Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH2:7][CH2:6]1.C(=O)([O-])O.[Na+]>C(O)C>[N:11]1([CH:8]2[CH2:9][CH2:10][N:5]([CH2:2][CH2:3][OH:4])[CH2:6][CH2:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OCCN1CCC(n2ccc3ccccc32)CC1
Yield: 65.6 %

Procedure:
A mixture of 2-bromoethanol (3.75 g), 1-(4-piperidinyl)-1H-indole (5 g) and sodium hydrogen carbonate (4.2 g) in ethanol (100 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was stirred in water and this mixture was extracted with CH2Cl2. The separated organic layer was dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE and the solvent was evaporated, yielding 4 g (64%) of 4-(1H-indol-1-yl)-1-piperidineethanol (intermediate 8).
Reaction SMILES: [CH:1]([NH:3][N:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)=[O:6])=O.[OH-].[K+]>CO.O>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[CH:1]=[N:3][N:4]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:5]2=[O:6])=[CH:13][CH:12]=1
Reactant: CN(C)CCOc1ccc(NC(=O)N(NC=O)c2ccc(Oc3ccccc3)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCOc1ccc(-n2cnn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1-Formyl-2-(4-phenoxyphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]semicarbazide (60 mg) was added to a solution of potassium hydroxide (15 mg) in methanol (20 mL). After 4 hours at room temperature, the mixture was heated at 40° C. for 24 hours. After cooling, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated. The product with the molecular weight of 416.48 (C24H24N4O3); MS (ESI): 417 ([M+H]+), was obtained in this way.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:28]1([NH:34]N)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and phenylhydrazine according to the method described for example 1. MS: M=447.1 (M+H)+
Reaction SMILES: [CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]([CH3:16])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([O:21]COC)=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.C([O-])(O)=O.[Na+]>CO.ClCCl>[CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]([CH3:16])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCC12CCCC(=O)C(C)=C1c1ccc(O)cc1C2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution of 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one (5 mg) in methanol (1 mL) was treated with aqueous 2N HCl (0.1 mL, 0.2 mmol). After stirring at 65° C. for two hours, the mixture was diluted with dichloromethane (2 mL), treated with solid NaHCO3, and purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 20% EtOAc in hexane. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 9a-butyl-2-hydroxy-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][C:14]([OH:16])=[O:15].CCOCC.Cl>C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.CO>[C:14]([CH2:13][NH:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:16])=[O:15]
Reactant: O=C(O)CCl
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: O=C(O)CNc1ccc(Cl)cc1C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
To a solution of 2-amino-5-chlorobenzoic acid (2.0 g, 11.6 mmol) in 15 ml of 2 N Na2CO3, a solution of chloroacetic acid (0.69 g, 7.3 mmol) in 7.5 ml of 2 N Na2CO3 was added dropwise. After stirred for 20 hours at 80° C., the reaction mixture was cooled down to room temperature. 50 ml ether and 8 ml of 2 N hydrochloric acid were added to the mixture. The organic phase was separated, and dried with MgSO4. After concentration, a light brown solid was obtained. A white solid (2-(N-carboxymethylamino)-5-chlorobenzoic acid) (1.58 g, yield: 59%; mp: 182-183° C.) was obtained through silica gel column chromatography (ethyl acetate/methanol, v/v, 1/1).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>C1COCC1>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:8])[CH2:21][O:22]1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(F)cc2F)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(2,4-difluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:20][CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ccc(Cl)nc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
To a solution of 3.2 g of 7-chloro-1,8-naphthyridin-2(1H)-one in 32 mL of N,N-dimethylformamide, 3.7 g of potassium carbonate was added, and the mixture was stirred at 50 to 60 C.° for 23 minutes, and then, thereto was added 2.2 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 60 to 78° C. for 25 minutes. Thereto were added 16 mL of N,N-dimethylformamide and 1.1 mL of 2-bromomethyl-1,3-dioxolan, the mixture was stirred at 90 to 95° C. for 2 hours 15 minutes, 3.7 g of potassium carbonate was added thereto, and the mixture was stirred for 20 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were then added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 3.6 g of 7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[S:40][C:41]([C:44]([NH2:46])=[O:45])=[CH:42][N:43]=1.ClC1SC(C(N)=O)=CN=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:3][CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:39]2[S:40][C:41]([C:44]([NH2:46])=[O:45])=[CH:42][N:43]=2)=[N:8][N:9]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: NC(=O)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NC(=O)c1cnc(Cl)s1
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4ncc(C(N)=O)s4)c3c2)o1
Yield: 40 %

Procedure:
The title compound (55 mg, 40% yield) as a yellow crystalline solid was prepared according to compound 275, using N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (150 mg, 0.287 mmol), 125 mg of the 1:1 mixture of 2-bromothiazole-5-carboxamide and 2-chlorothiazole-5-carboxamide, and Pd(PPh3)4 (Strem Chemicals, 17 mg) as the starting materials and reagent. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (1H, d, J=2.3 Hz), 8.66 (1H, s), 8.38 (1H, s), 8.31 (1H, d, J=2.7 Hz), 8.13 (1H, br.), 8.01 (1H, d, J=6.8 Hz), 7.77 (1H, dd, J=8.5, 1.7 Hz), 7.64 (1H, d, J=8.6 Hz), 7.56 (1H, br.), 3.77 (1H, m), 1.25 (6H, d, J=6.5 Hz). MS (ESI, pos. ion) m/z: 369.0 (M+H)+.
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[C:12]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:13][CH:14]=[CH:15][CH:16]=1)=[CH2:10])(C(C)(C)C)(C)C>C(COC)OC.C(Cl)Cl.[Ag+].FC(F)(F)S([O-])(=O)=O>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[CH:10]=[C:9]([OH:8])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[CH:17]=1
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccnc1C#Cc1ccccn1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: COCCOC
Solvent: ClCCl
Product: Oc1cc(-c2ccccn2)cc2ncccc12
Temperature: 70 °C
Reaction time: 7 h
Yield: 24.4 %

Procedure:
Step 3 (=Reaction 5): 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)-2-(pyridin-2-ylethynyl)pyridine was dissolved in 100 mL dimethoxyethane and 126 mg of trifluormethanesulfonic acid silver salt added and stirred 7 h at 70° C. The mixture is diluted with DCM and extracted with saturated NaHCO3 solution (3×). The organic phase was dried (MgSO4) and concentrated in vaccuo. The residual mixture was dissolved in 10 mL THF, 1.2 mL of tertbutylammoniumfluoride in THF (1N) was added and the mixture stirred for 2 h at 25° C. The mixture was diluted with DCM and extracted with water (1×) and the organic phase concentrated in vacuo and purified via FCC (100 g SiO2, DCM→DCM 93:7) to yield 165 mg of 7-(pyridin-2-yl)quinolin-5-ol 6.3 as solid. HPLC-MS: Rt=0.78 min (method E), M+H=223.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1>P(O)(O)O.C1(C)C=CC=CC=1>[CH3:2][C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:6]=1[OH:15])([CH3:4])[CH3:3]
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: OP(O)O
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 2,4-di-t-butylphenol (41.2 g), phosphorous acid (2 drops) and toluene (5 ml) was heated to 180°-200° in a three-necked flask fitted with a Dean-Stark trap containing toluene. 4-Methoxybenzyl alcohol (27.6 g) was melted and added in a slow stream to the mixture during 45 min. Heating was continued for a further 15 min by which time the theoretical amount of water (3.6 ml) had distilled. The reaction mixture was then distilled under pressure to give a pale yellow oil which rapidly crystallized. Recrystalization from methanol yielded colorless needless, m.p. and mixed m.p. with authentic material, 84°-85°; yield 59.3 g (91%). Found: C,80.9;H,9.26; calc for C,22H30O2 :C,81.0;H,9.21); 1Hmmr spectrum: δ1.30,9H,S; δ1.38,9H,S; δ3.79,3H,S; δ3.83,2H,S; δ4.61,H,S; δ6.84,2H,D(J=8 Hz); δ7.03, 1H,D(J=2 Hz); δ7.14,2H,D(J=8 Hz); δ7.23,1H,D(J=2 Hz).
Reaction SMILES: [BrH:1].[N+](=[CH:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N-]>>[Br:1][CH2:4][C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=CC(=O)CCc1ccccc1
Reactant: Br
Product: O=C(CBr)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 0° C. solution of the crude product from Step A (12.89 grams; dry dichloromethane; 150 mL) was treated dropwise with 48% HBr (36.0 mL). When outgassing ceased, the solution was warmed to ambient temperature. After 15 minutes, the reaction was partitioned (isopropyl acetate and water), washed twice with water and dried (magnesium sulfate). Filtration and evaporation furnished the title compound as an oil which crystallized on standing,
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.COC1C=CC([Mg]Br)=CC=1.[CH2:21]([O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38]1[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=1)=[C:33]([C:47]([O:49][CH3:50])=[O:48])[C:32]2=[O:51])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CCOCC.C1COCC1>[CH2:21]([O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38]1[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=1)=[C:33]([C:47]([O:49][CH3:50])=[O:48])[C:32]2([OH:51])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(Br)cc1
Reactant: COC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccc(OCc3ccccc3)cc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccc(OCc3ccccc3)cc2C1(O)c1ccc(OC)cc1
Yield: 110.8 %

Procedure:
To dry magnesium turnings (0.96 g, 40 mmol) under an argon atmosphere was added a solution of 4-bromoanisole (7.48 g, 40 mmol) in 9:1 Et2O/THF (50 ml). The resulting 4-methoxyphenyl magnesium bromide solution was added portionwise to a solution of methyl 5-benzyloxy-1-(3,4-methylenedioxyphenyl)-3-oxoindene-2-carboxylate (8.29 g, 20 mmol) in THF (250 ml) under an argon atmosphere. Upon completion of the addition, the mixture was quenched by the addition of 3M HCl and extracted with EtOAc. The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo to afford the title compound (11.58 g, 100%), which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31]>O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([O-:3])=[O:2]
Reactant: OCCOCCOCCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(OCCOCCOCCO)c1

Procedure:
While stirring a mixture of 27.8 g of m-nitrophenol, 120 ml of N,N-dimethylformamide, and 25 g of potassium carbonate at 80° C., 37 g of 2-(2-(2-chloroethoxy)ethoxy)-ethanol was added dropwise to the mixture. After stirring the mixture for one hour at 80° C., 200 ml of ethyl acetate and 200 ml of water were added to the reaction mixture and the ethyl acetate layer was extracted. The ethyl acetate layer was washed with 200 ml of water and concentrated to remove ethyl acetate to provide 2-(2-(2-(3-nitrophenoxy)ethoxy)ethoxy)ethanol (1-A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[C:34]([O:37][CH2:38]CBr)(=[O:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:22][C:23]([N:24]([CH3:26])[CH3:25])=[O:27])[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:35][C:34]([O:37][CH3:38])=[O:36])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: CC(=O)OCCBr
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc2ncnc(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 50 mg), potassium carbonate (138 mg), and bromoethyl acetate (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 37 mg (yield 60%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.[C-]#N.[Na+].[NH:48]1[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50][CH2:49]1>C1COCC1.[O-2].[Mn+4].[O-2]>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:44][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([C:21]([N:48]4[CH2:53][CH2:52][CH:51]([OH:54])[CH2:50][CH2:49]4)=[O:22])[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)[N:10]=2)=[CH:40][CH:39]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(=O)N4CCC(O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (0.054 g, 0.091 mmol) in THF (1.0 mL) at room temperature was treated with sodium cyanide (4.44 mg, 0.091 mmol) (Sigma-Aldrich), piperidin-4-ol (0.046 g, 0.453 mmol) (Aldrich) and manganese (IV) oxide (0.118 g, 1.360 mmol) (Sigma-Aldrich). The mixture was stirred at room temperature. After 1 h the reaction was incomplete, so a few granules of NaCN, and another 15 equiv. of manganese (IV) oxide (0.118 g, 1.360 mmol) were added. The mixture was stirred at room temperature for 18 h, then filtered through Celite® (diatomaceous earth). The organic layer was washed with water, then brine, dried over MgSO4, filtered and concentrated to give the title compound as a yellow film (85%). 1H NMR (400 MHz, d6-DMSO) δ 11.86 (s, 1H); 8.77 (d, J=2.3 Hz, 1H); 8.38 (d, J=2.3 Hz, 1H); 8.02-8.11 (m, 2H); 7.23-7.32 (m, 2H); 7.19 (m, J=8.6 Hz, 2H); 6.91 (m, 2H); 6.83 (d, J=8.8 Hz, 2H); 4.72-4.87 (m, 5H); 3.90-3.95 (m, 3H); 3.66-3.76 (m, 8H); 3.17-3.28 (m, 2H); 2.58 (s, 3H); 1.71 (br. s., 2H); 1.36 (br. s., 2H). m/z (ESI, +ve ion) 695.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cccc(F)c2F)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cccc(F)c3F)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 88A in analogy to the synthesis of the compound of Example 1. 8 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][C:9]([NH2:11])=[NH:10].[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:14]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30](S(C)=O)=[N:31][N:32]=1>C(O)(C)(C)C>[ClH:12].[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([Cl:20])[C:14]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30]([NH:10][C:9]([NH2:11])=[NH:8])=[N:31][N:32]=1
Reactant: N=C(N)N
Reactant: Cc1ccc(Cl)c(Nc2ccccc2-c2nnc(S(C)=O)o2)c1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nnc(NC(=N)N)o2)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 141.9 %

Procedure:
To a solution of potassium tert-butoxide (111.3 mg, 0.99 mmoles) in 15 ml of tert-butyl alcohol is added guanidine hydrochloride (108.2 mg, 1.13 mmoles). The reaction mixture is stirred at room temperature for 10 minutes, then 2,6-dichloro-3-methyl-N-[2-[5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl]phenyl]benzenamine (201.0 mg, 0.526 mmoles) is added, and the reaction mixture is heated at reflux for five minutes. The mixture is concentrated in vacuo. 20 ml of methanol is added to the residue followed by 100 ml of water. The resultant solid is collected by filtration and dissolved in 10% methanol in ethyl acetate. 50 ml of ether is added, followed by a few drops of saturated etheral hydrochloric acid. The white solid is collected and washed with ether to provide 154.4 mg (71%) of 5-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl-guanidine monohydrochloride, mp 245°-248° C.
Reaction SMILES: NC1C=CC=C(Cl)C=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[S:27]([NH:30][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=S)(=[O:29])=[O:28].C(Cl)(Cl)=O>>[Cl:26][C:22]1[C:21]2[S:27](=[O:29])(=[O:28])[N:30]=[C:31]([NH:33][CH:34]([CH3:36])[CH3:35])[NH:19][C:20]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)NC(=S)NS(=O)(=O)c1c(N)cccc1Cl
Agent: CC(C)N=C=S
Agent: Nc1cccc(Cl)c1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: CC(C)NC1=NS(=O)(=O)c2c(Cl)cccc2N1

Procedure:
Starting from 2-amino-6-chlorobenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-6-chlorobenzenesulfonyl)-N′-isopropylthiourea was prepared; m.p. 144-146° C. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 273-275° C.