture was refluxed for 4 h and evaporated. The crude product was purified by column chromatography over silica, eluting with n-hexane:ethyl acetate (95:5). The title compound (3.41 g, 18.4 mmol, 54%) was isolated as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.ClCCl.ClC(Cl)(Cl)C([N:44]=C=O)=O>C(Cl)(Cl)Cl.CO>[NH2:44][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (3.0 g, 8.79 mmol) in chloroform (60 mL) at rt was added m-chloroperbenzoic acid (m-CPBA, 3.2 g, 10.5 mmol). After 2 h, the solution was transferred to a separatory funnel and washed with 10% Na2CO3 (100 mL). The aqueous layer was back-extracted with chloroform. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to yield a light orange solid. To the solid was added dichloromethane (30 mL). Trichloroacetyl isocyanate (1.05 mL, 8.79 mL) was added dropwise. After 1 h, additional trichloroacetyl isocyanate (0.3 equivalent) was added. After 1 h, the volatiles were removed under reduced pressure and the residue was dissolved in methanol (30 mL). A solution of sodium methoxide in methanol (25%, 5.0 mL) was added and the solution stirred overnight at rt and concentrated under reduced pressure. The residue was partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was extracted with dichlormethane (2×100 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) to afford a clear oil that was triturated with isopropanol (50 mL) to afford white crystals. The crystals were dissolved in methanol, concentrated under reduced pressure, and dried in a vacuum oven at 80° C. to provide 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (1.27 g, 41%) as a white frothy solid, mp 212-214° C. 1H NMR (300 MHz, DMSO-d6) δ 8.33 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (dd, J=8.3, 1.2 Hz, 1H), 7.40 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 7.22 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 6.37 (br s, 2H), 4.90 (br s, 2H), 4.88 (s, 1H), 4.70 (br s, 2H), 3.62-3.47 (m, 6H), 1.87-1.74 (m, 2H), 1.28 (m, 2H), 1.14 (t, J=7.0 Hz, 3H); MS (APCI) m/z 357 (M+H)+; Anal. Calcd for C19H24N4O3: C, 64.03; H, 6.79; N, 15.72. Found: C, 63.75; H, 7.06; N, 15.71.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:16]([N:6]1[C@H:5]([CH3:8])[CH2:4][N:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:2]([CH3:1])[CH2:7]1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CCOC(=O)N1C[C@@H](C)NC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol), and sodium carbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile was heated at reflux for 1.5 hours. The reaction was cooled to room temperature, filtered, and the solvent removed under vacuum. The residue was dissolved in 4000 mL of dichloromethane and washed with two 500 mL portions of 1 M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate and the solvent was removed to give 630 g (81%) of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[OH:1][CH:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.5 g) was dissolved in THF (7.5 ml) and cooled to −5° C. NaBH4 (0.212 g) was then added and the mixture was stirred for 1 hour at room temperature (TLC monitoring). When the reaction was complete, acetic acid was added to the mixture and the methanol was then distilled off. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product so obtained was purified by column chromatography (silica gel, 30% ethyl acetate/hexane). Yield: 1.2 g (80%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[NH:10][S:9]1(=[O:19])=[O:18].[Br:20][CH:21](CC)[CH2:22]O>>[Br:20][CH2:21][CH2:22][N:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)Nc2ccccc2CN1c1ccccc1F
Reactant: CCC(Br)CO
Product: O=S1(=O)N(c2ccccc2F)Cc2ccccc2N1CCBr
Yield: 48.3 %

Procedure:
In an analogous manner to example 25, step 4, 3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.24 g, 0.86 mmol) was treated with 2-bromobutanol (0.073 mL g, 1.0 mmol) to give 1-(2-bromoethyl)-3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.16 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[CH:19][C:18]=1[CH3:28]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([O:16][CH3:15])=[C:18]([CH3:28])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccc(C=CC(=O)O)cc1C
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3)nc2n(CC)c1=O
Yield: 38.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.00 g (13.9 mmol) of 4-methoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylsulfoxide/water to give 1.70 g (yield 36%) of Compound 110 as white flocculent precipitates.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16](F)[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH:26](C)[CH3:27])(=[O:24])=[O:23].FC1C(C=O)=CC=CC=1NS(CCC)(=O)=O>>[F:11][C:12]1[C:17]([C:18]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([I:1])[CH:3]=3)[NH:8][CH:9]=2)=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: Ic1cnc2[nH]ccc2c1
Reactant: CC(C)CS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(I)cc23)c1F

Procedure:
was prepared similarly to the protocol of Scheme 10, replacing 5-bromo-1H-pyrrolo[2,3-b]pyridine 55 with 5-iodo-1H-pyrrolo[2,3-b]pyridine 24 and 2-methyl-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 59 with propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide 67 in step 1.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)(=O)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[C:20]1([NH:19][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(OCCOS(C)(=O)=O)cc1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(OCCNc2ccccc2)cc1
Reaction time: 64 h
Yield: 82.2 %

Procedure:
To a solution of methyl 4-[2-(methanesulfonyloxy)ethoxy]benzoate (2.74 g, 10 mmol) in MeCN (50 ml), was added aniline (9.1 ml, 100 mmol) at rt. The reaction was stirred for 64 hours at reflux. The mixture was poured into H2O (200 mL), extracted with EtOAc (100 mL×2), dried over MgSO4. After removal of the solvent in vacuo, the unreacted aniline was removed in vacuo by co-evaporation with toluene (10 mL×3) at 80° C. The residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, f50 mm×150 mm, CHCl3) to give methyl 4-[2-(N-phenylamino)ethoxy]benzoate (2.23 g, 82%) as a colorless oil. 1H-NMR (CDCl3) δ3.56 (t, J=5.1 Hz, 2 H), 3.90 (s, 3 H), 4.21 (t, J=5.1 Hz, 2 H), 6.68 (dd, J=1.0 Hz, 8.6 Hz, 2 H), 6.75 (t, J=7.3 Hz, 1 H), 7.20 (AB type d, J=7.3 Hz, 2 H), 8.00 (d, J=9.1 Hz, 2 H); MS (ESI) m/z 272 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[Cl:12][C:13](Cl)=[CH:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17]>CN(C)C=O>[Cl:12][CH:13]=[C:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17]
Reactant: Oc1ccc(Cl)cc1
Reactant: C=CC(C)(C)C=C(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(=CCl)Oc1ccc(Cl)cc1
Yield: 87.1 %

Procedure:
51.4 g (0.4 mol) of p-chlorophenol are reacted, in 300 ml of dimethylformamide, with 80 ml of 30% strength sodium methylate solution (0.4 mol), and the solvent is then stripped off at 30 mbar. 33 g (0.2 mol) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene are then added to the mixture, and the latter is heated under reflux during the course of 9 hours. The working-up is according to Example A1(a). The distillation at a boiling point of 122°-130° C./0.2 mm Hg yields 44.8 g of 1-chloro-3,3-dimethyl-2-(p-chlorophenoxy)-1,4-pentadiene, which are 87% of theory.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:19]=[C:18]([C:28]#[N:29])[N:17]=2)=[CH:12][C:11]=1[C:30]([F:33])([F:32])[F:31].C(N(C(C)C)CC)(C)C.Br[CH2:44][C:45]([NH2:47])=[O:46]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:28]([C:18]1[N:19]=[C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:26][CH2:27]2)[CH:21]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[C:11]([C:30]([F:31])([F:33])[F:32])[CH:12]=2)[N:17]=1)#[N:29]
Reactant: NC(=O)CBr
Reactant: COc1ccc(-c2cc(N3CCNCC3)nc(C#N)n2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(N3CCN(CC(N)=O)CC3)nc(C#N)n2)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
4-(4-Methoxy-3-trifluoromethyl-phenyl)-6-piperazin-1-yl-pyrimidine-2-carbonitrile trifluoroacetic acid salt (50 mg), diisopropylethylamine (40 mg) and 2-bromoacetamide (22 mg) were dissolved in acetonitrile (2 ml) and the mixture was stirred at 65° C. overnight. Mixture was partitioned between ethyl acetate (10 ml) and water (10 ml), organics were dried and evaporated under reduced pressure to afford a white solid. Purification by prep-HPLC afforded 18 mg of 2-{4-[2-Cyano-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-acetamide trifluoroacetic acid salt as a white solid.