Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([CH:28]([OH:30])[CH3:29])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:18]1[C:11]([N:9]2[CH:8]=[C:7]3[C:2]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]([OH:30])[CH3:29])[N:25]=[CH:26][N:27]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]3=[N:10]2)=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cccc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Reactant: CC(O)c1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(O)c1cc(Nc2ncc(F)c3nn(-c4c(Cl)cccc4C#N)cc23)ncn1
Temperature: 150 °C
Yield: 24.4 %

Procedure:
A mixture of 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-chlorobenzonitrile (211 mg, 0.61 mmol), 1-(6-aminopyrimidin-4-yl)-ethanol (92 mg, 0.66 mmol), Pd2(dba)3 (14 mg, 0.015 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (391 mg, 1.2 mmol) in dioxane (4.0 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 150° C. in the microwave for 30 minutes. The resultant mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ethyl acetate) to afford the title compound as a beige solid (61 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.47 (d, J=2.5 Hz, 1H), 8.72 (d, J=1.2 Hz, 1H), 8.59 (s, 1H), 8.24-8.21 (m, 2H), 8.02 (d, J=3.5 Hz, 1H), 7.90 (t, J=8.1 Hz, 1H), 5.54 (d, J=4.6 Hz, 1H), 4.70-4.63 (m, 1H), 1.39 (d, J=6.6 Hz, 3H). LCMS (Method B): RT=2.92 min, m/z: 410 [M+H+].
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:2]1[C:1]2([CH2:6][CH2:12][C:10](=[O:11])[CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1C=CC2(CCCC2)CC1
Temperature: 120 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of cyclopentanecarbaldehyde (10 g, 100 mmol) in toluene (100 mL) were added methyl vinyl ketone (7.8 g, 110 mmol) and p-toluenesulfonic acid (1.9 g, 10 mmol), and the mixture was stirred at 120° C. for 3 hours, using a Dean-Stark apparatus to remove water. The reaction mixture was air-cooled to room temperature, then saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 6.0 g of the title compound as a red oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:4]2([CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5]2)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:25]=[C:26]([C:28]1[CH:29]=[CH:30][C:31]([CH3:46])=[C:32]([NH:34][C:35]([C:37]2[N:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]3=[N:39][CH:38]=2)=[O:36])[CH:33]=1)[NH2:27]>CN1C(=O)CCC1>[CH3:46][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[N:25]=[C:8]([CH:6]3[CH2:5][C:4]4([CH2:3][C:2](=[O:1])[CH2:11]4)[CH2:7]3)[O:10][N:27]=2)=[CH:33][C:32]=1[NH:34][C:35]([C:37]1[N:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]2=[N:39][CH:38]=1)=[O:36]
Reactant: O=C1CC2(C1)CC(C(=O)O)C2
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC4(CC(=O)C4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of 6-oxospiro[3.3]heptane-2-carboxylic acid (50 mg, 0.32 mmol) in anhydrous NMP (1 mL) was added 1,1′-carbonyldiimidazole (CDI) (52.3 mg, 0.32 mmol). The reaction was stirred for 3 minutes. N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (100 mg, 0.32 mmol) was added and the reaction was stirred for 25 minutes. Then, the reaction was heated at 120° C. for 15 minutes. The crude reaction was purified by reverse phase preparative HPLC to give N-(2-methyl-5-(5-(6-oxospiro[3.3]heptan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F75). MS m/z 428.2 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][C@@H:15]([C:17]2[CH:28]=[CH:27][C:20]3[O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24][C:19]=3[CH:18]=2)[O:14][C:13]1=[O:29])[CH2:2][C:3]#[CH:4].Br[C:31]1[CH:32]=[C:33]([S:37]([N:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>N1CCCC1>[CH3:26][C:22]1([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][C:17]([C@H:15]3[O:14][C:13](=[O:29])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][C:3]#[C:4][C:35]4[CH:34]=[C:33]([S:37]([N:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])[CH:32]=[CH:31][CH:36]=4)[CH2:16]3)=[CH:18][C:19]=2[CH2:24][O:23]1
Reactant: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reactant: CN(C)S(=O)(=O)c1cccc(Br)c1
Solvent: C1CCNC1
Product: CN(C)S(=O)(=O)c1cccc(C#CCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
A mixture of (5R)-3-[6-(but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.256 g) and 3-bromo-N,N-dimethylbenzene sulphonamide (0.208 g) in pyrrolidine (4 ml) was degassed using vacuum/nitrogen cycle. Cuprous iodide (0.005 g) and dichlorobis(triphenylphosphine)palladium (0.037 g) were added and the mixture was stirred at 80° for 45 min under nitrogen. The mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc and the combined organic phases washed with brine, dried (Na2SO4) and evaporated to dryness. The residue was dissolved in CH2Cl2 and applied to a silica Bond Elut Cartridge (10 g). The cartridge was eluted with CH2Cl2, cyclohexane/Et2O, Et2O and EtOAc. Evaporation of the ether fractions gave an oil which was repurified by silica Bond Elut to give the title compound (0.23 g), ES+ve 585 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:23]=[C:24]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][CH:22]=1>>[CH:26]1[C:25]2[C:24](=[CH:23][C:20]3[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]4[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]5[CH:15]=[CH:14][N:13]=[CH:12]5)=[CH:4][CH:3]=4)[N:19]=3)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(C=C2c3ccccc3-c3ccccc32)n1
Product: C(=C1c2ccccc2-c2ccccc21)c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 84 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(9-fluorenylidene)methyloxazole to give 2-(9-fluorenylidenemethyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 84%. Recrystallization from ethyl acetate gave yellow prisms, mp 116-117° C.
Reaction SMILES: [F:1][C:2]([F:13])([S:9](Cl)(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(=O)([O-])O.[Na+].[OH:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>C(#N)C>[F:1][C:2]([F:13])([S:9]([O:19][N:20]1[C:24](=[O:25])[C:23]2[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]1=[O:30])(=[O:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)C(F)(F)CCO
Temperature: 0 °C
Yield: 69.7 %

Procedure:
In 100 mL of acetonitrile, 25 g of a liquid of 1,1,2,2-tetrafluoro-4-hydroxybutanesulfonyl chloride (purity: 99%, equivalent to 0.102 mol) was dissolved by stirring. The resulting solution was cooled to 0° C., admixed with 10.3 g (0.123 mol) of sodium hydrogencarbonate and 18.3 g (0.112 mol) of N-hydroxyphthalimide, and then, reacted at 0° C. for 24 hours. To the thus-obtained reaction solution, 125 mL of water was added. The reaction solution was subsequently extracted twice with 100 mL of ethyl acetate. The resulting organic layer was washed twice with 100 mL of water and subjected to concentration. With this, 26.4 g of the target compound was obtained as a pale yellow solid (yield: 57%, purity: 82%, pure content: 21.6 g).
Reaction SMILES: [C:1]([CH2:3][N:4]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)#[N:2]>CN(C=O)C>[C:1]([CH2:3][N:4]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[S:14]([CH3:17])(=[O:16])=[O:15])#[N:2]
Reactant: CS(=O)(=O)N(CC#N)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CC#N)c1ccc(N)cc1

Procedure:
Prepared analogously to Example 39c by catalytic hydrogenation of N-cyanomethyl-N-methylsulphonyl-4-nitroaniline in DMF.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[CH:21]=2)[S:5][CH:6]=1>C1COCC1.[OH-].[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:21]=2)[S:5][CH:6]=1
Reactant: COC(=O)C1=Cc2cc(-c3cc(C)cs3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1csc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
In THF (10 ml) was dissolved methyl 7-(4-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (420 mg), and to the mixture was added IN sodium hydroxide (8.4 ml). The mixture was stirred at room temperature for 15 hours. Under reduced pressure, the organic solvent was removed, and to the residue was added ethyl acetate. The mixture was extracted with water, and to the aqueous layer was added 6N hydrochloric acid to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7-(4-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (320 mg).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:21]=2)=[O:15])=[CH:12][CH:11]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:28][CH:27]=2)=[CH:21][C:20]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(OCCO)cc2)ccc1Cl
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-2-chloro-benzenesulfonamide (1.84 g, 3.92 mmol) is dissolved in tetrahydrofuran (50 mL), and treated with a solution of tetrabutylammonium fluoride reagent (1 M in tetrahydrofuran, 2.2 mmol). The reaction is allowed to stir for 1 hour. The reaction is diluted with water and extracted with ether. The organic phase is separated and concentrated in vacuo affording 1.39 g (100% yield) of the title compound. 1H NMR (DMSO) 3.75 (t, 2H, J=4.55 Hz), 4.12 (t, 2H, J=4.80 Hz), 4.95 (s, 2H), 7.12 (d, 2H, J=8.84 Hz), 7.76-7.90 (m, 4H), 8.24 (d, 1H, J=2.02). MS (m/z): 354 (M−1).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.Cl>CCOCC>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[CH2:7][C:6]2[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: OC(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Under a nitrogen atmosphere, 2.04 g (0.08 mol) of magnesium are covered with ether. 12.2 g (0.08 mol) of 4-fluorobenzyl chloride in 20 ml of ether are added dropwise to this in such a way that the ether boils gently. After addition is complete, the mixture is refluxed for a further 30 minutes, cooled to room temperature, and 8.3 g (0.07 mol) of 4-fluorobenzaldehyde in 20 ml of ether are slowly added dropwise. It may be necessary to cool with ice-water if the solution boils. After addition is complete, the mixture is left to reflux for 2 hours, then cooled and poured into 50 ml of ice-water. 50% concentrated hydrochloric acid is used to acidify, the phases are separated, and the aqueous phase is extracted 5 x with ether. The combined org. phases are neutralized with saturated sodium bicarbonate solution, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The colorless oil crystallizes completely and yields 15.7 g of white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])[C:5]2[O:10][CH2:9][C@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:7]3[C:17](=[O:20])[NH:18][C:19]=1[C:6]=23.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[CH3:27][C:22]1[C:21]([C:4]2[C:5]3[O:10][CH2:9][C@H:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[N:7]4[C:17](=[O:20])[NH:18][C:19]([C:6]=34)=[C:2]([CH:28]=[CH2:29])[CH:3]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: Cc1noc(C)c1-c1cc(Br)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(-c2c(C)noc2C)c2c3c1[nH]c(=O)n3[C@@H](c1ccccn1)CO2
Temperature: 80 °C
Yield: 64.3 %

Procedure:
A mixture of (4S)-9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (3.00 g, 7.02 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.14 mL, 12.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (570 mg, 0.70 mmol) and potassium carbonate (2.90 g, 21 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was heated at 80° C. for 1 h. The mixture was then poured over water and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by flash column chromatography (40% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) gave the desired product (1.69 g, 64%) as a single enantiomer. LCMS calculated for C21H19N4O3 (M+H)+: m/z=375.1. found: 375.1.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([O-])=[O:13].C(O)(=O)C>CO.O>[OH:13][N:12]=[C:15]1[S:16][C:17](=[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]#[N:11])[CH:18]=[CH:19]1
Reactant: N#CCc1ccccc1
Reactant: O=[N+]([O-])c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: N#CC(=C1C=CC(=NO)S1)c1ccccc1
Temperature: 0 °C
Yield: 37.4 %

Procedure:
14 g of KOH are dissolved in 50 ml of methanol. To the solution are added 7.1 ml (62 mmol) of phenylacetonitrile followed by 10 g (62 mmol) of 2-nitrothiophene dissolved in 30 ml of methanol. After the reaction mixture is stirred in the ice bath for 10 min, 200 ml of water are added with stirring. The resulting solution is acidified by addition of 55 ml of acetic acid in 50 ml of water, and extracted with ethyl acetate. The organic phase is washed with sodium chloride solution, and dried over MgSO4. After the solvent is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3), and recrystallization from toluene. 5.3 g (38%) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-phenyl-acetonitrile are obtained in the form of orange crystals having a melting point of 165° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=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.O.C(OCC)(=O)C.O1CCCC1.O1CCCC1>[N+:9]([C:5]1[C:6]([NH2:8])=[N:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.4 %

Procedure:
Under an argon stream, a mixture of 6-chloro-3-nitro-2-pyridine amine (2.0 g), phenylboric acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (1.3 g), 2 M sodium carbonate (35 ml), toluene (40 ml) and tetrahydrofuran (20 ml) was stirred at 90° C. for 12 hours. The mixture was distributed into ethyl acetate-tetrahydrofuran (3:1, v/v) and water. The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure and the resulting crystals were collected by filtration to obtain 3-nitro-6-phenyl-2-pyridine amine (1.3 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#N)=[CH:5][N:4]=1.Cl.NNC(N)=[O:15].C([O-])(=O)C.[Na+].C(O)C>[Ni].O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH:9]=[O:15])=[CH:7][CH:8]=1
Reactant: NNC(N)=O
Reactant: COc1ccc(C#N)cn1
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C=O)cn1
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A mixture of 2-methoxy-5-cyanopyridine (61.26 g), semicarbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) was hydrogenated at 344 kPa using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml, water (1000 ml) was added and the mixture was allowed to stand at 0° overnight. The mixture was filtered and the solid was washed with water and dissolved in 10% hydrochloric acid (1000 ml). Formaldehyde solution (36% w/v, 450 ml) was added and the mixture was warmed for 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether (3×500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50%) m.p. 48°-49°.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:17]([NH:19][C:20]3[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)=[O:41])=[O:25])=[CH:22][C:21]=3[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:54][N:55]1C(=O)C2=CC=CC=C2C1=O)=O)(C)(C)C>C(O)C.[OH-].[Na+].O>[NH2:55][CH2:54][C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[C:12]([C:17]([NH:19][C:20]1[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])=[O:25])=[CH:22][C:21]=1[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2c1cc(CN1C(=O)c3ccccc3C1=O)n2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN)cc12
Yield: 98.8 %

Procedure:
The solution of 4-[(1-tert-butoxycarbonyl-2-phthalimidomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (312 mg) in ethanol (5.0 ml) and 1N sodium hydroxide aqueous solution (1.76 ml) was stirred at ambient temperature for 6 hours. The resulting solution was diluted with water and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 4-[(2-aminomethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (228 mg).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>C1C=CC=CC=1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 60 %

Procedure:
A mixture of 1.5 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, 200 ml of benzene, 1.5 g of anhydrous potassium carbonate and 1.4 g of 4-tert.-butyl-benzyl chloride was subjected to reaction at a reflux temperature for 6 hours. Then, procedure similar to that in Synthesis Example 5 was conducted to obtain white crystals (yield: 60%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([N:20]=[C:21]([NH2:23])[NH2:22])[S:18][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)(=O)[NH2:7].O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[C:6]([C:9]1[N:14]=[C:13]([C:15]2[N:16]=[C:17]([N:20]=[C:21]([NH2:23])[NH2:22])[S:18][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)#[N:7]
Reactant: NC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(-c2csc(N=C(N)N)n2)n1
Yield: 90.2 %

Procedure:
Phosphorus oxychloride (0.7 ml) was dropwise added to a mixture of 4-(6-carbamoylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.0 g) in N,N-dimethylformamide (10 ml) at 2°-8° C. with stirring and the mixture was stirred for 5 hours at the same temperature. The reaction mixture was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with a mixture of ethyl acetate and ether to give 4-(6-cyanopyridin-2-yl)-2-(diaminomethyleneamino)-thiazole (0.84 g).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][NH2:22])[CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:22][CH2:21][CH2:20][O:19][C:4]1[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCN
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCNC(C)=O
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 4-amino-2-(2-aminoethoxy)-5-chloro-N-[2-(diethylamino)ethyl]benzamide (780 mg, 2.4 mmoles) (prepared in Example 47) in methylene chloride was added acetic anhydride (245 mg, 2.4 mmoles) and the mixture stirred for 30 minutes. This was concentrated in vacuo and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was concentrated and the residue flash-chromatographed on silica using methylene chloride:methanol:ammonia (100:4:0.5) solvent system. The appropriate fractions were combined and concentrated in vacuo. The residue was recrystallized from methylene chloride-ether to give 445 mg of the title compound as a white solid, mp. 143°-145° C.