Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl.Cl[CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:12][CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: NCCCl
Reactant: COc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(SCCN)cc1
Yield: 97 %

Procedure:
4-Methoxythiophenol (50 g, 0.357 mol), 2-chloroethylamine monohydrochloride (39.8 g, 0.343 mol.), K2CO3 (78.8 g, 0.57 mol) and diisopropyl ethylamine (32 mL, 0.178 mol) were mixed in 200 mL of THF. The mixture was degassed for 5 min. under reduced pressure and refluxed under argon overnight. The solvent was removed and water (300 mL) was added to the flask. The mixture was extracted with dichloromethane (3×200 mL). The organics were collected, dichloromethane was removed and 50 mL conc. HCl was added, followed by 200 mL of water. The solution was extracted with 1:1 EtOAc/hexane (3×200 mL). The aqueous layer was adjusted to pH 10 with 2 M NaOH, and was extracted with dichloromethane (3×200 mL). The combined organic solution was dried over anhydrous sodium sulfate. Removal of solvent provided 61 g of the target compound as a colorless liquid, with a yield of 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20](Cl)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[N:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20]([NH:23][C:24]3[CH:29]=[N:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[O:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)nc1)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A solution of 0.9 g of 1-(4-chlorophenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride in 10 mL of THF was added to a solution of 0.4 g of 5-amino-2-chloropyridine, 2.0 mL Of triethylamine and 10 mL of THF. The resulting suspension was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was triturated with 10 mL of methanol to afford 0.66 g of the title compound, mp 191°-193° C.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].O>C(OCC)(=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: CN(C)CCN
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 42 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and a solution of 2 parts by volume of N,N-dimethyl-ethylenediamine in 3 parts by volume of water with a yield of 42% of theory. Orange yellow crystals; m.p. 123°-125° C. (ethyl acetate).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)=[N+:18]=[N-:19].[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:27]([NH:26][C:24]([C:23]1[CH:29]=[CH:30][C:20]([N:17]2[C:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:10]([C:11]([OH:13])=[O:12])[N:19]=[N:18]2)=[CH:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Ethyl 5-phenyl-3-oxovalerate (1.27 g, 5.52 mmol, 1.25 eq.) obtained in Example 98a) and 4-azido-N-ethylbenzamide (0.842 g, 4.43 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (417 mg, 5.52 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 80° C. for 3 hr. 2% Aqueous sodium carbonate solution (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with water (20 ml) and washed with ethyl acetate-hexane (2:1, 40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (35 ml×2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and diethyl ether-ethyl acetate (2:1, about 8 ml) was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-brown powder (1.56 g, 4.27 mmol, 96.4%).
Reaction SMILES: Cl(O)(=O)(=O)=O.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16](=O)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH2:8]1.[H][H]>C(O)(=O)C.[Pd]>[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH2:8]1
Reactant: [H][H]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)CCCc1ccc2c(c1)CC(N)C2

Procedure:
3 ml of perchloric acid and 3 g of 10% palladium-on-charcoal are added to 15 g (52.8 mmol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate in 200 ml of glacial acetic acid and the mixture is hydrogenated at 50° C. and a hydrogen pressure of 5 bar. When the calculated amount of hydrogen has been absorbed, the catalyst is filtered off, the filtrate is evaporated, sodium hydroxide is added to the residue and the reaction product is extracted with ether. After drying and evaporation, the desired product is obtained in the form of an oil.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]1[S:7][CH:8]=[C:9]2[C:15]=1[C:14](=[O:16])[NH:13][C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[NH:10]2>C(Cl)Cl>[Cl:4][C:8]1[S:7][CH:6]=[C:15]2[C:14](=[O:16])[NH:13][C:12]3[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=3[NH:10][C:9]=12
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ccccc2Nc2c1csc2Cl

Procedure:
13.5 g of sulfuryl chloride in 100 ml of methylene chloride are added dropwise to a solution of 21.6 g of 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one in 300 ml of methylene chloride at -40° C. The mixture is left to stand at room temperature for a further hour and is then extracted by shaking it with sodium bicarbonate solution and washing it with water; the organic phase is dried and concentrated. The residue is made to crystallize with a little methanol. 3-Chloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one is thus obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[O:7][C@@H:6]1[S:25][C:26](=N)N)(=[O:3])[CH3:2].C(Br)[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(Cl)Cl>CCOC(C)=O>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[O:7][C@@H:6]1[S:25][CH2:26][CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2]
Reactant: BrCC=Cc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SC(=N)N)O[C@H](COS(C)(=O)=O)[C@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](COS(C)(=O)=O)[C@H]1OC(C)=O

Procedure:
The title compound is prepared from 2-S-(2,3,4-tri-O-acetyl-6-O-methylsulfonyl-α-D-mannopyranosyl)-2-thiopseudourea and cinnamyl bromide in the usual manner. The desired product is isolated by column chromatography (silica gel; CHCl3 --EtOAc, 92:8, v/v) in 65-70% yield: m.p. 111°-113° C. (ether-petroleum ether); [α]D27 +175±1.1° (C 1.0, chloroform).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=[O:11].O>CN(C)C=O>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[NH:12][C:10](=[O:11])[CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)Cn1ccnc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of 6.0 g of a 60% oil dispersion of sodium hydride in 90 ml of dimethylformamide was stirred and heated at 50° C. during the portionwise addition of 10.32 g of imidazole. After stirring for 20 minutes, 15.0 g of 2-chloro-N-(2,6-dimethylphenyl)acetamide was added and heating was continued for an additional 30 minutes. Water was added and the reaction mixture was evaporated to dryness. The residue was dissolved in 2N hydrochloric acid, washed with ether, made strongly basic with excess sodium hydroxide and the product was extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and evaporated to give 14 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-acetamide, mp 160°-162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][C:18]#[N:19]>>[CH3:15][C:12]1[N:13]([CH2:17][C:18]#[N:19])[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=1
Reactant: N#CCBr
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CC#N)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=237.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromoacetonitrile.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[N:7]=1)(=[O:5])[CH3:4].[BrH:17].C(O)(=O)C>C(O)(=O)C.CO>[BrH:1].[C:14]([NH:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:17])[N:7]=1)(=[O:16])[CH3:15]
Reactant: BrBr
Reactant: CC(=O)NCc1cccc(C(C)=O)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NCc1cccc(C(=O)CBr)n1

Procedure:
A solution of bromine (1.56 g) in acetic acid (5 ml) was added dropwise to a solution of 2-acetyl-6-(acetylaminomethyl)pyridine (1.87 g) and 30 weight % hydrogen bromide-acetic acid solution (4.2 ml) in a mixture of acetic acid (40 ml) and methanol (10 ml) at ambient temperature with stirring. The mixture was warmed to 60° to 70° C. and stirred for two hours. The solvent was evaporated in vacuo and the residue was triturated with diisopropyl ether to give 2-(acetylaminomethyl)-6-bromoacetylpyridine hydrobromide (3.78 g). IR (Nujol) : 1720, 1620 cm-1 NMR (CD3OD, δ): 2.10 (3H, s), 3.90 (2H, s), 4.83 (2H, s), 7.77 (1H, br s), 8.13 (2H, t, J=8 Hz) and 8.70 (1H, t, J=8 Hz)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](=O)[CH2:4][C:5]([C:7]1[C:16](=[O:17])[NH:15][C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[C:8]=1[OH:18])=[O:6].Cl.[NH2:23][OH:24]>C(O)C>[F:1][C:2]([F:21])([F:20])[C:3](=[N:23][OH:24])[CH2:4][C:5]([C:7]1[C:16](=[O:17])[NH:15][C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[C:8]=1[OH:18])=[O:6]
Reactant: O=C(CC(=O)C(F)(F)F)c1c(O)c2nccnc2[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=C(CC(=NO)C(F)(F)F)c1c(O)c2nccnc2[nH]c1=O
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a suspension of 4,4,4-trifluoro-1-(8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-7-yl)-butane-1,3-dione (Example 6.3) (0.170 g) in ethanol (2 ml) was added hydroxylamine hydrochloride (0.050 g). The reaction mixture was heated to reflux for 4 hours and was then stored at ambient temperature for 16 hours. The solid was isolated by filtration and washed with ethanol, ethyl acetate, and diethyl ether and dried to give 4,4,4-trifluoro-1-(8-hydroxy-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-7-yl)-butane-1,3-dione 3-oxime as a brown solid (0.078 g). 1H-NMR (400 MHz, d6-DMSO): 3.61 (d, 1H), 3.86 (d, 1H), 8.57 (d, 1H), 8.67 (d, 1H), 12.35 (s, 1H) ppm.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:12]([NH:28][C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCCCCCCCCCCCCCCCN
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cn1

Procedure:
A mixture of 5.13 g. of methyl 6-chloronicotinate, 7.23 g. of hexadecylamine and 150 ml. of hexamethylphosphoramide is stirred at 130° for 6 hours. Cooling and dilution with water affords a precipitate which is collected by filtration and recrystallized from ethyl acetate and then from acetone to yield methyl 6-hexadecylamino-3-pyridinecarboxylate as a tan solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].P(Br)(Br)[Br:18].O>CCOCC>[Br:18][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1ccccc1CCCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)Cc1ccccc1CCCBr

Procedure:
To a solution of ethyl [2-(3-hydroxypropyl)-phenyl]acetate (44.4 g., 0.20 mole) in ether (300 ml.) is added dropwise during 40 minutes a solution of phosphorus tribromide (20.7 g., 0.075 mole) in ether (100 ml.). The temperature is maintained at 25°-28° C. during this time by means of a cold water bath. The reaction solution is then heated a reflux for 4 hours. It is cooled and poured into iced-water. The ether layer is separated, washed with water, dried over magnesium sulfate, and evaporated in vacuo to yield ethyl [2-(3-Bromopropyl)phenyl]acetate.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CSc1cccc(C(O)Cc2ccncc2)c1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CSc1cccc(C(=O)C(=O)c2ccncc2)c1
Reaction time: 12 h
Yield: 5.5 %

Procedure:
To a solution of 1-(3-methylthiophenyl)-2-(4-pyridyl)ethanol (2.5 g, 10.2 mmol) in CH2Cl2 (150 mL) was added a mixture of celite (4.4 g) and pyridinium dichromate (4.4 g, 20.4 mmol). After stirring for 12 h, the mixture was filtered through celite. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 40-50% EtOAc/Hex to provide the title compound (144 mg, 5.5%): 1H NMR(CDCl3): δ8.88 (br d, 2H); 7.85 (s, 1H); 7.78 (d, 2H); 7.67(d, 1H); 7.56 (d, 1H); 7.44 (t, 1H); 2.55 (s, 3H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30]OS(C5C=CC(C)=CC=5)(=O)=O)[CH2:26][CH2:25]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:7]=[N:6]1.[ClH:42]>CS(C)=O.C(#N)C>[ClH:42].[CH3:4][N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N:24]4[CH2:25][CH2:26][CH:27]([CH2:30][C:1]#[N:2])[CH2:28][CH2:29]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:7]=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(c3nccnc3N3CCN(Cc4cnn(C)c4C)CC3)CC2)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1c(CN2CCN(c3nccnc3N3CCC(CC#N)CC3)CC2)cnn1C
Temperature: 50 °C
Reaction time: 5.75 h
Yield: 101.4 %

Procedure:
Add sodium cyanide (78.46 mg, 1.60 mmol, 2.4 eq) to a solution of toluene-4-sulfonic acid 1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-ylmethyl ester (0.36 g, 0.667 mmol, 1 eq) in dimethyl sulfoxide (5 mL). Heat the solution to 50° C. with stirring for 5.75 hr. and then cool to room temperature. Add water (20 mL) and extract the aqueous layer three times with DCM (20 mL). Combine the organic extracts, dry over magnesium sulphate, filter and concentrate. Purify by flash chromatography on a 40 g silica gel column, eluting with a gradient of 2-10% methanol in DCM. Further purify by high pH reverse phase HPLC (UV guided). Dissolve this material (148 mg, 0.38 mmol) in the minimum quantity of 50% aqueous acetonitrile. Add 2M aqueous hydrogen chloride (190 μL, 0.38 mmol) and lyophilize to give {1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-yl}-acetonitrile hydrochloride (166 mg, 58%). MS (m/z): 395.2 (M+1).
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: BrCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: [K]
Product: N#Cc1ccc(OCCCCBr)cc1

Procedure:
The intermediate 4-(4-cyanophenoxy)butyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,4-dibromobutane.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[N:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:19][C:16]1[CH:15]=[N:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[N:18][CH:17]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Clc1cnc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ncc(Cl)cn2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Palladium dichloro-bis(triphenylphosphine) (3.5 g) was added to a stirred solution of 4-formylbenzene boronic acid (32.5 g), 2,5-dichloro-pyrimidine (30 g) in toluene (1000 ml) and ethanol (100 ml) under an argon atmosphere. The solution was purged with argon and aqueous sodium carbonate (2N) (200 ml) was added. The reaction mixture was stirred at 60° C. for 90 minutes, cooled to ambient temperature, diluted with ethyl acetate, and washed successively with aqueous sodium hydrogen carbonate (saturated), water and brine. The combined organic extracts were treated with charcoal, dried over sodium sulfate, filtered through Hyflo® and concentrated in vacuo. The residue was triturated with diethyl ether (100 ml), the solid isolated by filtration and dried under high vacuum to give 4-(5-chloro-pyrimidin-2-yl)-benzaldehyde as a white solid. M.p. 186° C. 1H NMR (400 MHz, DMSO) 8.10 (d, 2H), 8.55 (d, 2H), 9.1 (s, 2H).
Reaction SMILES: [Li+].[Cl-].Br[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:23][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:21][CH:20]=1)CCC.CN(C=O)C>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>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([C:19]3[S:23][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[N:21][CH:20]=3)[CH:13]=2)[CH:8]=[N:9][CH:10]=1
Reactant: Brc1ccc2cncnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3cncnc3c2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a stirred mixture of flame-dried LiCl (45 mg, 1052 μmol), 7-bromoquinazoline (22 mg, 105 μmol), and Pd(Ph3P)4 (6.1 mg, 5.3 μmol), was added a solution of tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (77 mg, 158 μmol) in DMF (1.50 mL, 19372 μmol). The resulting mixture was stirred at 80° C. overnight. The mixture was concentrated, and the crude residue was dissolved in DCM and mixed with SiO2. The solvent was evaporated, and the residue was purified with flash column chromatography (pure DCM→5% MeOH in DCM) followed by washing with ether to obtain the desired product tert-butyl 5-(quinazolin-7-yl)thiazol-2-ylcarbamate (16 mg, 46%) as a pale yellow solid. LCMS (API-ES) m/z (%): 329.4 (100%, M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C(O)=O)[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:46])[C@@H:23]([NH:25][C:26]([C@@H:28]([N:30]([CH3:45])[C:31]([C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38](OC(C)(C)C)=[O:39])=[O:32])[CH3:29])=[O:27])[CH3:24])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(Cl)CCl>ClCCl>[CH3:24][C@@H:23]1[NH:25][C:26](=[O:27])[C@H:28]([CH3:29])[N:30]([CH3:45])[C:31](=[O:32])[C@H:33]2[N:34]([CH2:35][CH2:36][CH2:37]2)[C:38](=[O:39])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][O:14][C:15](=[O:16])[C@H:17]2[N:18]([CH2:19][CH2:20][CH2:21]2)[C:22]1=[O:46]
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)OCc2ccccc2)COC(=O)[C@@H]2CCCN2C1=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
109.0 g (158 mmol) of the carboxylic acid from example 9A and 116.4 g (632 mmol) of pentafluorophenol are dissolved in 1000 ml of anhydrous dichloromethane, cooled to −20° C. and 39.4 g (205 mmol) of EDC are introduced. The reaction mixture is stirred overnight with slow warming to RT. The solvent is removed in vacuo and the residue is treated with hydrogen chloride in dioxane (600 ml) with ice cooling. The mixture is stirred at RT for 3 h, the solvent is removed in vacuo and the residue is taken up three times using toluene and again concentrated to dryness. The residue is divided into thirds and each part is treated as follows: The intermediate product is taken up in dichloromethane (900 ml) and introduced with a flow rate of 0.8 ml/min at RT into a vigorously stirred 2-phase mixture of 1.5 l of aqueous sodium hydrogencarbonate solution and 5 l of dichloromethane and stirred for about 2 h. The organic phase is separated off, the aqueous phase is extracted three times with 500 ml each of dichloromethane, and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:38](=[O:41])[CH2:39][CH3:40])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CCC(=O)Cl
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N(C)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by propanoyl chloride (32 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 108 mg, 63%. 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz) 7.57-7.76 (2 H, m), 7.30 (2 H, dd, J=8.46, 5.68 Hz, 7.15 (2 H, t, J=8.84 Hz), 6.52 (1 H, s), 5.05-5.43 (2 H, m), 4.46-4.62 (0.5 H, m), 4.38 (1 H, d, J=12.63 Hz), 3.85-4.00 (3.5 H, m), 3.05-3.23 (1 H, m), 2.77 (2 H, s), 2.65 (1 H, s), 2.55-2.63 (1 H, m), 2.39 (1 H, q, J=7.33 Hz), 2.29 (1 H, q, J=7.33 Hz), 1.41-1.80 (4 H, m), 0.98 (3 H, q, J=7.49 Hz); m/z (APCI+) for C26H30N5O2F 464.2 (M+H)+.