Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.[CH2:25]([O:27][C:28](=[O:47])[C@H:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH3:26].C(N(CC)CC)C>CN(C=O)C>[O:23]=[C:9]1[C:8]2[C:7]3[CH:24]=[C:3]([CH2:2][NH:38][C:35]4[CH:36]=[CH:37][C:32]([C:31]([NH:30][C@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:47])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])=[CH:33][CH:34]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[NH:10]1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(NC(=O)C(C)(C)C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC

Procedure:
To a hot solution of N-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g, 3.0 mmol) in benzene (250 ml) under nitrogen were added N-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and 2,2'-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). The solution was stirred at reflux for 1.5 hours and then concentrated in vacuo to give crude N-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5 g, 7.8 mmol)(Aldrich) in DMF (10 ml) were stirred under nitrogen at 105°-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5 ml, 3.6 mmol) was added and the solution was concentrated under high vacuum. The residue was purified by chromatography on silica gel (130 g) eluting with ethyl acetate:methylene chloride (1:19->2:3), followed by recrystallization of the solid from ethanol/diethyl ether. This was filtered and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.32 g) as a white solid. The filtrate was concentrated and the residue purified by chromatography and crystallization to give an additional 0.243 g. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.16 (t, J=7 Hz, 3H, ester CH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, glu CH2), 2.39 (t, J=7 Hz, 2H, glu CH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.07 (q, J=7 Hz, 2H, ester CH2), 4.30-4.40 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 -CH2), 6.63 (d, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH), 7.63 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8,2 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.21 (d, J=8 Hz, 1H, glu NH), 8.22 (d, J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N2H), 12.30 (br s, 1H, NH). Mass spectrum (CI-CH4) 630 (M+1, 6.5%), 243 (100%). Anal. Calculated for C34H39N5O7 : C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74; H, 6.25; N, 11.10.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]2[O:15][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[N:7][C:6]([NH2:23])=[N:5]1.[C:24](=O)([O-])[O-:25].[K+].[K+]>CC(C)=O>[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]2[O:15][C:16]([CH2:19][N:20]([CH3:21])[CH3:22])=[CH:17][CH:18]=2)=[N:7][C:6]([NH:23][CH:24]=[O:25])=[N:5]1
Reactant: CN(C)Cc1ccc(CSCCNc2nc(N)nn2C)o1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)Cc1ccc(CSCCNc2nc(NC=O)nn2C)o1
Temperature: 5 °C
Yield: 13.9 %

Procedure:
A stirred suspension of 1-methyl-N5 -[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-1H-1,2,4-triazole-3,5-diamine, dihydrochloride (3.83 g) and potassium carbonate (3.04 g) in acetone (60 ml) was heated at reflux for 30 min, and then cooled to 5° C. Aceticformic anhydride (1.32 g) was added and the suspension was allowed to warm up to room temperature. The inorganic material was filtered off and the solution evaporated to give an oil which was chromatographed. The resulting oil was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and evaporated to afford the title compound (0.47 g) as a colourless oil. tlc System B, Rf 0.61. Nmr. (CDCl3) 0.28 brd, (1H); 0.93 d, (1H); 3.81,s, (2H); 5.25, brt (1H); 6.28,s, (2H); 6.47,s, (3H); 6.52 s+m (2H); 7.16,t, (2H) 7.74,s, (6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH3:19][CH:20]([N:22]1[C:26]([NH2:27])=[CH:25][CH:24]=[N:23]1)[CH3:21]>C1C=CC=CC=1>[CH3:19][CH:20]([N:22]1[C:26]2[N:27]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:25]=2[CH:24]=[N:23]1)[CH3:21]
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1cnn2C(C)C
Temperature: 62 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (600 mg, 2.397 mmol) in benzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and the reaction mixture was stirred at 62° C. overnight. The mixture was concentrated in vacuo and the residue was dissolved into acetic acid (3 mL). The solution was stirred at reflux for 1 h and concentrated in vacuo. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give 530 mg (65%) of product. LCMS E-S (M+H)=340.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.57 (m, 3 H), 1.61-1.71 (m, 6 H), 3.88-3.96 (s, 3 H), 4.55 (q, J=7.2 Hz, 2 H), 5.46 (m, 1 H), 7.03-7.12 (m, 2 H), 8.13-8.25 (m, 3 H), 8.36-8.43 (m, 1 H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])=[C:21]=[S:22].O(C(C)C)C(C)C>O1CCCC1>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:20][C:21]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)=[S:22])([O-:31])=[O:30]
Reactant: CCOC(=O)N1CCC(NCc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)N1CCC(N(Cc2ccccc2)C(=S)Nc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 42.5 parts of ethyl 4-[(phenylmethyl)amino]-1-piperidinecarboxylate, 30 parts of 1-isothiocyanato-2-nitrobenzene and 270 parts of tetrahydrofuran was stirred for 3 hours at room temperature. 2,2'-Oxybispropane was added and stirring was continued overnight. The precipitated product was filtered off and dried, yielding 48.5 parts (68.5%) of ethyl 4-[[[2-nitrophenyl)-amino]thioxomethyl(phenylmethyl)amino]-1-piperidinecarboxylate; mp. 140° C.; (intermediate 30).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.O>CN(C)C=O>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: Clc1nc2ccccc2o1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1nc2ccccc2o1

Procedure:
To a stirred solution of 1,3-propanediol (65 g) in dimethylformamide (60 ml) was added sodium hydride (3.0 g, 60% dispersion in oil) portionwise. The mixture was stirred until effervescence had ceased. A solution of 2-chlorobenzoxazole (11.4 g) in dimethylformamide (30 ml) was added dropwise. The reaction mixture was stirred at room temperature overnight. The mixture was added to water (600 ml) and extracted with ethyl acetate (3×300 ml). The combined organic extracts were washed with water (2×300 ml), brine (2×300 ml), dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as an oil following chromatography on silica gel in 3% methanol in dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2.I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[F:12][C:10]1[CH:11]=[C:2]([NH:1][C:32]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[NH:33])[CH:3]=[C:4]2[C:9]=1[N:8]([CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: CN(CCN1CCCc2cc(N)cc(F)c21)C(=O)Oc1ccccc1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a stirred solution of phenyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (426 mg, 1.241 mmol) in ethanol (12 ml) was added methyl thiophene-2-carbimidothioate hydroiodide (708 mg, 2.481 mmol). The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was then diluted with water and sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 40-100% ethyl acetate in hexanes, giving the desired phenyl 2-(8-fluoro-6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate 52 (422 mg, 0.933 mmol, 75% yield). 1H NMR (DMSO-d6) δ 7.74-7.71 (m, 1H); 7.59-7.57 (m, 1H); 7.41-7.36 (m, 2H); 7.23-7.18 (m, 1H); 7.14-7.07 (m, 3H); 6.50-6.42 (m, 3H); 6.37 (s, 1H); 3.62 (t, J=6 Hz, 1H); 3.51 (t, J=6 Hz, 1H); 3.30 (t, J=6 Hz, 1H); 3.23 (t, J=6 Hz, 1H); 3.15-3.09 (m, 2H); 3.09, 2.97 (2s, 3H); 2.69 (t, J=6 Hz, 2H); 1.83-1.75 (m, 2H). EI-MS (m/z, %): 452 (M+, 8); 288 (60); 179 (100).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:20]([NH2:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:16]([F:19])([F:18])[S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:23][CH2:20][CH2:21][CH3:22])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CCCN
Reactant: O=S(=O)(c1ccc2c(c1)OC(CBr)OC2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNCC1OCc2ccc(S(=O)(=O)C(F)(F)F)cc2O1
Yield: 58.5 %

Procedure:
2-(bromomethyl)-7-[(trifluoromethyl)sulfonyl]-4H-1,3-benzodioxine (1.0 g, 2.77 mmol), propan-1-amine (2.27 ml, 27.7 mmol), potassiumcarbonate (0.57 g, 4.15 mmol) and ACN were heated at 60° C. for 16 h. The volatiles were evaporated and the crude product was purified by flash column chromatography using EtOAc/MeOH (10:1) as eluent, to afford the title product (0.55 g, 58%). The amine (0.30 g) was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 201° C. MS m/z (rel. intensity, 70 eV) 339 (M+, 5), 310 (22), 239 (18), 222 (8), 72 (bp).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]([NH2:15])=O)[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cc(O)nc(SCC(N)=O)n1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1cc(Cl)nc(SCC#N)n1

Procedure:
To a suspension of 4.5 g. (0.02 mole) of 2-(4-hydroxy-6-propyl-2-pyrimidinylthio)acetamide in 50 ml of phosphorus oxychloride was added 2.98 g. of N,N-diethylaniline. The mixture was heated for ten minutes to reflux temperature. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured into 150 ml of ice-water. The water mixture was extracted with 100 ml of ether. The ether layer was dried over magnesium sulfate, filtered and evaporated in a rotary evaporator to give an oil. A small amount of the oil was dried in vacuo without purification to afford the analytical sample.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:28][OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([O:29][CH2:28][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=1)=[CH:14][CH:15]=2)(=[O:32])[CH3:31]
Reactant: OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1
Reactant: CC(=O)Cl
Product: CC(=O)OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from {1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol -2-yl}methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 440. 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.77 (d, 2H, J=8.87 Hz), 7.48-7.40 (m, 4H), 7.29-7.22 (m, 3H), 7.00 (d, 2H, J=7.01 Hz), 6.72 (s, 1H), 5.50 (s, 2H), 5.24 (s, 2H), and 1.80 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16](=[O:26])[NH:17][C@@H:18]([C:20]2C=CC=CC=2)C)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([O:15][C:16](=[O:26])[NH:17][CH2:18][CH3:20])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCNC(=O)O[C@H](c1ccccc1)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using ((R)-1-phenyl-ethyl)-carbamic acid 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N-:14]=[C:15]=[O:16].C([NH+](CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([NH:13][C:15]([NH2:14])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: [N-]=C=O
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
14.1 g of dodecylamine (0.076 mol) dissolved in 20 ml of chloroform were added dropwise at room temperature with stirring to 100 ml of a solution of 10 g of triethylammonium isocyanate (0.069 mol) in chloroform, prepared according to Example 1. After completion of the addition the mixture was subsequently stirred at room temperature for 24 hours and heated to reflux for 1 hour. The solvent was evaporated and the residue was recrystallized from chloroform. 9.45 g, i.e. 60% of theory, of dodecylurea were obtained in this way.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:13]=[C:12]([O:14]C)[C:11]([O:16][CH3:17])=[CH:10][C:7]=1[CH:8]=[O:9]>C(Cl)Cl>[F:5][C:6]1[CH:13]=[C:12]([OH:14])[C:11]([O:16][CH3:17])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C=O)c(F)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
AlCl3 (8.69 g, 65.2 mmol) was added to a solution of 2-fluoro-4,5-dimethoxy-benzaldehyde (2.00 g, 10.9 mmol) in DCM (100 mL) under an atmosphere of argon. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was slowly quenched with water. The layers were separated and the aqueous layer was then extracted with ethyl acetate (3×). The combined organic layers were dried over sodium sulfate and then evaporated to dryness to yield 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.82 g, 98%) as an off white solid. ESI-MS m/z calc. 170.0. found 171.0 (M+1)+. Retention time: 0.84 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 7.22 (d, J=6.7 Hz, 1H), 6.73 (d, J=11.9 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH3:12]
Reactant: CCCI
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(I)cc1
Yield: 91.6 %

Procedure:
A mixture of 4-iodophenol (6.6 g), 1-iodopropane (5.1 g), anhydrous potassium carbonate (13.8 g) and acetone (100 ml) was stirred at reflux for 6 hours. Two further portions of 1-iodopropane were added after one hour (5.1 g) and two hours (5.1 g). The acetone was removed by evaporation, the residue was treated with water (100 ml) and the mixture extracted with dichloromethane (2×30 ml). The organic extracts were combined, dried (MgSO4) and evaporated. The residue, an oil, was distilled at 150° C. and 0.5 mm pressure (using a Kugelrohr oven) to give 4-n-propoxyiodobenzene as a colourless oil (7.2 g), NMR(CDCl3): 0.9-1.08(3H,t), 1.7-1.9(2H,m), 3.82-3.92(2H,t), 6.62-6.72(2H,d), 7.5-7.6(2H,d); m/z 262 (M).
Reaction SMILES: [CH2:1]([S:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.CCCCCC>[C:15]1([S:21]([N:8]2[CH:4]([S:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]2=[O:9])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCSC1CCC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCSC1CCC(=O)N1S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
To 3.1 g of 5-ethylthio pyrrolidin-2-one in 130 cm3 of tetrahydrofuran there is added at -65° C., 14.2 cm3 of a 1.6M solution of butyllithium in hexane. After 20 minutes, there is added 3.77 g of benzenesulphonyl chloride in 15 cm3 of tetrahydrofuran. After allowing to return to ambient temperature and concentrating to dryness under reduced pressure, 4 g of the expected product is obtained. m.p. 100°-113° C., crystallized from ethanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:5](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=2)[S:6][CH:7]=1.NCCCN1C(CO[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=CSC1=NC1C=CC(OC(F)(F)F)=CC=1.Cl>>[NH2:20][CH2:19][CH2:18][CH2:17][N:4]1[C:3]([CH2:2][O:1][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:7][S:6][C:5]1=[N:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=1
Reactant: COc1ccc(N=c2scc(CO)n2CCCNC(=O)OC(C)(C)C)nc1
Reactant: NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: COc1ccc(N=c2scc(COCc3ccccc3)n2CCCN)nc1

Procedure:
The compound (283 mg) obtained in the above (1) was treated in a similar manner to in Example 208 (3), (4) to give the title compound (128 mg) as hydrochloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:4])=[O:3].[Br:17]Br.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:17][C:11]1[C:10]([O:15][CH3:16])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]2
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1Br
Reaction time: 24 h

Procedure:
A solution of 2-methanesulfonyl-6-methoxy-quinoline (237 mg, 1 mmole ) in CH2Cl2 was treated with 2 mmoles Br2 and stirred for 1 day. The mixture was poured into a solution of NaHCO3 and sodium thiosulfate. The product was extracted with CH2Cl2. The organic layer was dried and evaporated to afford 5-bromo-2-methanesulfonyl-6-methoxy-quinoline, 287 mg (91%), as white crystals.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)(C)C>[CH:1]1([NH:6][C:7]2[N:8]=[C:9]([NH:20][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=[C:11]([Cl:13])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1cc(Cl)nc(NC2CCCC2)n1
Reactant: NC1CCCC1
Solvent: CC(C)O
Product: Clc1cc(NC2CCCC2)nc(NC2CCCC2)n1
Reaction time: 6 h

Procedure:
5.0 g of 2-(cyclopentylamino)-4,6-dichloropyrimidine are dissolved in 25 ml of isopropanol, then 7.5 ml of cyclopentylamine are added and the mixture is boiled for 6 hours. Then the reaction mixture is evaporated, the residue is separated between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, dried and evaporated. The title compound is obtained by recrystallizing from hexane in a yield of 5.24 g (86.7%), m.p.: 94°-98° C.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4CCCCO4)=[CH:19][CH:18]=3)[CH:12]=[C:13]2[NH2:16])=[N:8]1.[Br:30][C:31]1[N:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:30][C:31]1[N:36]=[C:35]([C:37]([NH:16][C:13]2[CH:12]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:10]=[C:9]3[C:14]=2[CH:15]=[N:7][NH:8]3)=[O:38])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Nc1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2ccc(O)cc2)cc2[nH]ncc12)c1cccc(Br)n1
Temperature: 70 °C
Reaction time: 120 h

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (500 mg, 1.27 mmol), 6-bromo-2-pyridinecarboxylic acid (272 mg, 1.35 mmol), HATU (531 mg, 1.35 mmol) and DIPEA (0.442 ml, 2.54 mmol) were combined in DMF (10 ml) and heated at 70° C. overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with DCM:MeOH:ammonia. Appropriate fractions were combined and the solvent was removed in vacuo. The residue was dissolved in Methanol (20 ml) and 4 M HCl in dioxane (2 ml) and stirred at RT for 5 days. A small amount of the reaction mixture was removed (2 ml), the solvent was removed in vacuo and the residue purified by MDAP (Method B) to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:16]=[CH:15][C:10]([NH:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:16]=[CH:15][C:10]([N:11]([CH:12]([CH3:14])[CH3:13])[C:3](=[O:4])[CH2:2][Cl:1])=[CH:9][CH:8]=1
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Product: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
357.5 parts (3.2 mol) of chloroacetyl chloride are added dropwise over the course of 2 hours at from 10° to 20° C. to 920 parts of 4-fluoro-N-isopropylaniline solution (~3 mol of 4-fluoro-N-isopropylaniline) from Example 1. Stirring is subsequently carried out at 20° C. for one hour and then the majority of the hydrogen chloride formed is removed as a gas by heating to about 90° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][N:17]2[C:19](=[O:29])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=[C:16]2[N:15]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:31]=2)[CH2:14]1)C1C=CC=CC=1.ClCCl.[H][H]>[Pd].CO>[NH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][N:17]2[C:19](=[O:29])[CH:20]=[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:22]=[C:16]2[N:15]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:31]=2)[CH2:14]1
Reactant: [H][H]
Reactant: O=C(NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NCCC1CN(c2ccnc(NCCc3ccccc3)n2)c2nc(-c3ccccc3)cc(=O)n2C1

Procedure:
A solution of {2-[6-Oxo-1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido[1,2-a]pyrimidin-3-yl]-ethyl}-carbamic acid benzyl ester (100 mg, 0.17 mmol), dichloromethane (5 mL) and methanol (15 mL) was added 10% palladium on carbon (5 mg) and stirred at room temperature over an atmosphere of hydrogen overnight. Reaction filtered through a bed of Celite, and solvent removed under vacuum to afford a white solid. M+1=468.