Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.O[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=[N:11][C:10]=1[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>C1(C)C=CC=CC=1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:12]=[N:11][C:10]3[C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25](=[O:27])[O:26][C:9]=3[CH:14]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2cc(O)c(-c3ccccc3C(=O)O)nn2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3oc(=O)c4ccccc4c3nn2)cc1
Yield: 92 %

Procedure:
Acetic acid anhydride (100 ml), 2-[4-hydroxy-6-(4-methoxyphenyl)-3-pyridaziny]benzoic acid (11 g, 0.0342 mol) and toluene (100 ml) are reacted in a 250 ml flask; oil bath about 130° C. When the reaction is completed, the mixture toluene/acetic acid is distilled off at 96-108° C. (about 100 ml/1.5 hours). The acetic acid anhydride is eliminated under vacuum, the residue is taken up with methylene chloride (250 ml), washed with 5% aqueous sodium bicarbonate and then with water up to neutrality. THe organic layer is oven dried, and concentrated to dryness to give 3-(4-methoxyphenyl)-6H-[2]-benzopyrano[4,3-c]pyridazin-6-one 230°-231° C. (9,8 g; Yield 92%).
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C1COCC1>[NH2:1][C:2]1[C:3]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: OB(O)c1ccco1
Reactant: Cc1cc(Cl)nc(I)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc(-c2ccco2)c1N
Temperature: 90 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
3-Amino-6-chloro-2-iodo-4-methylpyridine (1.38 g), 2-furanboronic acid (861 mg), and sodium carbonate (815 mg) were suspended in a solvent mixture consistent of toluene (19 mL), THF (19 mL) and water (6 mL). The mixture was degassed using subsequent evaporation and flushing with nitrogen (5×) and tetrakis(triphenylphosphine)palladium(0) (658 mg) was added. The reaction mixture was stirred at 90° C. for 5 hours and 12 hours at room temperature. After addition of another portion of 2-furanboronic acid (430 mg) and tetrakis(triphenyl phosphine)palladium(0) (132 mg), the mixture was stirred again for 12 hours at 90° C. After 12 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=4:1, Rf=0.25) to afford 929 mg of the title compound of the formula
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([N+:21]([O-])=O)[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].CC(O)=O.C(OCC)C>C1COCC1.[Pt]>[NH2:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([Br:1])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6]
Reactant: COCCOCCOCCNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCCOCCNC(=O)c1cc(N)cc(Br)c1
Reaction time: 5 h
Yield: 90 %

Procedure:
The product from step (i) above (1 kg, 2.56 mol) was dissolved in THF (3.5 L) and AcOH (500 mL) and hydrogenated at 3 MPa (30 bar) H2 at up to 60° C. with 5% Pt/C (30 g of JM type 18 MA, 55% water). Analysis after 5 hrs showed a 1:1 ratio of ArNHOH and ArNH2. The reaction reached completion after being left overnight, with 1H NMR analysis showing 3% des-bromo side product. The catalyst was filtered off, then the residue was diluted with ethyl acetate (3 L) and washed with 20% potassium carbonate solution (3.5 L). The organics were then dried, filtered and concentrated in vacuo to provide a residue that was then slurried in 5 volumes of diethyl ether overnight to reduce the level of the des-bromo species (<2% after the slurry). The sub-title compound was obtained in 90% yield with a purity of 86% by LC.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
A mixture of (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (Stage 93.1, 60 mg, 0.110 mmol), pyrimidin-5-ylboronic acid (21 mg, 0.164 mmol), 2M Na2CO3 (0.2 mL, 0.4 mmol) and DME (4 mL) was flushed with argon. PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added and the mixture was subjected to MW irradiation 140° C. for 30 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 6) tR=0.88 min, m/z=445.0 [M+H]+.
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19](=[O:24])[C:18]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[CH:27][CH:26]=4)=[N:17]3)=[C:12]([F:36])[CH:11]=2)[C:6]1=[O:37])(C)(C)C>FC(F)(F)C(O)=O>[F:36][C:12]1[CH:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:5][C:6]2=[O:37])[CH:15]=[CH:14][C:13]=1[N:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19](=[O:24])[C:18]([C:25]2[N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:28]=[CH:27][CH:26]=2)=[N:17]1
Reactant: COc1cn(-c2ccc(N3CCN(C(C)(C)C)C3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(-c2ccc(N3CCNC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 1-[4-(3-tert-butyl-2-oxoimidazolidin-1-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (503 mg, 1.0 mmol) in trifluoroacetic acid (3.0 mL) was stirred at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was evaporated. The residue was recrystallized from AcOEt/MeOH to give the title compound (334 mg, 75% yield) as a pale yellow solid: mp 259-260° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.40-3.50 (2H, m), 3.77 (3H, s), 3.82-3.93 (2H, m), 6.95 (1H, d, J=2.3 Hz), 7.01 (1H, t, J=9.0 Hz), 7.23-7.49 (7H, m), 7.73 (1H, dd, J=14.1, 2.4 Hz), 7.78 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 447 [M+H]+. Anal. Calcd for C23H19FN6O3.0.75H2O: C, 60.06; H, 4.49; N, 18.27. Found: C, 60.05; H, 4.26; N, 18.16.
Reaction SMILES: S(=O)(=O)(O)O.O=[C:7]([CH3:20])[CH2:8][O:9][C:10]1[CH:18]=[C:14]([C:15]([NH2:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1.[NH2:21][CH2:22][CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H][H]>[Pt].CO>[C:15]([C:14]1[CH:18]=[C:10]([CH:11]=[CH:12][C:13]=1[OH:19])[O:9][CH2:8][CH:7]([NH:21][CH2:22][CH:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:20])(=[O:16])[NH2:17]
Reactant: NCC(O)c1ccccc1
Reactant: [H][H]
Reactant: CC(=O)COc1ccc(O)c(C(N)=O)c1
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(COc1ccc(O)c(C(N)=O)c1)NCC(O)c1ccccc1

Procedure:
After adding 0.32 g of concentrated sulfuric acid and 3 g of platinum-on-charcoal catalyst (5%), a solution of 26.8 g of 5-(2-oxo-propoxy)-salicylamide and 17.6 g of α-(aminomethyl)-benzyl alcohol in 450 ml of methanol is hydrogenated under normal conditions until 1 mol equivalent of hydrogen has been taken up. The catalyst is filtered off, the solvent is evaporated and the crude α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]aminomethyl]-benzyl alcohol thus obtained is dissolved hot in as little methanol as possible and the solution is cooled and seeded with crystals of the enantomer pair having the higher melting point. The crystals with a melting point of 160°-163° which are obtained after standing for several days yield, after a further crystallisation from methanol, one pur enantiomer pair with a melting point of 166°-168°. The enantiomer pair which has the lower melting point of 152°-154° is isolated from the first mother liquor after evaporating off the solvent, by fractional crystallisation using ethyl acetate or isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:26]C(O)=O)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C@@H:15](C)[CH2:14][CH2:13]C[C@H:11]1[CH3:17])=[O:9].CC1CCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH:11]1[CH3:17])=[O:9]
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)O)cc1Cl
Agent: CC1CCCN1
Product: COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2C)c(Cl)c1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using the product of step example 21 step a) and 2-methylpyrrolidine.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]1([CH2:24][C:25]([OH:27])=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN([CH:65]=[O:66])C>C(OCC)(=O)C>[CH3:65][O:66][C:21]1[CH:22]=[CH:23][C:18]([CH2:24][C:25]([NH:17]/[N:16]=[C:7]2\[NH:8][C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]\2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:27])=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CN(C)C=O
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCn1/c(=N/NC(=O)Cc2ccc(OC)cc2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.30 g, 1.3 mmol), benzeneacetic acid, 4-methoxy-(0.23 g, 1.4 mmol), benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.62 g, 1.40 mmol) and triethylamine (0.53 mL, 3.8 mmol) in DMF (10 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed sat. NaHCO3. The aqueous was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to yield the desired product (560 mg, 98%). LCMS calculated for C19H25N6O3(M+H): 385.2; found: 385.2.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].O=[CH:6][C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8].I.N1C=C[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:4])[O:8][C@@H:7]([C@H:9]2[O:10][C@@H:15]3[O:16][C:20]([CH3:21])([CH3:19])[O:14][C@@H:13]3[C@H:11]2[OH:12])[CH2:6][O:3]1
Reactant: c1ccncc1
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: I
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-glucose and 100 mg of hydrogen iodide and the mixture was refluxed with stirring in a water bath at 60° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of pyridine was added. The acetone was then distilled off under reduced pressure and the residue was dissolved in benzene, washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure to give 11.5 g (80.0%) of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose. After recrystallization from chloroform-hexane (1:2), it melted at 107°-109° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(F)cc2F)CCC1

Procedure:
using isopropyl 2,4-difluoro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2,4-difluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 149°-151° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>C(Cl)Cl.O>[CH2:1]([NH:3][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of ethylamine (69.4 mL, 139 mmol) and triethylamine (21.10 mL, 151 mmol) in DCM (150 mL) was added p-fluorobenzoyl chloride (15.13 mL, 126 mmol) at 0° C. The reaction was stirred at 0° C. for 1 hr and then warmed slowly to room temperature. The reaction mixture was diluted with water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The organic extract was dried in vacuo to provide the title compound as a tan solid (21 g, 100% yield).
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]([CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:16]C#N>>[OH:14][CH:15]([CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:16][C:13]1[NH:2][C:3](=[O:12])[C:4]2[C:5]([CH:11]=1)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2
Reactant: N#CCC(O)CN1CCCC1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CC(O)CN3CCCC3)cc12
Yield: 1.5 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (2.65 g) and 3-hydroxy-4-(pyrrolidin-1-yl)butyronitrile (2.31 g), 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinolin-1-one (0.066 g) was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[OH-:5].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]#[C-:15]>O.CC(C)=O>[CH:11]1[CH:10]=[C:9]([N:14]2[NH:3][N:2]=[N:1][C:15]2=[O:5])[C:8]([Cl:7])=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: [OH-]
Reactant: [C-]#[N+]c1ccccc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1nn[nH]n1-c1ccccc1Cl
Temperature: 50 °C
Yield: 94 %

Procedure:
To sodium azide (0.65 g) dissolved in water (3.5 ml) a solution of 2-chlorophenylisocyanide, dichloride (2.09 g) in acetone (8 ml) was added with stirring. The mixture was heated to 50° C. and stirred for 15 minutes while maintaining this temperature. Thereafter, the mixture was heated for further 30 minutes with refluxing. An aqueous sodium hydroxide solution (about 40%, 2.5 g) and water (5 ml) were added thereto and the mixture was heated for 5 hours under stirring. After completing the reaction, the organic solvent was distilled off under reduced pressure and the water layer was washed once with toluene (5 ml). The mixture was adjusted to a pH of 1 with hydrochloric acid and the precipitate was collected by filtration with suction. The precipitate was washed with water followed-by drying to obtain light tan crystals 1-(2-chlorophenyl)-5(4H)-tetrazolinone (yield: 94%). melting point: 122°-124° C.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:28]1([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.COCC(O)C>>[N:28]1([C:34]2[CH:35]=[C:36]([NH:40][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)[CH:37]=[CH:38][CH:39]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: c1cncc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Yield: 40.7 %

Procedure:
2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004839 mol), N,N-Diisopropylethylamine (0.126 mL, 0.000726 mol) and 3-Morpholin-4-yl-phenylamine (0.172 g, 0.000968 mol) were dissolved in 1-Methoxy-2-propanol (1.0 mL, 0.010 mol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 73.26 mg of (3-Morpholin-4-yl-phenyl)-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a lyophilized powder. (M+H)=373.7. 1H NMR (400 MHz, DMSO, d6) δ 9.45 (s, 2H), 9.07 (s, 1H), 8.81 (d, 1H, J=8.00 Hz), 8.70 (d, 1H, J=3.76 Hz), 7.78 (m, 1H), 7.35 (d, 1H, J=4.76 Hz), 7.30 (s, 1H), 7.18 (m, 2H), 7.02 (d, 1H, J=4.80 Hz), 6.62 (m, 1H), 3.69 (m, 4H), 3.02 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[OH-].[Na+].O>C(O)C.C(OCC)(=O)C>[Cl:12][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]([OH:13])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CNc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CNc1cccc(Cl)c1
Temperature: 60 °C
Yield: 86.2 %

Procedure:
(3-Chloro-phenylamino)-acetic acid methyl ester (4 g, 20.0 mmol) and sodium hydroxide (4.00 g, 100 mmol) were combined in ethanol (60.0 mL) and water (10 mL) to give a light yellow solution which was heated at 60° C. for 4 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with 1M aqueous hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (3-chloro-phenylamino)-acetic acid as a brown solid (3.20 g, 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1C2C(=CC=CC=2[N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)C=CC=1>>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: Clc1cc(Br)c2ncccc2c1
Product: O=C1CCN(c2cc(Cl)cc3cccnc23)CC1

Procedure:
This compound was prepared from the known 8-bromo-6-chloroquinoline (Lachowicz et al., Rocz. Chem., 40:1848 (1966)) using a synthetic sequence and reagents identical to those described for the synthesis of 1-quinolin-8-yl-piperidin-4-one (Step 5, Example A, above). The compound was obtained as an off-white solid; MP: 223-225° C.; MS (ES) m/z (relative intensity): 261 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH3:18].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:20]([Cl:19])(=[O:22])=[O:21])[S:17][C:11]=2[N:10]=[C:9]1[CH3:18]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1nc2sccc2c(=O)n1-c1ccccc1Cl
Product: Cc1nc2sc(S(=O)(=O)Cl)cc2c(=O)n1-c1ccccc1Cl
Reaction time: 1.5 h

Procedure:
To 140 ml of chlorosulfonic acid was added little by little 54.8 g of 3,4-dihydro-3-(2-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidine. After the mixture was heated at 70°-75° C. on the oil bath and stirred for 1.5 hours, the reaction mixture was cooled and then poured onto 2 l of icewater carefully. The precipitated crystals were collected by suction-filtration to afford 65 g of the title compound, m.p. 172°-174° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.[C:33]1([O:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40](=[O:41])[O:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:7]=3)=[C:10]([F:32])[CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A suspension of N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-c arboxamide (500 mg, 1.10 mmol) in DCM/pyridine (50 mL/25 mL) was cooled to 0° C., then a solution of phenylcarbonochloridate (450 mg, 2.90 mmol) in DCM (5 mL) was added to the mixture slowly over 0.5 hour. The reaction was stirred at rt for 2 hours, then diluted with DCM (250 mL). The mixture was washed with water (150 mL×3), followed by washing with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=150/1) to give the title compound as a white solid (352 mg, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[Cl-].[CH:15](=[N+:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][N:22]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([OH:13])=[O:12])[CH3:24]
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(C(=O)O)[nH]c2ccc(O)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-hydroxy-1H-indole-2-carboxylic acid and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16].[H-].[Na+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:26][CH:27]=1)[C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16]
Reactant: ClCc1ccc(-n2ccnc2)cc1
Reactant: Cc1c(CCC(=O)O)[nH]c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCC(=O)O)n(Cc2ccc(-n3ccnc3)cc2)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
A solution of 198 mg of 5-fluoro-3-methyl-1H-indole-2-propanoic acid in 20 ml of dry DMF is cooled at 0° C., and treated with 155 mg of 55% NaH. The reaction mixture is stirred for 60 minutes at 0° C., then 307 mg of 1-[4-(chloro-methyl)phenyl]-1H-imidazole hydrochloride are added portionwise under nitrogen at 0° C. After stirring at room temperature for 16 hours the mixture is poured into water and washed with methylene chloride. The aqueous solution is neutralized with diluted HCl and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue, taken up with acetone, filtered and dried, yields 35 mg of the title compound (m.p. 222° C.)