Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:22]([C:19]1[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nn1
Yield: 58 %

Procedure:
As described for example 42b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (44 mg, 58%) which was obtained as a white solid. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1B(O)O>>[CH:1]([N:14]1[CH:19]=[C:18]([C:25]2[CH:24]=[CH:23][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Reactant: OB(O)c1ccc2ccccc2c1
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccc2ccccc2c1
Yield: 82.4 %

Procedure:
The title compound: was obtained according to the procedure described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.11 g, 0.27 mmol) and 2-naphthylboronic acid (0.07 g, 0.41 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.09 g, 80%) as an off-white solid. 1H NMR (400 MHz, CDCl3): 7.17 (s, 1H), 7.24-7.27 (m, 2H), 7.36 (s, 1H), 7.38-7.47 (m, 10H), 7.76-7.88 (m, 5H), 8.28 for s, 1H). MS (ESI) m/z: 405 [M-H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1.Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)Cn1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Agent: Br
Product: CCOC(=O)C(Cc1ccccn1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
440 mg (1.22 mmol) of ethyl {4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetate and 464 mg (1.84 mmol) of 2-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 371 mg (purity 65%, 44% of theory) of the title compound and 270 mg (50% of theory) of the product which is already hydrolysed (Example 8.1D)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][C:5]#[N:6]
Reactant: N#CCc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#CCc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of 2-chloro-4-fluorobenzyl cyanide are dissolved at a temperature of -10° C., with stirring, in 85 ml of concentrated sulfuric acid, in the process of which a fine light-brown suspension is formed. There are then slowly added dropwise at -20° C., with stirring, 5 ml of fuming nitric acid. After completion of the addition, stirring is continued for a further half hour, the temperature rising to 0° C. The reaction mixture is poured onto 500 g of ice, and the substance which precipitates is extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate, and concentrated by evaporation to leave 10.5 g of 2-chloro-4-fluoro-5-nitrobenzyl cyanide in the form of white crystals having a melting point of 67°-68° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:30])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(NCc4ccccc4)cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A vial was charged with 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.250 g, 0.582 mmol), benzaldehyde (59.2 μL, 0.582 mmol), and 4 Å MS (0.25 g). DCE was added (1.9 mL) and the reaction mixture was stirred at room temperature for 18 h. Sodium triacetoxyborohydride (0.308 g, 1.46 mmol) was added and the reaction mixture was stirred for a further 24 h. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and was then extracted with DCM (3×15 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (2-40% EtOAc/hexanes) to yield the titled compound (0.273 g, 90% yield). MS (ESI/Cl): mass calcd. for C27H33N5O4Si, 519.2; m/z found, 520.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][CH2:15][CH3:16])[C:12]([S:17][CH3:18])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:18][S:17][C:12]1[N:13]([CH2:14][CH2:15][CH3:16])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:10][N:11]=1
Reactant: CCCn1c(-c2ccc(OC)cc2)cnc1SC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCn1c(-c2ccc(O)cc2)cnc1SC

Procedure:
A mixture of 3 parts of 5-(4-methoxyphenyl)-2-(methylthio)-1-propyl-1H-imidazole and 37.5 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed for 2.50 hours. The reaction mixture is cooled and neutralized with sodium hydrogen carbonate. The precipitated product is filtered off, washed with water and crystallized from a mixture of ethanol and water, yielding 2 parts of 4-[2-(methylthio)-1-propyl-1H-imidazol-5-yl]phenol; mp. 157.4° C.
Reaction SMILES: [NH2:1][P:2]([NH2:16])([NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)=[O:3].[H][H]>[Pd].CN(C)C=O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH:4][P:2]([NH2:16])([NH2:1])=[O:3])=[O:15])=[CH:7][CH:8]=1
Reactant: NP(N)(=O)NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NP(N)(N)=O)cc1
Reaction time: 60 h

Procedure:
30 g (0.12 mole) of N-[diaminophosphinyl]-4-nitrobenzamide in 800 ml of absolute alcohol was reduced using 4.0 g of 5% Pd/C containing 50% water. A hydrogen uptake of 19.9 psi. was recorded after 60 hr. (theoretical 24 psi.). Added 2000 ml of absolute alcohol and 2000 ml of dimethylformamide to dissolve. The catalyst was removed by filtration and the filtrate flash-evaporated down to 125 ml. Chilled to 0°, filtered and washed with anhydrous ethyl ether to yield 12.4 g (48%), m.p. darkens 168°-172°, softens 290°, decomposes 340°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[NH2:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([Cl:13])[N:7]=1.C(O)C>C(N(CC)CC)C>[NH2:5][C:6]1[N:11]=[C:10]([NH:4][CH2:3][CH2:2][OH:1])[CH:9]=[C:8]([Cl:13])[N:7]=1
Reactant: NCCO
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)cc(NCCO)n1
Yield: 59.6 %

Procedure:
To 2-hydroxyethylamine (2.6 g, 42.7 mmol) were added 2-amino-4,6-dichloropyrimidine (7.0 g, 42.7 mmol), ethanol (150 ml) and triethylamine (6.6 ml), and the mixture was refluxed for one day. The solvent was distilled away under reduced pressure and the residue was washed with water, which was followed by recrystallization from chloroform to give yellow prism crystals (4.8 g, 59.6%), m.p. 143-146° C. (chloroform).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[N:11][OH:12])=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:12][N:11]=[CH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C=NO)c([N+](=O)[O-])cc1OC
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=NOCc2ccccc2)c([N+](=O)[O-])cc1OC
Reaction time: 4 h

Procedure:
6-Nitroveratraldoxime (113 g, 0.5 mole) was dissolved in 2500 ml of dimethylformamide. To this solution was added sodium methoxide (27 g, 0.5 mole). The suspension was treated with benzyl chloride (63 g, 0.5 mole) and stirring was continued for an additional 4 hr. The orange suspension was diluted with 3 l. of water and the solid was filtered, m.p. 109°-113°, yield: 110 g (78%). A small amount of the material was recrystallized from toluene to give an analytical sample melting at 116°-117°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:11]=[C:10]([CH3:12])[NH:9][C:5]2=[N:6][C:7]=1Cl.N#N.B(O)(O)[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1.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].C(Cl)Cl>[CH3:12][C:10]1[NH:9][C:5]2=[N:6][C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:2]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[N:3]=[C:4]2[CH:11]=1
Reactant: Cc1cc2nc(Br)c(Cl)nc2[nH]1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nc3cc(C)[nH]c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
2-Bromo-3-chloro-6-methyl-5H-pyrrolo[2,3-b]pyrazine (step 3) (183 mg, 0.742 mmol) in dioxane (5 ml) was degassed with N2 and treated with p-tolylboronic acid (242 mg, 1.782 mmol), K2CO3 (308 mg, 2.227 mmol) and PdCl2(dppf)-CH2Cl2-adduct (60.6 mg, 0.074 mmol). The reaction mixture was heated at reflux for 3 hours. After cooling to RT, further portions of p-tolyl boronic acid (242 mg, 1.782 mmol) and PdCl2(dppf)-CH2Cl2-adduct (60.6 mg, 0.074 mmol) were added and heating continued at reflux for 2 hours. After cooling to RT, the mixture was diluted with water (50 ml). The resultant suspension was sonicated and filtered, rinsing the filter cake with water (×3). Purification of the crude product by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+].C1(OC2C=C(C3(C#CC4C=CC=C(N)C=4)CCC4(OCCO4)CC3)C=CC=2OC)CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.C(O)(=O)C.O.CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3].ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(C#Cc3cccc([N+](=O)[O-])c3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: [Ti+3]
Agent: COc1ccc(C2(C#Cc3cccc(N)c3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C2(C#Cc3cccc(N)c3)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-nitrophenylethynyl)cyclohexane (0.17 g, 0.35 mmol) in methanol (1 mL), acetic acid (1.2 mL) and water (1.2 mL) under an argon atmosphere was added titanium trichloride (0.3 g, 2 mmol). After stirring for 1.5 h at room temperature, titanium trichloride (0.3g, 2 mmol) and water (1.2 mL) were added, and the mixture was stirred for 0.5 h at room temperature and for 0.5 h at 45°-50°C., then was cooled to room temperature. Water (1.2 mL) and ammonium hydroxide (2.5 mL) were added. After stiinng an additional 1 h, methanol (17.5 mL), 5% sodium carbonate (17.5 mL) and dichloromethane (35 mL) were added, and stirring was continued for 2 h. The suspension was filtered through Celite®, was washed well with dichloromethane and the extract was evaporated. The residue was diluted with dichloromethane, the organic layer was washed with 5:95 ammonium hydroxide:water, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes, provided a mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-anminophenylethynyl)-cyclohexan-1-one and 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-aminophenylethynyl)cyclohexane (0.07 g). This mixture and a spatula-tip of pyridinium p-toluenesulfonate in acetone (4 mL) and water (1 mL) was refluxed for 3 days, then was evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)cyclohexan-1-one as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.22 (d, J=2.2 Hz, 1H), 7.14 (m, 2H), 6.87 (m, 2H), 6.82 (d, J=2.8 Hz, 1H), 6.66 (dd, J=9.0, 2.4 Hz, 1H), 4.81 m, 1H), 3.85 (s, 3H), 3.7 (br, 2H), 3.04 (dt, J=14.3, 6.0 Hz, 2H), 2.47 (br d, J=14.6 Hz, 2H), 2.2-2.3 (m, 4), 1.8-2.0 (m, 6H), 1.61 (m, 2H).
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:20]=[C:21]([OH:36])[C:22]2[C:27]([C:28]=1[O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[C:39]([C:41]1[C:42](=[O:69])[N:43]([CH3:68])[C:44]([OH:67])=[C:45]([N:48]=[N:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56]OS(C3C=CC=CC=3)(=O)=O)=[CH:52][CH:51]=2)[C:46]=1[CH3:47])#[N:40]>>[C:39]([C:41]1[C:42](=[O:69])[N:43]([CH3:68])[C:44]([OH:67])=[C:45]([N:48]=[N:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][O:36][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]([O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:19]([NH:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:20]=3)=[CH:52][CH:51]=2)[C:46]=1[CH3:47])#[N:40]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(O)c2ccccc2c1OCOCCOC
Reactant: Cc1c(N=Nc2ccc(COS(=O)(=O)c3ccccc3)cc2)c(O)n(C)c(=O)c1C#N
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(OCc2ccc(N=Nc3c(C)c(C#N)c(=O)n(C)c3O)cc2)c2ccccc2c1OCOCCOC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
5 g of Compound [1-f] was dissolved in 30 ml of dried diglime and to the solution was added 0.48 g of a 50% oily sodium hydride. Then, 4.4 g of Compound [2-b] was added and the mixture was stirred at 80° C. for 1.5 hours. By subjecting the same treatment as described in Step [1-i], 5.5 g of Compound [2-c] was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.P(Cl)(Cl)[Cl:12].[Cl-].[Cl-].[Cl-].[Al+3].ClCl>P(Cl)(Cl)(Cl)=O>[Cl:12][C:7]1[O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=2[N:6]=1
Reactant: Clc1ccc2ncoc2c1
Reactant: ClP(Cl)Cl
Agent: ClCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)oc2c1
Temperature: 100 °C
Yield: 1931.6 %

Procedure:
10 g (0.065 mol) of 6-chlorobenzoxazole, 0.45 g of phosphorus trichloride and 0.09 g of anhydrous aluminum trichloride were initially charged in 30 ml of phosphorus oxychloride (POCl3). With heating and stirring, chlorine gas was introduced at a rate of 0.6 equivalent of chlorine per hour. After an internal temperature of 80° C. had been reached, the stream of chlorine gas was reduced to 0.6 equivalent of chlorine per 6 hours, and the temperature was increased to 100° C. The reaction was monitored by gas chromatography. After all of the starting material had been consumed, most of the POCl3 was distilled off and the residue was subjected to fractional distillation under reduced pressure. This gave a pure fraction of 11.9 g of the 2,6-dichlorobenzoxazole, which solidifies on cooling (GC>99% pure) (>97% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](I)[CH2:21][CH2:22][CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)O
Product: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 73.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (50 g) is alkylated using pentyliodide (76.8 g; 0.38 mol) and K2CO3 (53.6 g; 0.38 mol) at 60° C. for 24 h. After aqueous work-up the crude material is de-acetylated under reflux in 2-propanol (500 ml) and hydrochloric acid (6 N; 300 ml). After aqueous work-up pure 5-amino-3,3-dimethyl-6-nitro-1-pentyl-1,3-dihydro-indol-2-one (40.7 g) is obtained by re-crystallization from MeCN.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[N:11][C:12](Cl)=[C:13]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:20][CH2:19]3)[N:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][CH:35]([F:38])[CH2:36][NH2:37].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[N:11][C:12]([NH:37][CH2:36][CH:35]([F:38])[F:34])=[C:13]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:20][CH2:19]3)[N:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)F
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine (261.1 mg, 0.554 mmol) and 2,2-difluoroethanamine (156 μL, 2.22 mmol) in toluene (1.85 mL) was treated with sodium tert-butoxide (107 mg, 1.11 mmol), BINAP (69.0 mg, 0.111 mmol), and Pd2(dba)3 (50.8 mg, 0.055 mmol). Nitrogen gas (balloon) was bubbled through the reaction mixture for 5 min. The reaction mixture was sealed and stirred at 90° C. overnight. The reaction mixture was allowed to cool to room temperature and was opened to air, and the solution was concentrated under reduced pressure. The residue was taken up in MeOH, filtered, and purified by HPLC Method B using a 35% to 60% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (181.2 mg, 51.9%). ESI-MS m/z [M+H]+ 516.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH2:28])[CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:24]2[CH2:25][CH2:26][CH2:27][N:22]([CH3:21])[CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCCC(N)C1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-methylpiperidin-3-amine (13.7 mg, 0.12 mmol). The title compound was obtained as a solid (23.0 mg, 51% yield). MS m/z: 447.02, 449.02 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].O[C:14]1[C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][N:2]([CH2:3][CH2:4][CH:5]([O:6][C:14]1[C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:1]
Reactant: Oc1cccc2c1OCO2
Reactant: CN(C)CCC(O)c1cccs1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCC(Oc1cccc2c1OCO2)c1cccs1
Reaction time: 24 h
Yield: 35 %

Procedure:
3-Dimethylamino-1-(thiophen-2-yl)-1-propanol (1.85 g, 0.01 mol), 4-hydroxyl-benzo[1,3]dioxolane (1.38 g, 0.01 mol) and triphenylphosphine (3.93 g, 0.015 mol) were dissolved in 80 ml of anhydrous tetrahydrofuran. The mixture was slowly added dropwise with the solution of diethyl azodicarboxylate (2.61 g, 0.015 mol) in 20 ml anhydrous tetrahydrofuran, the reaction temperature was controlled to be lower than −5° C. in an ice-salt bath. After completion of the addition, the ice-salt bath was removed, and the reaction was performed at room temperature for 24 h. After the end of reaction, tetrahydrofuran was distilled out under a reduced pressure, the resultant oily liquid was dissolved in 100 ml of ethyl acetate, washed with diluted sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution separately once, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 1.07 g of N,N-dimethyl-3-[(benzo[1,3]dioxolan-4-yl)-oxy]-3-(thiophen-2-yl)-propylamine as a pale yellow oily liquid, which was dissolved in 30 ml of ethyl acetate, added with oxalic acid (0.32 g, 0.035 mol) to generate a pale yellow solid. The mixture was heated to reflux, cooled to room temperature, frozen for 2 h and filtrated. The filter cake was washed with cold ethyl acetate to obtain 1.31 g of the target compound as a pale yellow powdery solid in a yield of 33.2% and a melting point of 85-88° C. MS (m/e): 306.5 (M+1+); 1H-NMR δ (ppm, DMSO-d6): 7.46-7.48 (d, 1H, 5′-H); 7.11-7.12 (d, 1H, 3′-H); 6.95-6.97 (dd, 1H, 4′-H); 6.66-6.70 (t, 1H, 6-H); 6.53-6.59 (dd, 2H, 5,7-H); 5.97-5.98 (d, 2H, 2-H); 5.71-5.75 (t, 1H, CHO); 2.27-2.30 (t, 2H, CH2N); 2.19-2.21 (m, 1H, CH2CH2N); 2.11 (s, 6H, N(CH3)2); 2.06-2.08 (m, 1H, CH2CH2N).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.[N:26]1C=CC=[CH:28][C:27]=1CN>>[NH2:20][C:8]([NH:4][CH2:5][C:6]1[CH:2]=[CH:1][CH:28]=[CH:27][N:26]=1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccc(Cl)cc2)n1
Reactant: NCc1ccccn1
Agent: CS(=O)(=O)O
Product: NC(=NS(=O)(=O)c1ccc(Cl)cc1)NCc1ccccn1

Procedure:
The compound of Example 21 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 327.79; found mol. wt. (M+H) 328.3; 655.6 (Dimer)