Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:9]([O:11][CH3:12])=[O:10].[OH-].[Na+].[Cu](C#N)[C:20]#[N:21]>O.Cl>[Cl:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[C:20]#[N:21]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A solution of sodium nitrite (1.28 g) in water (8 ml) was added over 10 min to a mixture of methyl 3-amino-4-chlorobenzoate (4.0 g) in water (40 ml) and concentrated hydrochloric acid (5 ml) at 0° C. After 30 min the mixture was neutralised with aqueous sodium hydroxide solution to pH˜7 then added portionwise to a solution of copper cyanide (prepared from sodium cyanide (2.87 g) and copper(I) chloride (2.23 g) in water (40 ml)) at 0° C. The mixture was stirred at room temperature for 2 h then partitioned between ethyl acetate and water. The organics were washed with water, dried and evaporated under reduced pressure. The residue was triturated with 20% ethyl acetate/isohexane to yield a solid (1.55 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CN(C=O)C.[NH2:29][C:30]1[S:31][C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[C:33]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]([NH:29][C:30]2[S:31][C:32]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[C:33]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[O:19])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 100 %

Procedure:
1-Benzyloxycarbonylpiperidine-4-carboxylic acid (5.00 g, 19.0 mmol) was dissolved in dichloromethane (80 mL), and thionyl chloride (6.93 mL, 95.0 mmol) and DMF (0.15 mL, 1.90 mmol) were added thereto, followed by 178, stirring under heating and reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (2 mL). The resulting solution was added to a solution of 2-amino-4-(2-furyl)-5-morpholinotliiazole (2.01 g, 8.00 mmol) in pyridine (32 mL) obtained in Step 1 of Example 29, and then N,N-dimethylaminopyridine (97.6 mg, 0.800 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:3) to afford the entitled Compound 43 (4.96 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([O-:26])=[O:25])#[N:2].[Na+].[C:28](Br)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([O:26][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:25])#[N:2]
Reactant: CC1=C(CC(=O)[O-])c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1=C(CC(=O)OC(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Reaction time: 5 h

Procedure:
A mixture of .06 mole of sodium 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetate and 0.05 mole of trityl bromide in 100 ml. anhydrous benzene is refluxed with rapid stirring under nitrogen for 5 hours. The hot reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is recrystallized from methyl ethyl ketone to give trityl 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetate.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]2[NH:12][C:11]([CH:13]=[C:14]3[N:36]=[C:17]([C:18](C(OCCC)=O)=[C:19]4[NH:29][C:22](=[CH:23][C:24]5[CH:25]=[CH:26][C:27]=1[N:28]=5)[CH:21]=[CH:20]4)[CH:16]=[CH:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:2][CH3:3]>CN(C=O)C>[CH2:1]([O:4][C:5]([C:7]1[C:8]2[NH:12][C:11]([CH:13]=[C:14]3[N:36]=[C:17]([CH:18]=[C:19]4[NH:29][C:22](=[CH:23][C:24]5[CH:25]=[CH:26][C:27]=1[N:28]=5)[CH:21]=[CH:20]4)[CH:16]=[CH:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1c2nc(cc3ccc([nH]3)c(C(=O)OCCC)c3nc(cc4ccc1[nH]4)C=C3)C=C2
Solvent: CN(C)C=O
Product: CCCOC(=O)c1c2nc(cc3ccc(cc4nc(cc5ccc1[nH]5)C=C4)[nH]3)C=C2
Temperature: 145 °C
Yield: 142.4 %

Procedure:
To a magnetically stirred solution of porphyrin 31 (30 mg, 0.062 mmol) in anhydrous DMF (25 mL) was added MnCl2 (39 mg, 0.27 mmol). The reaction flask was fitted with a reflux condenser and the solution was heated to 145° C. for 2 h then exposed to a stream of air. The reaction mixture was heated for an additional 34 h then the solution was allowed to cool to room temperature for 48 h under a stream of air. Evaporation of DMF in vacuo provided a crude product that was adsorbed onto silica gel (2 g). Purification by column chromatography (gradient elution with 5→7.5% MeOH/CH2Cl2) provided 30 (35 mg; 98%) as a dark solid: mp>300° C.; UV-vis λmax=452. nm, ε=6.10×104 L/cm-mole; FAB MS m/z=535 [C28H24MnN4O4]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([O-])=O.[H][H]>CC(O)=O.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2
Reactant: [H][H]
Reactant: O=c1ccc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc2[nH]c(=O)ccc12
Yield: 94.8 %

Procedure:
A solution of 2.1 g (11 mmol) of 5-nitro-1H-quinolin-2-one (Chem. Pharm. Bull. 1981, 29, 651) in 40 ml of AcOH is hydrogenated with 210 mg of 10% Pd/C in the presence of hydrogen for 24 h with vigorous stirring. The catalyst is filtered off and the mixture is evaporated. The residue is subjected to flash chromatography over SiO2 with a gradient of pure CH2Cl2 to CH2Cl2-MeOH 99-1. After evaporation, 1.67 g (yield 97%) of yellow crystals are obtained. 1H NMR (DMSO): 11.38 (s, 1H), 8.08 (d, 1H, J=8 Hz), 7.10 (t, 1H, J=7.6 Hz), 6.44 (d, 1H, J=8 Hz), 6.33 (d, 1H, J=8 Hz), 6.26 (d, 1H, J=10 Hz), 5.85 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:28])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:5]2[S:4]1.[CH3:29][N:30]1[C:34]([SH:35])=[N:33][N:32]=[N:31]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:29][N:30]1[C:34]([S:35][CH2:2][C:3]2([CH3:28])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]3[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]4[CH:25]=[N:24][N:23]=[N:22]4)[C@H:5]3[S:4]2)=[N:33][N:32]=[N:31]1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Cn1nnnc1S
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cn1nnnc1SCC1(C)S[C@@H]2C(NC(=O)Cn3cnnn3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
By treating in the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)-acetamido]penam-3-carboxylate and 1-methyl-1H-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carboxylate.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:10]1=[O:54])(C)(C)C>O1CCOCC1.ClCCl>[CH3:52][O:51][C:49](=[O:50])[NH:48][C@@H:44]([C:43]([N:39]1[CH2:40][CH2:41][CH2:42][CH:38]1[C:35]1[NH:34][C:33]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:18]4[NH:17][C:16]([CH2:15][N:11]5[CH2:12][CH2:13][CH2:14][CH:9]([NH2:8])[C:10]5=[O:54])=[N:20][CH:19]=4)=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)=[CH:37][N:36]=1)=[O:53])[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCC[C@@H](NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reaction time: 1 h

Procedure:
A solution of hydrogen chloride (4N, 8 mL) in dioxane was added to a solution of (R)-{1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester (175 mg, 0.24 mmol) in dichloromethane (2 mL). After 1 hour the solvent was removed under reduced pressure. The resulting residue was placed on a high vacuum for 1 hour to provide (R)-{1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester. The yield was assumed to be 100% percent. A sample suitable for analysis was obtained by subjection to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization. C35H42N8O4 calculated 638.3 observed [M+1]+ 639.4; rt=1.41 min. 1H (DMSO-d6): δ=8.33 (m, 1H), 8.12 (m, 1H), 7.99 (m, 1H), 7.92 (m, 6H), 7.26 (d, J=8.4 Hz, 1H), 5.13 (t, J=8.0 Hz, 1H), 4.83 (m, 2H), 4.09 (t J=8.0 Hz, 1H), 4.09-3.82 (series m, 6H), 2.36 (m, 2H), 2.14 (m, 2H), 1.96 (m, 4H), 0.76 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:42])[CH2:29][O:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:42])([CH2:29][O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)COCc1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(N2CC(O)(COCc3ccc4ccccc4n3)N=C2c2ccc(Cl)cc2)cc1

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (1 mmol) and sodium bicarbonate (2 mmol) in acetone (20 mL), 1-bromo-3-(2-quinolylmethoxy)-2-propanone from Step 1 (1.5 mmol) is added. After heating to reflux for 24 hours, the reaction mixture is filtered, washed with acetone and concentrated in vacuo. The crude product is purified by chromatography (silica gel, toluene/ethyl acetate) to give 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([CH:19]=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1.O>C1COCC1>[CH2:7]([O:8][C:12]1[C:13]2[N:14]([CH:19]=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)c2nccn2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of phenylmethanol (3.35 g, 31 mmol, 1.2 eq) in THF (80 mL), NaH (60% dispersion in mineral oil, 1.34 g, 33.5 mmol, 1.3 eq) is added in portions. The resulting mixture is stirred at RT for 30 min and then 8-bromo-6-chloroimidazo[1,2-b]pyridazine (D-3) (6 g, 25.8 mmol, 1.0 eq) is added. The resulting mixture is stirred at RT for an additional 2 h and then poured into water (30 mL). The mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine (D-4).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:18]=2)=[C:9]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH:8]=1)=[O:5])[CH3:2].[Li+].[OH-].C(#N)C>C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[CH:18]=2)=[C:9]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)OCC)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)O)c2)cn1
Temperature: 25 °C
Yield: 31 %

Procedure:
In a 25 mL round-bottomed flask ethyl 6′-{[(ethylamino)carbonyl]amino}-4′-(4-phenyl-1,3-thiazol-2-yl)-3,3′-bipyridine-5-carboxylate (Example 131, 0.20 g, 0.42 mmol) was suspended in THF (3 mL). 1N LiOH (1.20 mL, 1.21 mmol) was added and the solution was stirred at room temperature over night. The solvent was removed and the resulting residue was diluted with water. The pH was adjusted to 4 (pH paper) with 2N HCl. White solids formed. They were trichurated with acetonitrile for 30 minutes and then filtered, washed with acetonitrile and dried in vacuo to give 58 mg of the title compound. LC/MS (ES+)[(M+H)+]: 446 for C23H11N5O3S. 1H NMR (300 MHz, d6-DMSO): 1.10 (t, 3H), 3.21 (m, 2H), 7.32-7.40 (m, 3H), 7.65 (t, 1H), 7.70 (s, 1H), 7.72 (s, 1H), 8.22 (s, 1H), 8.23-8.26 (m, 2H), 8.31 (s, 1H), 8.73 (d, 1H), 9.08 (d, 1H), 9.45 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23](=[O:25])[CH3:24])=[C:18]([OH:26])[CH:17]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23](=[O:25])[CH3:24])=[C:18]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:17]=1
Reactant: CC(=O)c1cc(C)c(Br)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)c(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.45 g, 10.48 mmol) and benzyl bromide (0.65 ml, 5.50 mmol) were added to a solution of 1-(4-bromo-2-hydroxy-5-methylphenyl)ethanone (may be prepared as described in Description 10; 1.2 g, 5.24 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred at room temperature overnight. Water (20 ml) and ethyl acetate (30 ml) were added and the organic layer was separated, washed with water (2×20 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (5-10% ethyl acetate/hexane) yielded the title compound. 607 mg.
Reaction SMILES: O[C:2]1[C:11](C)=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][C:3]=1C.C(C1C=CC([C:20]([O:22][CH2:23][CH3:24])=[O:21])=CC=1)#N>>[CH2:23]([O:22][C:20](=[O:21])[C:2]1[CH:3]=[CH:4][C:5]([C:6](=[NH:7])[NH:8][OH:9])=[CH:10][CH:11]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Product: CCOC(=O)c1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to 4,N-dihydroxy-3,5-dimethyl-benzamidine starting from ethyl 4-cyanobenzoate; LC-MS: tR=0.55 min, [M+1]+=209.05; 1H NMR (D6-DMSO): δ 1.33 (t, J=7.0 Hz, 3H), 4.32 (q, J=7.0 Hz, 2H), 5.94 (s, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.95 (d, J=7.8 Hz, 2H), 9.91 (s, 1H).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[F:46][C:47]1[CH:55]=[C:54]2[C:50]([C:51]([CH:56]3[CH2:60][N:59]([S:61]([CH3:64])(=[O:63])=[O:62])[CH:58]4[CH2:65][CH2:66][NH:67][CH:57]34)=[CH:52][NH:53]2)=[CH:49][CH:48]=1>CN1C(=O)CCC1.C(OCC)C.CCOC(C)=O>[C:11]([O:10][C:8](=[O:9])[NH:1][CH:2]([C:5]([N:67]1[CH2:66][CH2:65][CH:58]2[N:59]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:60][CH:56]([C:51]3[C:50]4[C:54](=[CH:55][C:47]([F:46])=[CH:48][CH:49]=4)[NH:53][CH:52]=3)[CH:57]12)=[O:7])[CH2:3][CH3:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CS(=O)(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2NCCC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution containing Boc-L-Abu-OH (170 mg, 0.83 mmol) in anhydrous NMP (2 mL) was cooled to 0° C. HATU (316 mg, 0.83 mmol) and NMM (115 mg, 1.08 mmol) were added followed by the addition of crude 63 (242 mg, 0.75 mmol) in anhydrous NMP (4 mL). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and EtOAc (10:1) and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2″ Dynamax C18, 40-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 270 mg (71%) of 64. Mass spectrum, m/z [509.2] (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22](SC)=[N:23][CH:24]=2)[N:19]1[C:30]1[N:35]=[C:34]([N:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]2=[O:43])[CH:33]=[CH:32][CH:31]=1)[CH:16]=[CH2:17]>>[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:23][CH:24]=2)[N:19]1[C:30]1[N:35]=[C:34]([N:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]2=[O:43])[CH:33]=[CH:32][CH:31]=1)[CH:16]=[CH2:17]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(-n2cc(F)ccc2=O)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(-n2cc(F)ccc2=O)n1

Procedure:
The entitled compound was obtained as a yellow solid (23.6 mg) in the same manner as in Production Example 12-2, for which, however, 4-(4-methylpiperazin-1-yl)aniline was used in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Production Example 12-2, and 6′-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-5-fluoro-2H-1,2′-bipyridin-2-one was used in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][CH3:13]>[Pd].C(O)C>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([O:12][CH3:13])=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1c(C)cc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)cc(N)cc1C
Yield: 98 %

Procedure:
2,6-Dimethyl-4-nitroanisole (3, 29 g, 160 mmol), 10% Pd-C (200 mg) and ethanol (300 mL) were placed in a 500-mL Parr hydrogenation flask and hydrogenated at 50 psi for 24 h. The resulting solution was filtered through a silica gel column using ethyl acetate as eluent. Concentration of the solvent and drying under vacuum gave 23.7 g (98% yield) of 4-amino-2,6-dimethylanisole (4) as a brown-colored solid, mp 59°-60° C. (lit.: Bruice, T. C.; Kharasch, N.; Winzler, R. J. J. Org. Chem. 1953, 18, 83; 63° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([OH:27])[C:23](=[O:26])[CH:24]=[CH2:25])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:28])=[CH:4][N:3]=1.[CH3:29][O:30][CH2:31][CH2:32][O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.CCCCCC.C(OCC)(=O)C.O>O1CCOCC1>[F:28][C:5]1[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([OH:27])[C:23](=[O:26])[CH:24]=[CH2:25])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][C:2]([NH:38][C:37]2[CH:36]=[CH:35][C:34]([O:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:40][CH:39]=2)=[N:3][CH:4]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: C=CC(=O)N(O)c1cccc(N(C(=O)OC(C)(C)C)c2nc(Cl)ncc2F)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C=CC(=O)N(O)c1cccc(N(C(=O)OC(C)(C)C)c2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
In a 25 mL three neck RBF with thermometer pocket, a solution of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate (0.250 g) in 1,4-dioxane (8.0 mL) was added. 4-(2-Methoxyethoxy)aniline (0.122 g) was added and the reaction was degassed for 10 minutes under argon. After 10 minutes, Xantphose (0.0176 g) and Cs2CO3 (0.396 g) were added and again degassed the reaction for 10 minutes followed by addition of Pd (OAc)2 (0.003 g) under argon. The reaction was heated to 80° C. and stirred for 3.5 hr under argon. The reaction was monitored on TLC using hexane:ethyl acetate (2:8) as mobile phase. After completion of the reaction, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 ml). Ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give 0.250 g of tert-butyl (5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate. This crude material was used in the next step without any further purification. M+1=539.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:50])[CH:5]=[C:6]([Cl:49])[C:7]=1[CH2:8][C@@H:9]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:10][C:11](=[O:33])[CH2:12][O:13]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C(Cl)Cl.Br>[Cl:49][C:6]1[CH:5]=[N+:4]([O-:50])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:10][C:11](=[O:33])[CH2:12][OH:13]
Reactant: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Br
Solvent: O
Solvent: ClCCl
Product: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(trityloxy)acetoxy)ethyl)pyridine 1-oxide (4.0 g, 5.55 mmol) in DCM (1 Lt) cooled at 0° C., 160 drops of 48% HBr were added, and the reaction was stirred for 1 hour (temperature below 10° C.). Water was added to the mixture, the organic phase was separated, dried over Na2SO4 and evaporated under vacuum (bath temperature=25° C.). The crude compound was dissolved in DCM, and hexanes was added. The white precipitate thus formed was filtered and washed with plenty of hexanes. After drying, (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide was obtained (2.26 g, 4.73 mmol, 76% yield, MS/ESI+ 478.0 [MH]+) and used in the following step without further purification.