Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](Cl)=[O:44]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([C:43](=[O:44])[CH2:42][N:41]([CH3:46])[CH3:40])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide and 2-(dimethylamino)acetyl chloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.25 (m, 1 H) 1.33-1.46 (m, 3 H) 1.48-1.65 (m, 3 H) 1.72-1.90 (m, 6 H) 2.35 (s, 6 H) 2.72 (t, J=12.2 Hz, 1 H) 2.72 (t, 1 H) 3.10 (t, J=11.8 Hz, 1 H) 3.31 (s, 3 H) 3.47 (d, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.5 Hz, 2 H) 3.97-4.12 (m, 2 H) 4.35 (d, 1 H) 4.46 (br. s., 1 H) 7.47 (dd, J=8.4, 1.6 Hz, 1 H) 7.50 (d, J=1.7 Hz, 1 H) 7.91 (s, 1 H) 8.19 (d, J=8.1 Hz, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.3 Hz, 1 H). Melting point: 190-191° C. [M+H] calc'd for C31H42F2N8O4 629; found 629.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.CCOCC>O1CCOCC1.C(Cl)(Cl)Cl>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:2][CH:3]([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[C:4]([OH:6])=[O:5])=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
1.14 Grams of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in Reference Example 1, 1.3 g of dicyclohexylcarbodiimide (DCC) and 1.0 g of p-chlorobenzoic acid were suspended in 10 ml of dioxane, then the suspension was stirred at 60°-70° C. for 5 hours. After the reaction was completed, the solvent was removed by evaporation, to the residue thus obtained was added ether, and the crystals formed were removed by filtration. The filtrate obtained was concentrated, then the residue thus obtained was dissolved by adding chloroform, the chloroform solution was washed with water and a saturated sodium chloride aqueous solution. The chloroform solution was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from methanol-water to obtain 290 mg of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate in the form of colorless powdery substance. Melting
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1N)[O:7][CH3:8])([O-:3])=[O:2].[OH-:13].[K+].Cl>O>[N+:1]([C:4]1[CH:5]=[C:6]([O:7][CH3:8])[CH:9]=[CH:10][C:11]=1[OH:13])([O-:3])=[O:2]
Reactant: [OH-]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A mixture of 168 g. (0.93 m.) of 3-nitro-p-anisidine, 130 g. of KOH and 1500 ml. of H2O was refluxed with stirring overnight. The solution was acidified with conc. HCl, keeping the temperature below 20°C. The crude product was collected by filtration washed with H2O and air-dried to give 279 g. m.p. 74°-76°C. A recrystallization from 2000 ml. of ethanol yields 106 g. m.p.76°-78°C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:18][C@H:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20](OCC)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].O1CCCC1.O>CCCCCC>[Si:11]([O:18][C@H:19]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:20]=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CCOC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccccc1
Temperature: -40 °C
Reaction time: 4 h

Procedure:
20 ml of a 1M hexane solution of diisobutylaluminum hydride were added dropwise at -65° C. and in an atmosphere of nitrogen to a solution of 5.9 g of ethyl (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetate (prepared as described in Preparation 23) in 300 ml of dry hexane, and the resulting mixture was stirred at -40° C. for 4 hours. At the end of this time, 10 ml of a tetrahydrofuran solution containing 1 ml of water was added dropwise to the reaction mixture at -40° C., and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:60 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound having an Rf=0.64 (thin layer chromatography over silica gel, using a 1:50 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1)[CH3:2].[CH3:21][I:22]>[N+](C)([O-])=O.COC(C)(C)C>[I-:22].[CH2:1]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:19])([CH3:20])[N+:18]=1[CH3:21])[CH3:2]
Reactant: CI
Reactant: CCc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Solvent: C[N+](=O)[O-]
Solvent: COC(C)(C)C
Product: CCc1c(C2=[N+](C)C(C)(C)CO2)ccc(C(F)(F)F)c1C
Product: [I-]
Temperature: 70 °C

Procedure:
To a solution of 837 mg (2.9 mmol) 2-(2-ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 8 ml nitromethane were added 1.47 ml (23.5 mmol) methyl iodide and the mixture heated in a sealed tube to 70° C. for 18 h. The brown solution was diluted with tert-butyl methyl ether, the suspension filtered and the precipitate washed with tert-butyl methyl ether and dried. 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide was obtained as colourless solid: MS (ISP): 300.1 (M+.).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:2]3[CH2:3][CH2:4][C:5]4[NH:6][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=5[C:13]=4[CH2:1]3)[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: c1ccc2c3c([nH]c2c1)CCNC3
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: c1ccc(CN2CCC(N3CCc4[nH]c5ccccc5c4C3)CC2)cc1
Yield: 99.9 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole (0.2 mol) and 1-(phenyl-methyl)-4-piperidinone (0.2 mol) in methanol (700 ml) was hydrogenated at 50° C. with palladium-on-charcoal (10%; 3 g) as a catalyst in the presence of thiophene (4%; 2 ml). After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding 69 g 2,3,4,5-tetrahydro-2-[1-(phenylmethyl)-4-piperidinyl]-1H-pyrido [4,3-b]indole (intermediate 24).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.Br.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 89 %

Procedure:
80 g (0.31 mol) of ethyl 2,3-dibromopropionate diluted in 300 ml of benzene are added dropwise, but fairly rapidly, to a warm solution of 72 g (0.3 mol) of N,N'-dibenzylethylenediamine, 700 ml of benzene and 50 ml (0.36 mol) of triethylamine. After the addition, reflux is maintained for 3 hours (triethylamine hydrobromide precipitates in the reaction mixture). The mixture is cooled and filtered through fritted glass, and the solid is washed with ether. The flitrate is washed with 200 ml of saturated sodium hydrogen carbonate solution and then twice with 100 ml of water. The organic phases are dried over magnesium sulfate and the solvents are evaporated off in vacuo. Approximately 100 ml of toluene are added, and evaporation is continued. The resulting residue is diluted in 400 ml of absolute ethanol and saturated with gaseous hydrogen chloride. The salt precipitates by the addition of ether. Filtering, washing with ether and drying yield from 100 to 110 g of white crystals.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:39])[N:24]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:20]=[C:19]([Cl:40])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:40][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCCn2cncn2)C2CCCC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCCn1cncn1)C1CCCC1
Yield: 45.5 %

Procedure:
A solution of {2-[3-chloro-5-(cyclopentyl-(4-[1,2,4]triazol-1-yl-butyl)-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.069 g) and trifluoroacetic acid (0.5 ml) in dichloromethane (0.5 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (92:8:1 v/v/v), to give the title compound as a white foam (0.026 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7]/[N:8]=[CH:9]/[CH2:10][CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18](/[CH:22]=[C:23](/[C:26]2[CH:31]=[CH:30]C(Cl)=[CH:28][CH:27]=2)\[C:24]#[N:25])[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.Cl[CH2:41][Cl:42]>>[C:1]([O:5][C:6]([CH:7]1[CH:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)[C:23]([C:26]2[CH:27]=[CH:28][C:41]([Cl:42])=[CH:30][CH:31]=2)([C:24]#[N:25])[CH:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 20 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 31a (2 g, 10 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (2 g, 7.3 mmol) prepared in Example 1b, AgF (1.3 g, 10 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.7 g, 20%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH3:55])=[CH:50][CH:49]=2)[C:44]([Cl:56])=[CH:43][C:42]=1[CH:57]=[CH2:58])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:60].O[Li].O>C1COCC1.CO.O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:41]1[C:42](=[CH:43][C:44]([Cl:56])=[C:45]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([CH2:54][CH3:55])=[CH:52][CH:53]=3)[CH:46]=1)[CH:57]([OH:60])[CH2:58]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@]1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
To (2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-5-(4-ethylbenzyl)-2-vinylphenyl)tetrahydro-2H-pyran-2-ol (120 mg, 0.15 mmol) was added TFA (1.5 mL) at −10° C. After the reaction mixture was stirred for 6 h, the solvent was removed under vacuum and aqueous saturated NaHCO3 (10 mL) was added to the residue. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent afforded the crude product, which was dissolved in 1.9 mL of a mixture of THF:CH3OH:H2O (2:3:1) followed by addition of 6 mg of LiOH.H2O at room temperature. After stirring for 2 h, the volatiles were removed using a rotary evaporator. The residue, after being dissolved in ethyl acetate, was washed with brine (10 mL×2), 5% aqueous KHSO4 (10 mL) and finally with brine (10 mL) prior to drying over Na2SO4. The volatiles were removed and the resulting oil was purified by preparative TLC to obtain 44 mg of the title product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][Br:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Br-:12].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: [Br-]
Product: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
A solution of 3-benzyloxy-1-bromopropane (41.0 g., 0.18 mole) and triphenylphosphine (52.4 g., 0.2 mole) in benzene (500 ml.) is stirred and heated at reflux for 92 hours. After removing the solvent in vacuo, the residual gum is dissolved in acetonitrile (50 ml.) providing a pale yellow solution which is diluted with ethyl acetate (400 ml.) to incipient cloudiness and stirred at 25° for 48 hours. Deposited crystals are collected; the yield is 48 g. (53%). Recrystallization from ethyl acetate-acetonitrile (4:1) provides colorless needles, m.p. 151°-152°; pmr (CDCl3)δ2.0 (2H,m), 3.78 (4H,m), 4.49 (2H,s), 7.29 (5H,s) and 7.70 (15H,m).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O>COCCOC>[Si:1]([O:8][CH2:9][C@H:10]([NH:17][C:18](=[S:36])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cccc(I)c1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=S)c1cccc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of N-(1-tert-butyldimethylsilyloxy-2(R)-phenylethan-2-yl)-3-iodobenzamide (13.1 g, 27.2 mmol) in 1,2-dimethoxyethane (80 ml) was added Lawesson's reagent (8.2 g, 20 mmol). The reaction mixture was stirred at ambient temperature for 1 h and then at 60° C. for 2 hours, cooled and poured into water (100 ml). The mixture was extracted with CH2 Cl2 (2×50 ml), washed with brine (100 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (=1:7) to afford N-(1-tert-butyldimethylsilyloxy-2(R)-phenyl-ethan-2-yl)-3-iodobenzthiamide (4.99 g, 50%) as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.O[C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:17]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]2)=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Tetrahydrofuran (200 ml) was added to 2,6-dichloropurine (6 g, 31.8 mmol), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (5.94 g, 31.8 mmol), and triphenylphosphine (9.2 g, 34.9 mmol) and the resulting mixture was made uniform. Diisopropyl azodicarboxylate (6.9 ml, 35 mmol) was added with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=7:3 to 6:4 to 5:5 to 4:6) to give the title compound (10.5 g, 92%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:4]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1>ClCCCl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[CH2:6]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)NCC1CN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23 mg of (S)-6-[3-(aminomethyl) azetidin-1-yl]-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 7 μl of acetic anhydride and 11 μl of pyridine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 20 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH3:9][C:10]([S:15][C:16]#[N:17])([CH3:14])[C:11](=O)[CH3:12]>O.C(O)C>[N:2](=[C:16]1[N:17]=[C:11]([CH3:12])[C:10]([CH3:14])([CH3:9])[S:15]1)[OH:3]
Reactant: NO
Reactant: CC(=O)C(C)(C)SC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1=NC(=NO)SC1(C)C
Reaction time: 1 h

Procedure:
8.3 g (0.12 mol) of hydroxylamine hydrochloride are dissolved in 50 ml of water and treated with 10.1 g (0.12 mol) of sodium bicarbonate. This solution (pH 6-7) is added at room temperature while stirring to a solution of 14.3 g (0.1 mol) of 3-methyl-3-thiocyanato-2-butanone in 100 ml of ethanol. The temperature of the mixture rises rapidly to 37° C. The mixture is subsequently stirred for an additional 1 hour and 120 mlof the solvent are distilled off at 50° C. under reduced pressure. The residue is extracted three times with 100 ml of diethyl ether each time and the organic phase is washed with a small amount of water, dried over anhydrous sodium sulfate and concentrated until crystallization begins. After cooling, the crystal slurry is treated with 10 ml of n-hexane. The crystals are filtered off under suction, washed with diethylether/n-hexane (2:1) and dried to yield 2-oxo-4,5,5-trimethyl-3-thiazoline oxime, m.p. 151°-153° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=[O:3])[CH3:2].[CH:10]1[CH:11]=[CH:12][C:13]2[NH:18][CH:17]=[C:16]([CH2:19][CH2:20]O)[C:14]=2[CH:15]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:2][C:1]1([CH:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[C:17]2[NH:18][C:13]3[C:14]([C:16]=2[CH2:19][CH2:20][O:3]1)=[CH:15][CH:10]=[CH:11][CH:12]=3
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21

Procedure:
To a solution consisting of 3-acetyldihydro-2(3H)-furanone (25.6 g, 0.2 mole), tryptophol (32.2 g, 0.2 mole) and benzene (700 ml), p-toluenesulfonic acid (0.50 g) is added. The flask is equipped with a water separator and a condenser. The mixture is stirred at reflux for one hr. More p-toluenesulfonic acid (0.50 g) is added and the solution is refluxed for 18 hr. The dark solution is cooled and stirred in presence of silica gel (100 g) for 5 min. The mixture is filtered on diatomaceous earth and charcoal. The silica gel is washed with diethyl ether (2×100 ml) and the filtrates are evaporated to afford an oil which is a mixture of two diasteroisomers of the title compound. If desired, the latter oil can be crystallizated from methanol to obtain crystals (17 g) of isomer A of the title compound, mp 162°-164° C. The mother liquor of this crystallization is evaporated to obtain a residue (20 g) containing mainly isomer B of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@H:18]([OH:20])[CH3:19])[C:15]([OH:17])=O)=[CH:5][CH:4]=1)#[N:2].[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][NH:30][C:15](=[O:17])[C@H:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C@H:18]([OH:20])[CH3:19])=[O:28])=[CH:31][CH:32]=1)#[N:22]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoic acid (1.50 g, 5.55 mmol) and 4-cyanobenzohydrazide (894 mg, 5.55 mmol) in anhydrous THF (80 mL) was added 1-Hydroxybenzotriazole monohydrate (850 mg, 5.55 mmol) and N-(3-Dimethylaminopropyl)-Y-ethylcarbodimide-HCl (2.13 g, 11.1 mmol) at −45° C. followed by triethylamine (1.55 mL, 11.1 mmol). The reaction mixture warmed to room temperature and stirred for 24 h, then quenched with 5% aq. citric acid (300 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×150 mL), sat. aq. NaHCO3 (3×150 mL), H2O (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a light brown solid (2.12 g, 92%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.84 (s, 1H), 10.44 (s, 1H), 8.48 (d, J=8.8 Hz, 2H), 8.04-7.93 (m, 4H), 7.91 (d, J=8.2 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 5.25 (d, J=4.5 Hz, 1H), 4.32-3.97 (m, 3H), 1.32 (d, J=6.1 Hz, 3H).