Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[S:9]([O:13][CH:17]1[CH:16]2[CH2:2][CH2:1][N:3]([CH2:14][CH2:15]2)[C:4]1=[CH2:5])(=[O:11])(=[O:10])[CH3:8]
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Product: C=C1C(OS(C)(=O)=O)C2CCN1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 8 g (58 mmol) of the alcohol of Preparation A and 60 mL of tetrahydrofuran. To thesystem (cooled in an ice/acetone bath) was added 17.9 mL (128 mmol) of triethylamine followed by 5.13 mL (66 mmol) of methanesulfonyl Chloride over a period of 15 minutes. The mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was partitioned between 2N aqueous sodium hydroxide and chloroform, the layers were separated and the aqueous phase was extracted with chloroform. The combined chloroform fractions were dried (Na2SO4) and concentrated (rotary evaporator). The crude material was purified by flashcolumn chromatography (300 g of silica gel) using 1:9 methanol/chloroform as the eluant to obtain 5.3 g of the desired product. 1HNMR (CDCl3) delta 1.48 (m, 2H), 1.68 (m, 1H), 1.84 (m, 1H), 2.28 (m, 1H),2.76 (m, 1 H), 2.94 (m, 3H), 3.04 (s, 3H), 5.08 (d, 1H, J=5), 5.14 (s, 1H),5.24 (d, 1H, J=5).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1>>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=3)=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C(O)c1cccc(COc2ccc(-c3ccc4c(c3)OCO4)cc2)c1

Procedure:
3-(4-Benzo[1,3]dioxol-5-yl-phenoxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3,4-methylenedioxybenzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=349.
Reaction SMILES: [F:1][C:2]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].Cl[S:20]([OH:23])(=[O:22])=[O:21].[OH-:24].[Na+:25]>O>[S:20]([O-:23])([O-:24])(=[O:22])=[O:21].[Na+:25].[F:1][C:2]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])([C:7]([F:9])([F:10])[F:8])[C:3]([F:6])([F:5])[F:4].[Na+:25]
Reactant: O=S(=O)(O)Cl
Reactant: [OH-]
Agent: OCCCCCCOC(F)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])[O-]
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A 100 ml four-necked flask fitted with a stirrer, thermometer, addition funnel and gas inlet was charged with 24.1 g (0.08 m) of 6-hydroxyhexyl perfluoroisopropyl ether, cooled under nitrogen to 15° C. and held for one half hour. Chlorosulfonic acid (10.3 g, 0.08 m) was added over a period of 30 minutes with stirring while maintaining the temperature at 15°-20° C., reaction was quite exothermic. Stirring was continued for one hour when the addition was completed. The reaction mixture was poured into a solution of 6.9 g of 50% sodium hydroxide in 68 g of cold water. The resulting solution was clear and colorless containing 27.2% by weight of 6-hydroxy perfluoroisopropyl ether sodium sulfate and was designated as Product I (A).
Reaction SMILES: [CH3:1][C:2]1([OH:6])[CH2:5][CH2:4][CH2:3]1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:7]([O:6][C:2]1([CH3:1])[CH2:5][CH2:4][CH2:3]1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(O)CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(C)CCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 1-methylcyclobutanol (6.2 g, 72.0 mmol) in DCM (50 mL) was added DMAP (0.440 g, 3.60 mmol) and TEA (15.05 mL, 108 mmol). Then, the mixture was cooled to 0° C. and acetic anhydride (13.46 mL, 108 mmol) was added and stirred at room temp for 24 h. The mixture was then washed with sat.NaHCO3 (100 mL), 1N HCl (100 mL), 10% NaOH (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to afford 1-methylcyclobutyl acetate (8 g, 62.4 mmol, 87% yield) as light yellow oil which was used in the next step as is without further purification. 1H NMR (500 MHz, CDCl3) δ 2.36-2.26 (m, 2H), 2.18-2.11 (m, 2H), 2.01-1.98 (m, 3H), 1.87-1.76 (m, 1H), 1.72-1.63 (m, 1H), 1.55 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:8][C:9]2[C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11](=[O:21])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1([CH3:40])[O:35][CH:33](O)[C@H:32]([OH:36])[C@H:31]([OH:37])[C@H:30]1[O:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[CH3:28][C:29]1([CH3:40])[O:35][C@@H:33]([O:20][C:17]2[CH:16]=[CH:15][C:14]3[C:9]([O:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:10][C:11](=[O:21])[O:12][C:13]=3[C:18]=2[CH3:19])[C@H:32]([OH:36])[C@H:31]([OH:37])[C@H:30]1[O:38][CH3:39]
Reactant: Cc1c(O)ccc2c(OC(c3ccccc3)c3ccccc3)cc(=O)oc12
Reactant: CO[C@@H]1[C@@H](O)[C@@H](O)C(O)OC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2ccc3c(OC(c4ccccc4)c4ccccc4)cc(=O)oc3c2C)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A mixture of 91.13 g of the product of Stage B, 58.6 g of 6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranose and 80 g of triphenylphosphine in 900 ml of dichloromethane is cooled down to 0° C. 60 ml of diisopropylazodicarboxylate is added dropwise. Agitation is carried out for 1 hour at ambient temperature. 34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added. Agitation is carried out for 1 hour at ambient temperature. 34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added and agitation is carried out for 12 hours at ambient temperature. The reaction medium is concentrated under vacuum then chromatographed eluting with a toluene/isopropyl alcohol mixture (95-5). After combining the fractions, evaporating the solvents, and recrystallization from isopropyl ether, 86.33 g of sought product is obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]12([N:14]=[C:15]=[S:16])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2>CCO>[C:4]12([NH:14][C:15](=[S:16])[NH:2][NH2:3])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=S)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of 1.5 g (0.03 mol) of hydrazine hydrate in 50 mL of EtOH was treated with 3.86 g (0.02 mol) of 1-adamantyl isothiocyanate, and stirred for 1 hr at room temp. The product was collected and washed 2 times with EtOH, affording 4.33 g (96%) of 4-(1-adamantyl)-3-thiosemicarbazide, mp 206°-207° C. dec. This thiosemicarbazide is disclosed in Chemical Abstracts, 70:11223 (1969); and in U.S. Pat. No. 3,406,180.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4](P(OCC)(OCC)=O)[CH3:5].[H-].[Na+].[C:17]([O:21][C:22]([C:24]1[S:25][C:26]([CH:29]=O)=[CH:27][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([C:24]1[S:25][C:26](/[CH:29]=[C:4](/[C:3]([O:2][CH3:1])=[O:14])\[CH3:5])=[CH:27][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reactant: CCOP(=O)(OCC)C(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C/c1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
2-(Diethylphosphono)propanoic acid methyl ester (23.0 g, 0.103 mol) was dissolved in tetrahydrofuran (150 mL), 60% sodium hydride (2.4 g, 0.06 mol) was added at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example 1, step 2(11.0 g, 0.052 mol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N-hydrochloric acid solution, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography to give the title compound (13.1 g, 0.047 mol, 90%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20].[CH3:23][N:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=3)[CH:32]=[CH:31][N:30]=2)[CH:26]=[N:25]1>C(Cl)Cl.O>[CH:1]1([N:7]2[CH2:11][CH2:10][N:9]([C:19]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][C:33]4[CH:32]=[CH:31][N:30]=[C:29]([C:27]5[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=5)[CH:34]=4)=[CH:41][N:40]=3)=[O:20])[C:8]2=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCN1C1CCCCC1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCCCC5)C4=O)nc3)ccn2)cn1
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
A solution of Example B7 (0.085 g, 0.505 mmol) and pyridine (0.133 g, 1.684 mmol) in DCM (2 mL) was added to phosgene (20% in toluene, 0.833 g, 1.684 mmol), under Ar, stirred for 15 min, then concentrated to dryness. The residue was dissolved in DCM (2 mL), treated with a solution of Example A2 (0.09 g, 0.337 mmol) and TEA (0.102 g, 1.010 mmol) in DCM (2 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-cyclohexyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (100 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.96 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 6.70 (dd, J=5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.79 (m, 2 H), 3.61 (m, 1 H), 3.43 (m, 2 H), 1.67 (m, 5 H), 1.35 (m, 4 H), 1.08 (m, 1 H); MS (ESI) m/z: 462.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(C)c4)nc23)ccn1
Yield: 51.8 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (113 mg, 52%). MS (ISP) 437.5 [(M+H)+]; mp 237° C.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH:13]1([CH2:19][CH2:20][C:21](OC)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1.C(O)(=O)C.O>[CH:13]1([CH2:19][CH2:20][C:21](=[O:22])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CCC1CCCCC1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
n-Butyl lithium (1.63N, 45.1 ml, 73 mmol) was added dropwise to a stirred solution of dimethyl methylphosphonate (9.05 g, 73 mmol) in 100 ml of anhydrous THF at -78° C. under argon atmosphere. After 30 minutes, a solution of methyl 3-cyclohexylpropionate (5.0 g, 29.4 mmol) in 10 ml of anhydrous THF was further added dropwise and the mixture was stirred for 30 minutes. This reaction solution was allowed to warm to 0° C., diluted with 4.4 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml ×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 4-cyclohexyl-2-oxobutylphosphonate (6.3 g, 24 mmol, yield 81.7%, b.p. 138°-142° C./0.05 mmHg), which was assigned the structure by the following data:
Reaction SMILES: C(OC(N1CCCCC1C1N2C(C=NC(NC3C=CC(N4CCOCC4)=CC=3)=N2)=CC=1)=O)(C)(C)C.C(OC([N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55]3[N:63]4[C:58]([CH:59]=[N:60][C:61]([NH:64][C:65]5[CH:70]=[CH:69][C:68]([N:71]6[CH2:76][CH2:75][N:74]([CH3:77])[CH2:73][CH2:72]6)=[CH:67][CH:66]=5)=[N:62]4)=[CH:57][CH:56]=3)[CH:50]=2)[CH2:45][CH2:44]1)=O)(C)(C)C>>[CH3:77][N:74]1[CH2:75][CH2:76][N:71]([C:68]2[CH:69]=[CH:70][C:65]([NH:64][C:61]3[N:60]=[CH:59][C:58]4=[CH:57][CH:56]=[C:55]([C:51]5[CH:52]=[CH:53][CH:54]=[C:49]([N:46]6[CH2:45][CH2:44][NH:43][CH2:48][CH2:47]6)[CH:50]=5)[N:63]4[N:62]=3)=[CH:66][CH:67]=2)[CH2:72][CH2:73]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(N6CCN(C(=O)OC(C)(C)C)CC6)c5)n4n3)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCCCC1c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(N6CCNCC6)c5)n4n3)cc2)CC1

Procedure:
The titled compound was prepared in an analogous fashion to Example 1129 replacing [2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester with 4-(3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester to give a yellow solid (180 mg, 76%). LCMS (E/I+) 469.21 (M+H). NMR 1H (DMSO-d6)-975 (s, 1H), 9.31 (s, 1H), 8.94 (s, 1H), 8.61 (bs, 1H), 7.89 (q, 1H, J=7.30 Hz), 7.68 (d, 2H, J=7.76 Hz), 7.56 (s, 1H), 7.45 (t, 1H, J=7.76 Hz), 7.18 (d, 1H, J=4.57 Hz), 7.04 (d, 1H, J=8.22 Hz), 6.89-6.99 (m, 3H), 3.77 (d, 2H, J=13.72 Hz), 3.54 (d, 2H, J=11.76 Hz), 3.41 (bs, 4H), 3.24 (bs, 4H), 3.10-3.21 (m, 2H), 2.82-2.98 (m, 5H).
Reaction SMILES: C([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)OC(C1C=CC=CC=1)=C(O)C2=O)=C.BrC1C=CC([CH:32]=[O:33])=CC=1>>[C:21]1([C:4]2[CH:3]=[CH:12][CH:11]=[CH:10][CH:5]=2)[CH:22]=[CH:23][C:24]([CH:32]=[O:33])=[CH:25][CH:26]=1
Reactant: C=Cc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1-c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=Cc1ccc(-c2ccccc2)cc1

Procedure:
Alternatively, a vinyl phenyl hydroxyflavone may be prepared by synthesizing 4-styrene trimethyltin and combining it with 4-bromobenzaldehyde to produce 4'-vinyl, 4-biphenyl aldehyde. This intermediate compound is then reacted with 2-hydroxyacetophenone to produce the vinyl phenyl hydroxyflavone. This reaction scheme proceeds as follows: ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[F:12].[CH3:13][CH2:14][N:15](C(C)C)C(C)C.[Si](OCCN)(C(C)(C)C)(C)C>C(#N)C>[CH2:14]([NH:15][C:5]1[CH:4]=[C:3]([F:12])[C:2]([F:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: CC(C)(C)[Si](C)(C)OCCN
Solvent: CC#N
Product: CCNc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (0.5 g, 0.0028 mol) in acetonitrile (5 ml) was added DIPEA (0.98 ml, 0.0056 mol) and 2-(tert-butyldimethylsilyloxy)ethanamine (0.49 g, 0.0028 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 4 h. The reaction was concentrated and diluted with water (20 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product N-ethyl-4,5-difluoro-2-nitroaniline. (37 as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.37 (bs, 1H), 8.13-8.17 (dd, J=8.4, 8.4 Hz, 1H), 7.21-7.27 (dd, J=7.2, 7.2 Hz, 1H), 3.8-3.82 (t, J=5.2 Hz, 2H) 3.45-3.49 (m, 2H), 0.84 (s, 9H), 0.021 (s, 6H). MS (M+1=333).
Reaction SMILES: C(N)CCC.C1(=O)OCCC1.[CH2:12]([NH:16][C:17](=O)[CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:14][CH3:15].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNC(=O)CCCO
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O=C1CCCO1
Solvent: CCCCN
Product: CCCCNCCCCO
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To a solution of 3.18 gm (20 mmol) of the resultant N-butyl-4-hydroxybutyramide in 50 ml of toluene were added 120 ml (120 mmol) DIBAL(25% W). The solution was heated with stirring at 70° C. for 18 hours. After cooling to 0° C., the reaction was quenched with methanol (113 amount of DIBAL solution was used) followed by addition of saturated solution of Rochelle's salt. The mixture was extracted twice with EtOAc; the organic extracts were washed with brine and dried over Na2SO4.
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[C:4]#[C:5][C:6]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[C:12]([C:18]#[C:19][CH:20]([CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]2[S:9][CH:10]=[CH:11][C:7]=12)[CH3:2].[C:33]([Li])([CH3:36])([CH3:35])C.[CH:38]([Si:41](Cl)([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])([CH3:40])[CH3:39]>C1COCC1>[CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[C:4]#[C:5][C:6]1[C:14]2[S:15][C:16]([Si:41]([CH:42]([CH3:44])[CH3:43])([CH:33]([CH3:36])[CH3:35])[CH:38]([CH3:40])[CH3:39])=[CH:17][C:13]=2[C:12]([C:18]#[C:19][CH:20]([CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]2[S:9][C:10]([Si:41]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:38]([CH3:40])[CH3:39])=[CH:11][C:7]=12)[CH3:2]
Reactant: CCCCCCC(C#Cc1c2ccsc2c(C#CC(CC)CCCC)c2ccsc12)CC
Reactant: [Li]C(C)(C)C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCC(C#Cc1c2cc([Si](C(C)C)(C(C)C)C(C)C)sc2c(C#CC(CC)CCCC)c2cc([Si](C(C)C)(C(C)C)C(C)C)sc12)CC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A dry 250-mL three-neck flask was flushed with N2 and was charged with 4-(3-ethylhept-1-yn-1-yl)-8-(3-ethylnon-1-yn-1-yl)benzo[1,2-b:4,5-b′]dithiophene (2.0 g, 4.6 mmol) and THF (100 mL, 0.05 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 1.3 M solution of tert-butyllithium in hexanes (8.8 mL, 0.012 mol) was added drop-wise via deoxygenated syringe. After 30 minutes of stirring at −78° C., the solution was chilled to 0° C. and stirring was continued for 5 minutes, at which point the reaction mixture was cooled back to −78° C. Triisopropylsilyl chloride (4.0 mL, 0.018 mol) was added to the reaction flask drop-wise and stirring continued for 30 minutes at −76° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. As the reaction was completed, cool DI water (20 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 100 mL of cool water and extracted with MTBE (150 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by precipitation into methanol from a chloroform solution to yield white solid (3.13 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:12](OCC)=[O:13])[N:8]2[CH3:11])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:26][NH:25][C:12](=[O:13])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1n[nH]c(=O)c2c1c1ccc(Cl)cc1n2C

Procedure:
A solution of 4.38 g (13.5 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate (disclosed in WO-A-00/44751), of 65 ml of glacial acetic acid and of 2.7 ml (55.7 mmol) of hydrazine monohydrate is brought to reflux for 3 h.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:18]=[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=3)[N:10]=2)[CH2:5][CH2:4]1)#[N:2].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C>C1(C)C=CC=CC=1>[ClH:30].[NH:35]1[C:1]([CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[N:18]=[C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]5[O:27][CH2:28][O:29][C:23]=5[CH:22]=4)[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=4)[N:10]=3)[CH2:5][CH2:4]2)=[N:2][N:37]=[N:36]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CC1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Solvent: Cc1ccccc1
Product: Cl
Product: Clc1ccc2nc(N3CCC(c4nnn[nH]4)CC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 25 °C
Yield: 199.5 %

Procedure:
10 ml of toluene was added to a mixture comprising 0.50 g (0.0012 mol) of 2-(4-cyanopiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline and 0.50 g (0.0024 mol) of trimethyl stannylazide. The mixture thus obtained was heated under reflux for two days. The reaction mixture was distilled under a reduced pressure to remove the solvent. The residue was suspended in 10 ml of ethanol, followed by the addition of 10 ml of 1N hydrochloric acid. The mixture thus obtained was stirred at room temperature for several hours. The mixture was filtered to recover the crystal. The crystal was washed with water and air-dried to give 0.60 g of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](S(C)=O)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2].[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1>O1CCOCC1>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([NH:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Solvent: C1COCCO1
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(NC3CCC(O)CC3)nc21
Temperature: 95 °C
Yield: 61.1 %

Procedure:
A flask was charged with 0.312 g (0.79 mmol) of 1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one, 15 mL dioxane, and 0.273 g (2.37 mmol) of trans-4-Aminocyclohexanol, and the mixture was heated 48 hours at 95° C. The dioxane was removed under reduced pressure, and the crude residue was purified directly via column chromatography (20:1 dichloromethane/methanol). This procedure gave 0.215 g (66%) of 1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp=198° C.–204° C.; MS (APCI) m+1/z 462.