Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:10][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16]C(OC(C3CC3)C)=O)[C@H:4]1[S:3]2>C(O)=O>[CH3:1][C:2]12[CH2:10][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH2:16])[C@H:4]1[S:3]2
Reactant: CC(OC(=O)NC(C(=O)NC1C(=O)N2[C@@H]1SC1(C)CC21C(=O)O)c1ccccc1)C1CC1
Solvent: O=CO
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]1S2
Yield: 62.6 %

Procedure:
A solution of 2-methyl-2,3-methylene-6-[N-(1-cyclopropylethoxy) carbonyl-2-phenylglycyl]aminopenam-3-carboxylic acid (1.88 g.) in formic acid (10 ml.) was stirred for 1 hour at room temperature and the solvent was distilled off under reduced pressure at room temperature. The residue was pulverized by adding ether and fitered. The powder was added to a mixture of acetonitrile (10 ml.) and water (1 ml.) and precipitated crystals were collected by filtration, washed with acetonitrile and dried to give 2-methyl-2,3-methylene-6-(2-phenylglycyl)aminopenam-3-carboxylic acid (0.89 g.), mp 200° to 202°C (dec.).
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2([C:20]([O:22][CH3:23])=[O:21])[CH2:19][CH2:18][N:17]([CH2:4][CH:3]=[CH2:2])[CH2:16][CH2:15]2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C1(Nc2cccc(OC)c2)CCNCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=CCN1CCC(Nc2cccc(OC)c2)(C(=O)OC)CC1

Procedure:
A mixture of 2.66 parts of 3-bromo-1-propene, 6.1 parts of methyl 4-[N-(3-methoxyphenyl)amino]-4-piperidinecarboxylate, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 100 parts of 4-methyl-2-pentanone is stirred and refluxed for 10 hours. The reaction mixture is cooled overnight to room temperature and poured onto water. The layers are separated and the organic phase is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 6% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding methyl 4-[(3-methoxyphenyl)amino]-1-(2-propenyl)-4-piperidinecarboxylate as an oily residue.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CC1(C)CC(CBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (223 mg) and potassium carbonate (264 mg) in dry DMF (2 mL) were heated at 60° C. under nitrogen with stirring for 1 h. 4-(Bromomethyl)-2,2-dimethyltetrahydro-2H-pyran (158 mg) was added and the reaction was stirred for 16 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give a brown oil. The crude material was purified by normal phase chromatography (ISCO) using 5-20% methanol/EtOAc as eluent to give a pale oil (181 mg). The material was re-purified by normal phase chromatography (ISCO) using 0-15% methanol/EtOAc as eluent to give the title compound (161 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:18]([OH:21])[C:19]#[CH:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1>[O-2].[Mn+6].[O-2].[O-2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18](=[O:21])[C:19]#[CH:20])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: C#CC(O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Agent: [Mn+6]
Agent: [O-2]
Product: C#CC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12

Procedure:
1-[6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-propyn-1-ol (2 g, 5.8 mmoles) was treated with manganese(VI)oxide in a similar manner as described in Example 2 to give, after filtration and silica gel chromatogaphy (2% methanol in dichloromethane), 1-[6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-propyn-1-one (1.2 g, 60%) as a solid. 1H NMR (CDCl3): δ 9.94 (s, 1H), 7.75 (m, 4H), 7.22 (t, 2H), 2.94 (s, 1H); 19F NMR (CDCl3) δ −111.3.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:11])[C:9]=1[NH2:10].[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15](Cl)=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[C:14]=1[C:15]([NH:10][C:9]1[C:8]([F:11])=[CH:7][N:6]=[CH:5][C:4]=1[F:3])=[O:16]
Reactant: Nc1c(F)cncc1F
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C(=O)Nc2c(F)cncc2F)c(Cl)c1
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
NaH (461 mg, 11.54 mmol) was added portionwise to a solution of 3,5-difluoropyridin-4-ylamine (1.0 g, 7.69 mmol) in DMF (20 mL) at 0° C. under a nitrogen atmosphere. A solution of 2,6-dichloro-4-cyano-benzoyl chloride (1.98 g, 8.46 mmol) in DMF (15 mL) was then added whilst maintaining the internal temperature below 10° C. Stirring was continued for 1.5 hours. The reaction mixture was quenched by addition of a saturated solution of NH4Cl and partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were washed with water, then with brine, dried (MgSO4) and concentrated under reduced pressure. The resultant residue was combined with the crude reaction mixture obtained following the same method starting from 3,5-difluoro-pyridin-4-ylamine (100 mg, 0.77 mmol) and purified by column chromatography on silica gel eluting with 0-50% EtOAc in cyclohexane to afford the title compound as an off-white solid (1.35 g, 49% yield). LCMS (Method D): RT=3.02 min, m/z: 328 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:6](=[O:8])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[Cl:1])[CH3:9])[N+:19]([O-:21])=[O:20]
Reactant: CC(Oc1ccccc1Cl)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(Oc1ccccc1Cl)C(=O)NCCO[N+](=O)[O-]
Yield: 42.1 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-(2-chlorophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.43 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[F:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]O)[CH2:22][CH2:21]2)=[O:19])=[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>CN(C)C=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:5]3[C:4](=[O:8])[N:3]4[CH2:9][CH2:10][CH2:11][CH2:12][C:2]4=[N:1][C:6]3=[O:7])[CH2:22][CH2:21]2)=[O:19])=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)nc3n(c2=O)CCCC3)CC1

Procedure:
In the manner described in Example 1-2), 6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in Example 1-1) and 4-(4-fluorobenzoyl)-1-(3-hydroxypropyl)piperidine were condensed in N,N-dimethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as an oily substance.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH3:9])[C:3]([O:5]CC)=O.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].[OH-].[K+].Cl>CO>[OH:15][C:14]1[N:16]=[C:3]([OH:5])[C:2]([CH3:1])=[C:8]([CH3:9])[C:13]=1[C:11]#[N:12]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(O)nc(O)c(C#N)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a slurry of ethyl 2-methyl-3-oxobutanoate (10 g, 69.4 mmol, 1 equiv) and 2-cyanoacetamide (5.8 g, 69.4 mmol, 1 equiv) was slowly added a solution of KOH (4.9 g, 87 mmol, 1.25 equiv) in MeOH (35 mL). Stir for 1 h during which time solution became homogenous yellow before developing a cream colored precipitate. Heat at reflux for 3 h. Upon cooling to ambient temperature, concentrated HCl (9 mL) was added. The off white solid was filtered and washed with ether to provide the product (10.7 g, 94%) as a cream colored solid. 1H NMR (500 MHz, DMSO-d6) δ 2.22 (s, 3H), 1.90 (s, 3H); LCMS (ESI, M+1): 165.05.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:31])[C:10]([C@@H:12]1[CH2:17][C@@H:16]([NH:18][S:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:21])=[O:20])[C@H:15]([OH:30])[CH2:14][CH2:13]1)=[O:11].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(#N)C>[CH3:32][S:33]([O:30][C@@H:15]1[CH2:14][CH2:13][C@H:12]([C:10](=[O:11])[N:9]([CH3:8])[CH3:31])[CH2:17][C@H:16]1[NH:18][S:19](=[O:20])(=[O:21])[NH:22][C:23]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:29])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Acetonitrile (460 ml) and triethylamine (87.0 ml) were added to a solution of tert-butyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (138.5 g) in acetonitrile (300 ml), and the obtained solution was then cooled to approximately 0° C. Methanesulfonyl chloride (38.5 ml) was added dropwise to the reaction solution, and the obtained mixture was then stirred for approximately 30 minutes. Thereafter, water (610 ml) was added to the reaction mixture, and the obtained mixture was stirred for approximately 30 minutes. Subsequently, water (930 ml) was added to the reaction mixture, and the obtained mixture was further stirred for approximately 3 hours. Thereafter, the precipitated solid was collected by filtration and was then washed with 27.5% aqueous acetonitrile (300 ml). The obtained solid was dried under reduced pressure to obtain the title compound (138.5 g, yield: 82%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>CN(C=O)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:12]=2[N:20]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (0.042 mL, 0.440 mmol) in DMF (1.60 mL) was added NaH (21.0 mg, 55% dispersion in mineral oil, 0.480 mmol) at 0° C. After stirring for 30 min at room temperature, 4,6-dichloropyrido[3,2-d]pyrimidine (80.0 mg, 0.400 mmol) was added to the mixture at 0° C. After stirring for 2 hours at room temperature, the reaction mixture was quenched with saturated aq. NH4Cl, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (60.0 mg, 57%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.18-2.23 (2H, m), 3.62-3.68 (2H, m), 4.08-4.13 (2H, m), 5.59-5.63 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (2H, d, J=8.8 Hz), 8.81 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[NH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.[OH-].[Na+]>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:28])[CH3:29])=[CH:21][CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Reactant: C[C@H](N)c1ccc(C(C)(C)C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)Cn1cnc2ccc(F)c(Cl)c21)c1ccc(C(C)(C)C#N)cc1
Reaction time: 2 h

Procedure:
A mixture of (7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acid (1.00 g, 4.39 mmol) prepared according to scheme 12, (S)(−)-2-{4-[1-aminoethyl]phenyl}-2-methylpropanenitrile (825 mg 4.39 mmol) prepared according to scheme 20 or 21 and Et3N (1.33 g, 13.2 mmol, 1.84 mL) is stirred in MeCN (50.0 mL). HATU (1.67 g, 4.39 mmol) is added, and, after 2 hours of stirring, the mixture is diluted with 1N NaOH (100 mL) and then extracted 4 times with EtOAc (4×75.0 mL). The organic phases are combined and dried over Na2SO4. The mixture is filtered and concentrated. The product is purified by a Gilson prep pump, flow rate: 30 ml/min, column: Gemini™ (5u) 21.2×50 mm, mobile phase: A=10 mM ammonium bicarbonate, B=MeCN (1.01 g, 58%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.39 (d, J=7.03 Hz, 3H) 1.66 (s, 6H) 4.92 (quint, J=7.23 Hz, 1H) 5.19 (s, 2H) 7.23 (dd, J=10.16, 8.98 Hz, 1H) 7.37 (d, J=8.20 Hz, 2 H) 7.47 (d, J=8.59 Hz, 2H) 7.63 (dd, J=8.79, 4.49 Hz, 1H) 8.21 (s, 1H) 8.81 (d, J=7.81 Hz, 1 H) MS [M+H], calcd: 399.1. found: 399.2, [α]D=−165 (c=1.02 METHANOL) HRMS (ESI+) calcd for C21H21ClFN4O 399.13824 [M+H]+ found 399.13832.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)N>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=23)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCCO)c1C#N
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: OCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 52.1 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(3-hydroxypropoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (150 mg, 0.63 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (148 mg, 0.63 mmol) to give the title compound as a white solid (140 mg, 52%); NMR Spectrum: 1.94-1.98 (m, 2H), 3.59-3.62 (m, 2H), 4.39 (t, 2H), 4.62 (br s, 1H), 5.29 (s, 2H), 7.23 (d, 1H), 7.35-7.38 (m, 1H), 7.54-7.59 (m, 2H), 7.86-7.91 (m, 2H), 8.28 (s, 1H), 8.43 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 427 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.C.[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=[CH:23][N:22]=1.C1COCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][O:30][C:2]2[C:3]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Reactant: CN(C)CCOc1ncccc1OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Temperature: 100 °C
Reaction time: 0.42 h

Procedure:
(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (20 L in toulene solution; see Example 8 for preparation) and active charcoal (201 g) was added to the 328 L-reactor containing 2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethanol (Example 1C) in toluene solution. The mixture was stirred for 25 minutes before transferred to a through a GAF-filter (containing a Telfon filter bag) to a 250 L-stainless steel reactor. The mixture was heated to 100° C. before the prepared “THF/potassium tert-butoxide-solution” was added to the reactor using a 50L addition bowl. After 10 L “THF/potassium tert-butoxide-solution” was added, an IP-HPLC was taken to ensure that the title compound had started to form. The total addition of THF/potassium tert-butoxide-solution was made during 2 h and 13 minutes. Water (21 L) and sodium chloride (1 kg) was added to a 198 L-glasslined reactor. The salt was dissolved before the reaction mixture was transferred from the 328 L-reactor and quenched into the 198 L-reactor. Toluene (10 L) was also transferred to make sure that no reaction-mixture was left in the hoses used for the transfer. The mixture was then heated to 70° C. before the mechanical stirrer was turned off. The phases were allowed to separate for 30 minutes before the water phase (25 L) was discharged. The mixture was heated to reflux and toluene (10 L) was distilled off. Water (100 L) was added and the mixture was heated to reflux again and 60 L of water was distilled off. The remaining solution was then cooled to RT. The title compound was never isolated; it was directly used in the next step (Example 3C). IP sample (HPLC) of the toluene mixture confirmed the retention time for the desired product (tref=2.2 minutes).
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].[Br:11]Br.C(N(CC)CC)C.C(OCC)C>ClCCl>[Br:11][C:4]([C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])=[C:2]([CH3:3])[CH3:1]
Reactant: BrBr
Reactant: CCCCC(=O)C=C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCC(=O)C(Br)=C(C)C

Procedure:
To a magnetically stirred and ice-cooled solution of 2-methyl-oct-2-en-4-one (9.30 gram, 63 mmol) in dichloromethane (90 ml) was slowly added bromine (3.23 ml, 33 mmol; dissolved in 10 ml dichloromethane) and the resulting mixture was stirred for 10 minutes. To the obtained mixture was slowly added triethylamine (13.10 ml, 94.5 mmol: dissolved in 25 ml dichloromethane). The resulting mixture was allowed to attain room temperature and stirred for 1 hour and subsequently stirred for 16 hours at 40° C. The obtained mixture was washed with 1N HCl (100 ml), dried over MgSO4, filtered and concentrated in vacuo to give crude 3-bromo-2-methyl-oct-2-en-4-one. Sepacore (40×300 mm column) separation (Gradient: first eluant: petroleum ether (40-60); second eluant: petroleum ether (40-60)/diethyl ether=98/2 (v/v)); third eluant: petroleum ether (40-60)/diethyl ether=95/5 (v/v)) gave 3-bromo-2-methyl-oct-2-en-4-one (Intermediate IIIc-1) pale-yellow oil (11.80 gram, 77% yield). 1H-NMR (400 MHz, CDCl3) δ 0.92 (t, J=7.2 Hz, 3H), 1.29-1.39 (m, 2H), 1.56-1.66 (m, 2H), 2.00 (br s, 6H), 2.78 (t, J=7.4 Hz, 2H).
Reaction SMILES: CS(O[CH2:6][CH:7]([CH2:26][CH:27]([O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=O)=O.[N-:38]=[N+:39]=[N-:40].[Li+].N(CC(NC(OC(C)(C)C)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>CN(C)C=O>[N:38]([CH2:6][CH:7]([CH2:26][CH:27]([O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)CC(C)OC(=O)c1ccccc1
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])CC(C)OC(=O)c1ccccc1
Yield: 96.6 %

Procedure:
A mixture of the previously obtained 2-(2-benzoyloxypropan-1-yl)-3-n-hexadecylthiopropyl methanesulfonate m12a and 1.297 g (26.5 mM) of lithium azide in 50 ml of dimethylformamide is allowed to react by the same procedure as described in (53) and 1.291 g (96.6% yield) of the titled compound m12b is obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:42]1[C:37]([N:34]2[C:30]3[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]4[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=4)=[O:17])[C:29]=3[CH:36]=[N:35]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1.40 mL, 1.40 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (315 mg, 1.40 mmol) in THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (372 mg, 1.40 mmol) in anhydrous THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with EtOAc to afford (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyrazin-2-yl)propanamide (330 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 1.24 (3H, t), 2.54 (3H, s), 3.60-3.68 (2H, m), 4.07-4.16 (2H, m), 6.09 (1H, t), 7.47 (1H, dd), 8.01 (1H, dd), 8.12 (1H, d), 8.47 (1H, s), 8.62 (1H, dd), 8.64 (1H, s), 8.66 (1H, s), 9.44 (1H, d); m/z (ESI+) (M+H)+=455; HPLC tR=1.77 min.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[Cl-:11].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:11][C:1]1[CH:6]=[CH:5][C:4]([C:7]([C:3]2[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 122.6 %

Procedure:
A stirred solution of m-toluoyl chloride (10.0 g, 64.7 mmol) in chlorobenzene (13.2 ml) at 80° C. was treated with aluminum chloride (8.63 g, 64.7 mmol) in portions over 30 minutes. The mixture was stirred 15 hours at 80° C., cooled to ambient temperature, stirred 16 hours, and quenched by addition of ice and concentrated hydrochloric acid (5.0 ml). The mixture was extracted three times with dichloromethane, and the combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was dissolved in boiling n-hexane, treated with activated charcoal, filtered, and cooled. The product was filtered and dried to provide 9.15 g of 3-(4-chlorobenzoyl) toluene. The filtrate was concentrated under vacuum and filtered to provide an additional 0.28 g of product. Total yield was 9.42 g (63%), m.p. 103°-105° C.