Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](O)=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([O-:21])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CBr>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:18][O:21][CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: BrCCCCCCBr
Reactant: Oc1ccc2c(c1)CCN2c1ccc(F)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(N2c3ccccc3CC2OCCCCCCBr)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
460 mg (2 mmol) 1-(4-Fluoro-phenyl)-2,3-dihydro-1H-indol-5-ol in 6 ml acetone were treated with 830 mg (6 mmol) powdered K2CO3 and 1 ml (6 mmol) 1,6-dibromohexane. The suspension was stirred at 60° C. for 6 h, cooled to RT, diluted with acetone, filtered and concentrated. Column chromatography on silica gel with a gradient hexane to hexane/EtOAc 19:1 yielded 210 mg (25%) (6-Bromo-hexyloxy)-1-(4-fluoro-phenyl)-2,3-dihydro-1H-indole as yellow oil, MS: 392(MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[CH:27]=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:27][C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=Cc1ncccn1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCc3ncccn3)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and pyrimidin-2-carbaldehyde using decaborane yielded the title compound as a white foam. MS (ESI): m/z=371.3 [M+H]+.
Reaction SMILES: [CH2:1]=O.[C:3]([BH3-])#[N:4].[Na+].N[CH:8]([CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[OH-].[Na+]>C(#N)C.C(O)(=O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][CH:8]([N:4]([CH3:3])[CH3:1])[CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(N)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)C(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 37% aqueous solution of formaldehyde (0.75 ml; 10 mmol) and sodium cyanoborohydride (194 mg; 3.0 mmol) were added to a solution in acetonitrile (15 ml) of 2-amino-1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)propane (373 mg; 0.88 mmol) synthesized by the above process, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was then added to the solution to adjust the pH to about 5, and the mixture was stirred further for 30 minutes at room temperature. The reaction mixture was brought to pH about 10 by addition of aqueous 2.5N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 388 mg (yield: 98%) of the title compound as a colorless oil.
Reaction SMILES: [Li+].[BH4-].Cl[Si](C)(C)C.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].CO>O1CCCC1>[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C(=O)O)c1C
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CO)c1C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a stirred mixture of LiBH4 (2.62 g; 120 mmol) in tetrahydrofuran (60 mL) was slowly added, via syringe, chlorotrimethylsilane (30.1 mL; 241 mmol). After stirring for 10 minutes, 3-methoxy-2-methylbenzoic acid (10.0 g, 60 mmol) was added in small portions. The mixture was stirred at ambient temperature for 18 hours. The mixture was cooled in an ice bath and methanol was slowly added until bubbling ceased and the solution turned clear. The reaction solution was evaporated to dryness. The residue was dispersed in dichloromethane and water. The phases were separated. The aqueous phase was basified with NaOH solution to pH 9-10 extracted with dichloromethane. The extracts were combined, dried over MgSO4, and evaporated to give (3-methoxy-2-methylphenyl)methanol 25, 9.10 g, 99% yield.
Reaction SMILES: C(O)(C)C.[OH:5][CH:6]([CH2:16][OH:17])[CH2:7][NH:8][C:9]([CH3:15])=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[N:20]=[C:21]([N+:27]([O-:29])=[O:28])[C:22]([NH2:26])=[N:23][C:24]=1Cl>C(N(CC)CC)C>[NH2:26][C:22]1[N:23]=[C:24]([C:10](=[C:9]([NH:8][CH2:7][CH:6]([OH:5])[CH2:16][OH:17])[CH3:15])[C:11]([O:13][CH3:14])=[O:12])[C:19]([Cl:18])=[N:20][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Reactant: COC(=O)C=C(C)NCC(O)CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)NCC(O)CO)c1nc(N)c([N+](=O)[O-])nc1Cl

Procedure:
To 75 ml of isopropanol is added 3.3 g (0.017 m) methyl 3-(2,3-dihydroxypropyl)amino-2-butenoate (3), 4.18 g (0.02 m) 5,6-dichloro-3-nitropyrazinamine (5), and 2.0 g (0.02 m) triethylamine. This solution is heated at 60°-65° for two days. The reaction mixture is then stripped on the rotary evaporator and the residue chromatographed on silica gel eluted with 12% methanol/chloroform. Material with Rf =0.5 is collected and after crystallization from acetonitrile the desired product is an orange solid, m.p. 184°-186° (dec).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (500 mg, 2.19 mmol) in MeOH (5 mL) was added a 30% solution of sodium methoxide (0.40 mL, 2.26 mmol). The reaction mixture was stirred at RT for 2 h then concentrated. The residue was dissolved in water (5 mL) and extracted with EA (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated to afford 432 mg (88%) of 5-bromo-2-chloro-4-methoxypyrimidine as white solid. LCMS-ESI (m/z) calculated for C5H4BrClN2O: 223.4. found 224.2 [M+H]+, tR=7.66 min. (Method 2).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:28][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: O=C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCC2)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour with 2.4 g of cyclopentanone at -70°, and heated to 25°. Then water is added, the mixture is extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.21 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1

Procedure:
Conc. sulfuric acid (50 mL) was added to 2-chlorobenzothiazole (10 g) under ice-cooling, and conc. nitric acid (5 mL) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 1 hr, and iced water (600 mL) was added to the reaction mixture. The precipitated solid was collected by filtration, which was then recrystallized from acetone to give 2-chloro-6-nitrobenzothiazole (6.36 g) as a pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br.C(O)(=[O:25])C>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]([NH2:15])=[O:25])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#CC1(c2ccccc2)CCN(c2ncc(Br)cn2)CC1
Agent: Br
Product: NC(=O)C1(c2ccccc2)CCN(c2ncc(Br)cn2)CC1
Temperature: 0 °C

Procedure:
A solution of 1-(5-bromopyrimidin-2-yl)-4-phenylpiperidine-4-carbonitrile (0.31 g, 0.9 mmol) in HBr-acetic acid (12 mL) was refluxed for 16 h. After completion of reaction (by TLC), the mixture was poured into 100 mL of ice cold water and extracted with EtOAc (3×150 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to obtain the desired product as a white solid (0.12 g). MS: 361.15 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15](=[O:23])[CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:13]>O>[CH2:12]([O:14][C:15](=[O:23])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: O
Product: CCOC(=O)CC1CCN(c2ccc(Cl)cc2[N+](=O)[O-])CC1
Temperature: 105 °C
Yield: 94.4 %

Procedure:
A mixture of 0.500 g (2.60 mmol) of 2,5-dichloronitrobenzene and 1.0 mL (mmol) of 2-(piperdin-4-yl)-acetic acid ethyl ester is heated overnight at 105° C. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.803 g (94.4%) of [1-(4-chloro-2-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester as a red oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([NH2:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CCOC(C)=O>N1C=CC=CC=1.CCCCCC>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:9]2[NH:10][N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Nc1nnc(-c2ccccc2)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
To a solution of 5-phenyl-4H-1,2,4-triazol-3-amine (354 mg, 2 mmol) in dry pyridine (10 mL) was added 4-methylbenzenesulfonyl chloride (427 mg, 2.24 mmol). The solution was stirred at room temperature under Argon. After 48 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between CH2Cl2 and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with CH2Cl2. After drying over Na2SO4, the solvent was removed in vacuo to give 0.41 g crude product. The crude product was dissolved hot EtOAc (16 mL), diluted with hexane (16 mL), and seeded to give fine white needles (304 mg) with mp 220-221° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]4[CH2:23][NH:24]C(=O)OC(C)(C)C)[C:14]([F:32])=[CH:13][N:12]=3)[CH:8]=2)[CH:3]=[N:2]1>C(O)(C(F)(F)F)=O>[NH2:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][N:17]1[C:15]1[C:14]([F:32])=[CH:13][N:12]=[C:11]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1c1nc(Nc2ccc3cn[nH]c3c2)ncc1F
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCCCN1c1nc(Nc2ccc3cn[nH]c3c2)ncc1F
Yield: 78.7 %

Procedure:
A solution of tert-butyl (1-(2-(1H-indazol-6-ylamino)-5-fluoropyrimidin-4-yl)piperidin-2-yl)methylcarbamate (41 mg, 0.093 mmol) in TFA (4 mL) was stirred at room temperature for 60 min. TFA was removed in vacuo. The residue was purified by HPLC to give N-(4-(2-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-yl)-1H-indazol-6-amine (25 mg) MS 342.3 (M+H); UV 201.8, 246.8, 278.8 nm.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([OH:27])[CH3:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)([OH:27])[CH3:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(C)(O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(C)(O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogencarbonate (2.9 g) and dimethyl sulfoxide (40 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-fluorophenyl)-2-hydroxypropyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (40 mL). N,N′-Carbonyldiimidazole (0.5 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.5 g, 27%).
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[O:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>>[CH3:8][N:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]([N:19]2[CH2:20][CH2:21][CH:17]([O:16][C:15]3[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=3[C:13]([F:12])([F:27])[F:26])[CH2:18]2)=[N:7]1.[CH2:15]([OH:16])[CH2:14][CH2:25][CH3:24]
Reactant: FC(F)(F)c1ccccc1OC1CCNC1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Product: CCCCO
Product: Cn1nc(N2CCC(Oc3ccccc3C(F)(F)F)C2)c(=O)n(C)c1=O
Yield: 60 %

Procedure:
The compound 37 (solid) is prepared from the triazine 1b and from the intermediate 11a according to the synthesis method 1 in n-butanol (yield: 60%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][C@@:22]([C@@H:26]([CH3:34])[CH2:27][CH2:28][C@@H:29](O)[CH:30]([CH3:32])[CH3:31])([CH3:25])[C:21]1([CH3:36])[CH3:35])([C:14]([CH3:17])([CH3:16])[CH3:15])(C1C=CC=CC=1)C1C=CC=CC=1.N1[CH:41]=[CH:40]N=C1.[Si:42](Cl)([C:55]([CH3:58])([CH3:57])[CH3:56])([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>N1C=CC=CC=1.C(OCC)C.O>[C:14]([SiH2:1][O:18][C:19]([C:41]1[CH:40]=[CH:51][CH:50]=[CH:49][CH:54]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:20]1[CH2:24][CH2:23][C:22]([CH:26]([CH3:34])[CH2:27][CH2:28][CH:29]([Si:42]([C:55]([CH3:56])([CH3:57])[CH3:58])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:30]([CH3:32])[CH3:31])([CH3:25])[C:21]1([CH3:35])[CH3:36])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Reactant: CC(C)[C@H](O)CC[C@H](C)[C@@]1(C)CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1(C)C
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(CCC(C)C1(C)CCC(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)C1(C)C)[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 48 h

Procedure:
To a solution of intermediate (16) (0.045 g, 0.088 mmol) and imidazole (0.0252 g, 0.366 mmol) in dry pyridine (1 mL) was added tert-butyl-diphenylsilyl chloride (97 μL, 0.366 mmol) at 20° C. and the reaction mixture was stirred for 48 hours. Water (30 mL) and diethyl ether (30 mL) were added and the mixture was neutralized to pH=6 using a 1 N hydrogen chloride solution. The aqueous layer was extracted with diethyl ether and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was purified over silica (isooctane/ethyl acetate, 98:2) and then used directly in the next step.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH:18]([CH3:22])[NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH:18]([CH3:22])[N:19]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC1NCCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CCN1S(C)(=O)=O

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.027 mmol), DIPEA (14.2 μL, 0.081 mmol), and methanesulfonyl chloride (3.2 μL, 0.041 mmol) in DCM (271 μL) was stirred overnight. Purification by HPLC Method A gave the title compound as a TFA salt (6.4 mg) as a white film. 1H NMR (500 MHz, methanol-d4) δ ppm 1.54 (d, J=6.8 Hz, 3H), 1.91-2.02 (m, 2H), 2.07-2.19 (m, 2H), 2.66 (dd, J=16.8, 3.2 Hz, 1H), 2.91 (s, 3H), 2.93-3.06 (m, 3H), 3.34-3.48 (m, 3H), 3.68-3.88 (m, 2H), 3.98 (dd, J=14.2, 6.4 Hz, 1H), 4.45 (dt, J=7.4, 3.8, Hz, 1H), 4.77 (q, J=6.8 Hz, 1H), 5.87-6.21 (m, 1H), 6.82-6.92 (m, 1H), 6.98 (ddd, J=11.4, 8.7, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 518.80.
Reaction SMILES: COC1C=CC(N)=CC=1.C(N(CC)CC)C.[N+](C1C=C(S(Cl)(=O)=O)C=CC=1)([O-])=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38](C2C=CC(OC)=CC=2)[S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=2)(=[O:41])=[O:40])=[CH:34][CH:33]=1>ClCCl>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=2)(=[O:41])=[O:40])=[CH:34][CH:33]=1
Reactant: COc1ccc(N(c2ccc(OC)cc2)S(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: COc1ccc(N)cc1
Product: COc1ccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 8 h

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer. The flask was charged with p-anisidine (13.0 mmol) followed by dichloromethane (50 mL). Triethylamine (25.9 mmol) was added followed by 3-nitrobenzenesulfonyl chloride (16.2 mmol). Additional dichloromethane (75 mL) was added for solubility. The reaction was allowed to stir overnight. After 18 hours, TLC (dichloromethane/silica) indicated that the reaction was not complete. One additional equivalent of 3-nitrobenzenesulfonyl chloride (13.0 mmol), and two equivalents of triethylamine (25.9 mmol) were added to the reaction. After 10 minutes, TLC indicated that two products had formed and all starting anisidine was consumed. The reaction was washed with 2N HCl (100 mL), dried (Na2SO4), filtered, and the solvent removed under diminished pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g). The silica plug was eluted with dichloromethane (100 mL fractions) until the first product eluted from the filter column (TLC, dichloromethane/silica). The solvent system was changed to 9:1 dichloromethane/ethyl acetate and fractions were taken (100 mL) until the second product eluted from the filter column. The solvent from both samples was removed under reduced pressure to yield a mixture of the undesired N,N-bis-(4-methoxyphenyl)-3-nitrobenzenesulfonamide and the desired product.
Reaction SMILES: Cl.IC1C=CNC(=O)C=1[C:10]1[NH:11][C:12]2[C:20]([N:21]=1)=[C:19]([CH3:22])[C:18]1[C:17](=[O:23])[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:15](=[O:31])[C:14]=1[CH:13]=2.Cl.Cl[C:34]1[CH:39]=[CH:38][NH:37][C:36](=[O:40])[C:35]=1C1NC2C(N=1)=C(C)C1C(=O)N(C3CCN(C)CC3)C(=O)C=1C=2.[NH2:63][CH2:64][C@@H:65]([OH:76])[CH2:66][O:67][C:68]1[CH:73]=[CH:72][C:71]([CH3:74])=[CH:70][C:69]=1[CH3:75].CCN(CC)CC>CCO>[CH3:75][C:69]1[CH:70]=[C:71]([CH3:74])[CH:72]=[CH:73][C:68]=1[O:67][CH2:66][C@H:65]([OH:76])[CH2:64][NH:63][C:34]1[CH:39]=[CH:38][NH:37][C:36](=[O:40])[C:35]=1[N:11]1[C:12]2[C:20](=[C:19]([CH3:22])[C:18]3[C:17](=[O:23])[N:16]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[C:15](=[O:31])[C:14]=3[CH:13]=2)[N:21]=[CH:10]1
Reactant: Cc1c2c(cc3[nH]c(-c4c(I)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-n2cnc3c(C)c4c(cc32)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Yield: 57 %

Procedure:
To a suspension of 2-(4-Iodo-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione Hydrochloride and 2-(4-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione Hydrochloride (0.75 g, 1.45 mmol), (R)-3-amino-1-(2,4-dimethylphenoxy)-2-propanol (0.34 g, 1.73 mmol) in EtOH (20 mL) was added Et3N (0.61 mL, 4.35 mmol) and the resulting mixture was heated at reflux for overnight. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography (10% (6% NH3/MeOH)/CHCl3) to afford 2-{[4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (0.45 g, 57%) as a yellow solid.