Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)C=1CCC(OCC)=O)C.[CH2:49]([O:51][C:52](=[O:98])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:75]=[C:74]([C:76](=[O:89])[NH:77][CH2:78][C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=3[O:85][CH:86]([F:88])[F:87])[CH:73]=[C:72](Br)[CH:71]=2)[C:58]=1[CH2:91][CH2:92][C:93]([O:95][CH2:96][CH3:97])=[O:94])[CH3:50].[CH2:99]1[O:107][C:106]2[CH:105]=[CH:104][C:103](B(O)O)=[CH:102][C:101]=2[O:100]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:49]([O:51][C:52](=[O:98])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:75]=[C:74]([C:76](=[O:89])[NH:77][CH2:78][C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=3[O:85][CH:86]([F:88])[F:87])[CH:73]=[C:72]([C:104]3[CH:103]=[CH:102][C:101]4[O:100][CH2:99][O:107][C:106]=4[CH:105]=3)[CH:71]=2)[C:58]=1[CH2:91][CH2:92][C:93]([O:95][CH2:96][CH3:97])=[O:94])[CH3:50]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)NCc3ccccc3OC(F)F)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Yield: 87.4 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-[3-{6-[3-bromo-5-(2-difluoromethoxy-benzylcarbamoyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (200 mg, 0.262 mmol), 3,4-methylenedioxyphenylboronic acid (87 mg, 0.524 mmol), PdCl2(dppf) (29 mg, 0.04 mmol) and cesium carbonate (171 mg, 0.524 mmol) in 1,2-dimethoxyethane (5.0 mL) to obtain 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(2-difluoromethoxy-benzylcarbamoyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (184 mg, 88%) as a colorless oil.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:25][C:26](=[O:33])[CH2:27][C:28](OCC)=[O:29])=O)C.[H-].[Na+]>C1COCC1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:6]3[C:28]([OH:29])=[CH:27][C:26](=[O:33])[NH:25][C:7]=3[S:8][CH:9]=2)=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(=O)Nc1scc(-c2ccc(OCc3ccccc3)cc2)c1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2c(-c3ccc(OCc4ccccc4)cc3)csc2[nH]1
Yield: 77.2 %

Procedure:
To a solution of 4.42 g (9.45 mmol) of 4-(4-benzyloxy-phenyl)-2-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid ethyl ester from Example 7c in 50 mL of THF was added 1.6 g (40 mmol) of 60% NaH in mineral oil. The mixture was stirred at reflux under N2 for 17 h, then the excess NaH was quenched by the addition of 25 mL H2O. The reaction was concentrated in vacuo to remove most of the THF, then the remaining mixture was taken up in 75 mL of 2M NaOH and 75 mL of ethanol and heated at reflux for 6.5 h. The ethanol was removed in vacuo, and the aqueous solution was diluted with water to a total volume of 150 mL. The solution was extracted with diethyl ether (3×30 mL) to remove the mineral oil, then the aqueous layer was filtered through diatomaceous earth to remove some cloudiness. The solution was made acidic by addition of 80 mL of 4M HCl, and filtered after bubbling had ceased (about 5 min). The precipitate was washed with water, then dried on the filter to give 2.55 g (77%) of a tan solid as the titled compound. MS (ESI) m/e 350, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 5.13 (s, 2H) 5.70 (s, 1H) 6.92 (s, 1H) 6.98 (m, 2H) 7.40 (m, 7H) 10.82 (s, 1H).
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[Mg+2].C([O:31]S([O-])(=O)=O)CCCCCCCCCCC.C(O)CCCCCCCCCCC>>[C:5]([OH:31])(=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Mg+2]
Solvent: CCCCCCCCCCCCO
Product: CCCCCCCCCCCC(=O)O

Procedure:
The magnesium lauryl sulfate is desirably prepared from lauryl alcohol, resulting from the hydrogenation of lauric acid, but alternatively may be prepared from other fatty acids.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:23][CH3:24])[N:14]([CH3:25])[CH:13]=[C:12]2[C:10]1[N:9]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][C:3]([CH2:2][N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[C:4]2[CH:11]=1
Reactant: COc1cc2c(-c3cc4c(CCl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reactant: CN1CCNCC1
Product: COc1cc2c(-c3cc4c(CN5CCN(C)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-4-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine is prepared as described in Example 200b starting with 0.055 g of 4-chloromethyl-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.03 cm3 of 1-methylpiperazine instead of the piperid-4-ol used in Example 200b. 0.043 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-4-(4-methylpiperazin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH3:32].O>CN(C=O)C>[CH2:31]([O:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:32]
Reactant: CN1CC(C(Oc2ccccc2O)c2ccccc2)OCC1=O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1OC(c1ccccc1)C1CN(C)C(=O)CO1
Temperature: 60 °C
Yield: 78 %

Procedure:
To a solution of 10 g of 2-[α-(2-hydroxy-phenoxy)-benzyl]-4-methylmorpholin -5-one in 150 ml of anhydrous DMF addition was made of 4.8 g of potassium carbonate, and then dropwise addition was made under stirring of 2.6 ml of bromoethane in 20 ml of DMF. The mixture was heated for 4 hours at 60° C. under stirring. The mixture was poured into 1.5 liters of water and extracted with ethyl acetate. The organic extracts were washed with H2O, dehydrated over Na2SO4 and concentrated under reduced pressure. There was obtained 8.49 g (Yield 78%) of 2-[α-(2-ethoxy-phenoxy)-benzyl]-4-methyl-morpholin -5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:13][CH2:14][CH2:15][OH:16].[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:13][CH2:14][CH2:15][OH:16])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cl)cc1C(=O)NCCO
Reaction time: 2 h

Procedure:
5-Chloro-2-methoxybenzoyl chloride (5.0 g) was added to a vigorously stirred mixture of 2-aminoethanol (10.12 g, 10 ml) and sodium hydroxide solution (1M, 100 ml). Stirring was continued for 2 hours at room temperature, then dilute hydrochloric acid (10% v/v, 100 ml) was added and the mixture extracted with dichloromethane (3×200 ml). The combined dichloromethane layers were dried (MgSO4) and evaporated, and the resulting oil chromatographed on silica gel with 1% methanol in dichloromethane as solvent to afford the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10](=O)[CH2:11][O:12][C:8]=2[CH:7]=1.C([O-])(=O)C.[Na+].Cl.[CH3:27][O:28][NH2:29]>CO>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[N:29][O:28][CH3:27])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: O=C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Yield: 56.7 %

Procedure:
To a mixture of 6-(2,4-dichlorobenzyloxy)benzofuran-3(2H)-one (2.0 g) in MeOH (20 mL) were added sodium acetate (0.531 g) and O-methylhydroxylamine hydrochloride (0.540 g). The mixture was refluxed overnight. After cooling, the mixture was concentrated. The residue was washed with water and EtOAc to give the title compound (1.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[OH-].[Na+].[C:12](O)(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h

Procedure:
A solution of 25.0 g (144 mmol) of 2-amino-5-bromopyridine in 50 mL of acetic acid and 250 mL of acetic anhydride was heated at reflux for about 2 hours. The reaction mixture was then cooled and poured into 750 mL of water with stirring. After about 1 hour, the solution was adjusted to pH=10 with 50% sodium hydroxide solution and the precipitate was filtered, washed with water and dried to give 26.5 g of the title product as a white flaky solid, mp 175-176° C. 1H nmr (deuteriochloroform): δ=8.29 (d, 1 H); 8.12 (d, 1 H); 7.96 (br, 1 H); 7.78 (d of d, 1 H); 2.19 (s, 3 H). MS (El): m/z =214, 216 (M+, Br isotopes).
Reaction SMILES: [CH2:1]([O:8][C@@:9]1([C:36]([F:39])([F:38])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH2:35])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45].[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C@@:9]1([C:36]([F:38])([F:39])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][N:35]2[CH2:41][CH2:42][CH2:43][S:44]2(=[O:46])=[O:45])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: O=S(=O)(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S1(=O)CCCN1C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 50 °C
Yield: 64.2 %

Procedure:
A solution of ((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methanamine (34, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=Benzyl) (82 mg, 0.153 mmol) in DCM (3 mL) was treated with TEA (0.021 mL, 0.153 mmol) and 3-chloro-propane-1-sulfonyl chloride (0.023 mL, 0.19 mmol) at rt under nitrogen for about 1 h. The organic layer was washed with 2N aq. HCl (2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and added dropwise to a suspension of sodium hydride (60 wt % in oil, 7.6 mg, 0.30 mmol) in DMF (1 mL). The reaction was heated at about 50° C. for 2 h and then cooled to rt and concentrate under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-30% EtOAc in DCM. Product fractions were combined and concentrated to yield 2-(((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)isothiazolidine 1,1-dioxide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=Benzyl) (63 mg, 64%) as an oil. LC/MS, method 3, Rt=3.01 min, MS m/z 642 (M+H)+. The oil was used in step #2 without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:6][O:5][C:4]([C:7]2[CH:29]=[CH:28][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18](CC4C=CC=CC=4)[CH2:17][CH2:16]3)=[CH:9][CH:8]=2)=[N:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:30])[CH2:6][O:5][C:4]([C:7]2[CH:29]=[CH:28][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)=[N:3]1
Reactant: [H][H]
Reactant: CC1(C)COC(c2ccc(OCCCC3CCN(Cc4ccccc4)CC3)cc2)=N1
Agent: [Pd]
Solvent: CO
Product: CC1(C)COC(c2ccc(OCCCC3CCNCC3)cc2)=N1
Yield: 90.9 %

Procedure:
A mixture of 13.5 parts of 4-[3-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]propyl]-1-(phenylmethyl)piperidine and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 9.5 parts (90.9%) of 4-[3-[4-(4,5-dihydro -4,4-dimethyl-2-oxazolyl)phenoxy]propyl]piperidine as a residue (int. 74).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C=C(C)C=1)C(O)=O.CC1C=C(C(Cl)=O)C=C(C)C=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[CH:51]=[C:52]([C:57]([N:59]=[C:60]=[S:61])=[O:58])[CH:53]=[C:54]([CH3:56])[CH:55]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:52]2[CH:51]=[C:50]([CH3:49])[CH:55]=[C:54]([CH3:56])[CH:53]=2)=[S:61])=[CH:44][CH:43]=1
Reactant: Cc1cc(C)cc(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1cc(C)cc(C(=O)Cl)c1
Agent: Cc1cc(C)cc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)cc(C)c4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) was added to commercially available 3,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3,5-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 3,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,5-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (39 mg, yield 47%).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29]>[Cu]I.O1CCOCC1>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COc1ccccc1I
Reactant: CC(N)=O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1NC(C)=O
Temperature: 90 °C
Reaction time: 23 h
Yield: 94.3 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), acetamide (180 mg, 3.05 mmol), K3PO4 (450 mg, 2.12 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 10 mol %), 2-iodoanisole (135 μL, 1.04 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 90° C. for 23 h. The resulting light green suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 2:3; 20 mL fractions). Fractions 10-16 provided 162 mg (94% yield) of the product as white crystals. The 1H NMR spectrum was in accord with that reported. Hibbert, F.; Mills, J. F.; Nyburg, S. C.; Parkins, A. W. J. Chem. Soc., Perkin Trans. 1 1998, 629.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:11]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3O[C:13](=O)[C:14]4[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)(O)O.[NH2:30][NH:31][C:32]([NH2:34])=[NH:33]>N1C=CC=CC=1>[NH2:34][C:32]1[N:33]=[C:13]2[N:30]([C:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:16][C:15]3[CH:17]=[C:18]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:19]=[CH:20][C:14]=32)[N:31]=1
Reactant: NS(=O)(=O)c1ccc2c(=O)oc(Cc3ccc4c(c3)OCO4)nc2c1
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Nc1nc2c3ccc(S(N)(=O)=O)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Temperature: 180 °C
Yield: 36.3 %

Procedure:
A mixture of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4-sulfamoyl-benzoic acid (0.10 g, 0.26 mmol), acetic acid (1.5 mL) and acetic anhydride (0.10 mL, 1.06 mmol) was stirred at reflux for 1 h. The reaction was diluted with ethyl acetate and washed with NaHCO3 satured solution, then with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to give the 2-benzo[1,3]dioxol-5-ylmethyl-4-oxo-4H-benzo[d][1,3]oxazine-7-sulfonic acid amide intermediate (0.032 g) as yellow oil. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-4-oxo-4H-benzo[d][1,3]oxazine-7-sulfonic acid amide (0.032 g, 0.09 mmol) in dry pyridine (1 mL) was added aminoguanidine hydrogencarbonate (0.013 g, 0.098 mmol) and the mixture was heated under microwave condition at 180° C. for 1.5 h. The solvent was then evaporated and the crude was taken up in methanol to give the title compound (0.013 g, 12% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@@H:9]1[CH2:11][C@H:10]1[C:12](=O)[CH3:13].N1C=CC=CC=1.Cl.[CH3:22][O:23][NH2:24]>CO.O>[CH3:22][O:23][N:24]=[C:12]([C@@H:10]1[CH2:11][C@H:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:13]
Reactant: CON
Reactant: CC(=O)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CON=C(C)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a stirred solution of trans 1-[2-(2-Chloro-6-fluoro-phenyl)-cyclopropyl]-ethanone (1.0 g; 4.7 mmol) in methanol (10 ml) at ambient temperature was added pyridine (0.60 ml; 7.0 mmol) and methoxyamine hydrochloride (0.60 g; 7.0 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (50 ml) and extracted with dichloromethane (3×30 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 1.1 g (100% of theory) of trans 1-[2-(2-Chloro-6-fluoro-phenyl)-cyclopropyl]-ethanone O-methyl-oxime as an E/Z mixture in form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][N:13]3[CH:19]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]3[C:17](=[O:18])[N:16]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:15][CH2:14][N:13]3[CH:19]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(COc2cn3c(cc2=O)C(=O)NCC3)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cn3c(cc2=O)C(=O)N(CCN2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of 7-((4-methoxybenzyl)oxy)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (4.15 g, 13.82 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added sodium hydride (1.382 g, 34.5 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Then the mixture of 1-(2-chloroethyl)pyrrolidine, hydrochloride (Aldrich) (2.90 g, 17.03 mmol) and triethylamine (2.438 mL, 17.49 mmol) in N,N-dimethylformamide (DMF) (25.00 mL) was added. The reaction was stirred at 50° C. for 30 h. The solvent was evaporated and the residue was dissolved in water (50 mL) and extracted with dichloromethane (50 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to afford light yellow crude product, which was then purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with dichloromethane/methanol/ammonium hydroxide (v:v:v=80:20:2) over 16 min to afford 7-((4-methoxybenzyl)oxy)-2-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (3 g, 7.55 mmol, 54.6% yield) as light yellow solid. LCMS (M+H)+: 398.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CC(C)Cn1c(N)cc(=O)[nH]c1=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Yield: 96.4 %

Procedure:
6-Amino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.0 g, 5.0 mmol) was suspended in 10% acetic acid (20 mL). Sodium nitrite (0.38 g, 5.5 mmol) was added and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture became first pink and then purple. The purple mixture was cooled to room temperature. Then water (20 mL) was added and the purple solid was collected by filtration and washed with water to give the title compound (1.1 g, 92% yield). This solid was used in the following step without further purification.