Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[OH:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1O
Temperature: 0 °C

Procedure:
2-methyl-5-nitroaniline (40 g) was dissolved in refluxing 10% sulphuric acid (600 ml), cooled to 0° C. whereupon the salt separates out. With continuous stirring, sodium nitrite solid (18 g) was added in small portions. The diazitization was complete when a positive starch/KI test was observed. This diazonium solution was added at once to a vigorously refluxing solution of water (800 ml) and concentrated sulphuric acid (400 ml). Refluxing was continued until all gassing had ceased. A solid had precipitated out and, upon cooling to ambient temperature, was collected and dried to give crude 2-methyl-5-nitrophenol. This crude phenol (36.8 g) in dimethylformamide (200 ml) along with anhydrous K2CO3 (35 g) and 2-bromopropane (50 ml) was stirred and warmed to 60° C. for 12 hours. After cooling, the solvent was removed, the residue treated with water and the product extracted with ether. This ether solution was washed with 2N KOH, water, dried (MgSO4) and evaporated to give 1-(1-methylethoxy)-2-methyl-5-nitrobenzene, bp. 80°-85° C./0.15 mm., 34.5 g. This nitrobenzene (34.5 g) in methanol (250 ml) was reduced on a parr hydrogenator using Raney nickel. After removal of the catalyst and solvent, the product, 3-(1-methylethoxy)-4-methyl-benzenamine, bp. 80°-85° C./0.05 mm., 25 g. was obtained. This amine (10 g) in methylene chloride (50 ml) and crushed ice (50 g) was stirred whilst thiophosgene (6.5 ml) in methylene chloride (25 ml) was added dropwise. The reaction was stirred overnight at ambient temperature. After separating the organic layer, the methylene chloride solution was washed with water, dried and evaporated to leave a pale yellow oil, bp. 80°-85° C./0.04 mm of 5-isothiocyanato-1-(methylethoxy)-2-methylbenzene, 12,4 g. Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (11 g) was added portionwise to a stirred suspension of sodium hydride (2.5 g, 60%) in tetrahydrofuran (50 ml) at 15° C. When complete, the reaction was chilled to -70° C. (acetone/ dry ice), whereupon the above isothiocyanate (12.4 g.) in THF (25 ml) was added at once. The temperature rose to -50° C. before cooling to -70° C. After stirring to ambient temperature and leaving overnight a solid had precipitated out. The solvent was removed, water added, washed with ether and acidified. A pale yellow solid had precipitated out. This was collected on a filter, washed with water, dried and recrystallized from IPA to give 2,3 dihydro-3-[3-(1-methylethoxy)-4-methylphenyl]- 2-thioxo-6-(trifluoromethyl)-4(1H)-pyrimidinone, mp. 227°-228°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([OH:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[N+:16]([C:19]1[CH:24]=[C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)([O-:18])=[O:17]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[C:2]([O:1][C:20]2[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])=[CH:11][C:10]([CH3:12])=[CH:9][C:8]=1[O:13][C:20]1[CH:21]=[CH:22][C:23]([S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(=O)c1c(O)cc(C)cc1O
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1c(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc(C)cc1Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Using procedure as in Example 10, a reaction of methyl 2,6-dihydroxy-4-methylbenzoate (50 mg, 0.274 mmol), NaH (24 mg, 2.2 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (159 mg, 2 equiv.) afforded 4-methyl-2,6-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzoic acid methyl ester. 1HNMR (360 MHz, DMSO-d6) δ 8.80 (d, J=2.2 Hz, 2H), 8.32 (dd, J=2.2 & 9.0 Hz, 2H), 7.48 (d, J=2.7 Hz, 2H), 7.44 (s, 2H), 3.50 (s, 3H, OCH3), 1.23 (s, 3H, CH3). MS-APCI (negative mode) m/z 686.6 [M+−2].
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:24])[CH:10]2[NH:14][C:15](=[O:23])[CH2:16][C:17]2[S:18][C:19](=[O:22])[S:20][CH:21]=2)[C:7]=1[C:25]([OH:27])=[O:26])(=O)C.[CH2:28]([CH:30]1[S:34][C:33](=[S:35])[N:32]=[N:31]1)[CH3:29].Cl>O.C(=O)(O)[O-].[Na+]>[C:25]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][S:35][C:33]1[S:34][C:30]([CH2:28][CH3:29])=[N:31][N:32]=1)[CH:10]([NH:14][C:15](=[O:23])[CH2:16][C:17]1[S:18][C:19](=[O:22])[S:20][CH:21]=1)[C:9]2=[O:24])([OH:27])=[O:26]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: CCC1N=NC(=S)S1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)s1
Temperature: 60 °C
Yield: 23.8 %

Procedure:
3-Acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (7 g.) is dissolved in distilled water (100 cc.) and sodium bicarbonate (1.46 g.). A solution of 5-ethyl-2-thioxo-1,3,4-thiadiazoline (2.63 g.) in distilled water (60 cc.) and sodium bicarbonate (1.46 g.) is added and the resulting solution is heated to 60° C. for 6 hours. After cooling, it is acidified to pH 5.5 by adding 4 N hydrochloric acid and is then extracted twice with ethyl acetate (100 cc.). The organic extracts are discarded. The acidification is continued in the presence of ethyl acetate (300 cc.) until the pH is 2. After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 200 cc.). The combined organic extracts are washed twice with water (200 cc.), dried over magnesium sulphate, treated with decolourising charcoal and then filtered and concentrated to dryness under reduced pressure (20 mm.Hg). The residue obtained is recrystallised from methanol (100 cc.) to give 2-carboxy-3-[(5-ethyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (2 g.) m.p. 155° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1ccccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of methyl 4-hydroxybenzoate in DMF (5 ml) was treated with K2CO3 (2.76, 20 mmol) and 2-benzyloxy benzyl bromide (1.52 g, 10 mmol). The reaction was stirred at ambient temperature over night. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed well with water dried (MgSO4) and evaporated. The crude material was purified by chromatography [EtOAc:hexane] to give methyl 4-(2-(benzyloxy)benzyloxy)benzoate as a white solid (3.06 g, 88%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=1[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=1[C:26]([O:28][CH3:29])=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
38 g of potassium carbonate and 12.65 ml, (14 g) of benzyl chloride are added to 20.8 g of 4'-hydroxy-3'-methoxycarbonylpropiophenone in 100 ml of dimethylformamide. The mixture is heated at 60° C. for 4 hours, with stirring. It is then poured into iced water, the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried and evaporated to dryness. The residual oil crystallises on trituration with pentane. The crystals are filtered off and recrystallised from ethanol. 18 g of crystals melting at 76°-78° C. are collected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)[CH3:25]>>[CH:24]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=2)=[O:22])[N:30]=1)([CH3:25])[CH3:23]
Reactant: CC(C)c1nc(CN)cs1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: CC(C)c1nc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 2-(1-methylethyl)-4-thiazole-methanamine, as starting materials; LC-MS (UV peak area/ESI) 80%, 470.902 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][N:13]=1>ClCCl>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:14][N:13]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1cnc(Cl)nc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 72613.2 %

Procedure:
A solution of ethylamine (4.26 g, 0.0946 mol) and triethylamine (28.7 g, 0.284 mol) in dichloromethane (75 mL), pre-cooled to −15 to −10° C., was added dropwise to a solution of 2-chloropyrimidine-5-carbonyl chloride (16.64 g, 0.0946 mmol) in dry dichloromethane (250 mL) at −15° C., then the reaction mixture was stirred at −15° C. for 1 hour. The reaction was quenched by the addition of a solution of concentrated hydrochloric acid (32.3 mL) in water (300 mL). The resulting mixture was stirred at room temperature for 1 hour. The layers were separated, and the aqueous phase was further extracted with dichloromethane (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via column chromatography to provide 2-chloro-N-ethylpyrimidine-5-carboxamide (12.75 g, 72%).
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[F:12])[CH2:3][CH3:4].C[Si]([C:17]#[N:18])(C)C>>[F:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[CH:2]([CH2:3][CH3:4])[C:17]#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: CCC(Br)c1cc(F)ccc1F
Product: CCC(C#N)c1cc(F)ccc1F

Procedure:
rac-2-(2,5-Difluoro-phenyl)-butyronitrile was prepared from rac-2-(1-bromo-propyl)-1,4-difluoro-benzene and trimethylsilyl cyanide in analogy to Example 23 c): colourless oil.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:18][C:19]#[CH:20].O>O1CCCC1>[CH3:3][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)([O:1][CH2:20][C:19]#[CH:18])[CH3:4]
Reactant: CCOC(=O)c1cc(C(C)(C)O)on1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOC(C)(C)c1cc(C(=O)OCC)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.5 %

Procedure:
2.00 g of ethyl 5-(1-hydroxy-1-methylethyl)isoxazole-3-carboxylate was dissolved in 20 ml of tetrahydrofuran, and 0.44 g of sodium hydride and 1.32 g of 3-bromo-1-propyne were then added under ice-cooling. The mixture was stirred at room temperature for 5 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-ethyl acetate to obtain 0.25 g of ethyl 5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazole-3-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].CS(C)=O>O>[N:10]1[N:11]=[N:12][N:7]2[C:2]=1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6]2
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Cl)nn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc2nnnn2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.7 %

Procedure:
A mixture of 6-chloropyridazine-3-carbonitrile (291 mg, 2.12 mmol) (Szilagyi, G., et al; European J. Med. Chem. 19:111-117, 1984), sodium azide (149 mg, 2.29 mmol), and DMSO (0.9 mL) was stirred at rt for 20 min, then diluted with water (10 mL), and extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine (1×10 mL), dried (Na2SO4), and the clear pink solution was passed through a silica plug (EtOAc eluent). Treatment with decolorizing charcoal, filtration, and concentration with rotary evaporation afforded the title compound as an off-white solid (243 mg, 1.69 mmol, 80% yield). 1H-NMR (300 MHz, CDCl3) δ 8.66 (d, J=9.3 Hz, 1H), 7.81 (d, J=9.3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
1.8 g (60 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 7.5 g (50 mmol) of 4-formylbenzoic acid, dissolved in 100 ml of DMF, are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. A solution of 7.1 ml (60 mmol) of benzyl bromide in 50 ml of DMF is then introduced dropwise and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (50:50). After evaporation of the solvents, 10.9 g (91%) of the expected benzyl ester are collected in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[CH2:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:43]=2)[CH2:38][CH2:37]1)=[O:35].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:41]3[CH:40]=[C:39]4[C:44](=[CH:43][CH:42]=3)[N:36]([C:34](=[O:35])[CH2:33][C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[F:25])[CH2:37][CH2:38]4)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (138 mg, 0.348 mmol), and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (167 mg, 0.418 mmol) were dissolved in 1,4-Dioxane (5. mL) then added saturated NaHCO3 (2 mL). The mixture was then bubbled with N2 gas for 10 min then Pd(Ph3P)4 (40.2 mg, 0.035 mmol) was added, and then the mixture was bubbled for 5 additional minutes. The reaction was then capped and heated at 100° C. for 4 hr. The mixture was allowed to cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organic were combined, washed with brine, dried over MgSO4, filtered and concentrated to isolated a amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane eluting with a gradient of 0 to 10% MeOH in DCM for 30 min. to give 1,1-dimethylethyl 4-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (160 mg, 0.272 mmol, 78% yield) as a amber color oil. LC/MS (ES) m/z=589.6 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[S:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CCC>[S:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][N:17]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc2nc(Cl)nc(N)c2c1
Reactant: c1ccc2c(c1)CNCCS2
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(N)c2c1
Temperature: 150 °C
Yield: 100 %

Procedure:
To a solution of 2-chloro-6-methylquinazolin-4-amine (454 mg, 2.345 mmol) in n-butanol (5 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (388 mg, 2.345 mmol). After being heated at 150° C. for 1.5 hours under microwave irradiation, the reaction mixture was filtered and the collected solid was washed with ether to afford 756 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 323, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (s, 1 H), 7.83-7.81 (d, J=8.0 Hz, 1 H), 7.62-7.60 (d, J=8.0 Hz, 1 H), 7.53-7.49 (m, 2 H), 7.29-7.25 (m, 1 H), 7.22-7.19 (m, 1 H), 4.98 (s, 2 H), 4.25 (s, 2 H), 2.98 (s, 2 H), 2.35 (s, 3 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:12]1[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccnc1Oc1cccc(CCl)c1
Reactant: CCOP(OCC)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(Oc2ncccc2C)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-3-methylpyridine (3.6 g, 15 mmol) from Step 2 was treated neat with triethylphosphite (3.3 mL, 19.3 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-60%, EtOAc:CH2Cl2) to afford the title compound (4.3 g, 83% yield) as a thick oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2>>[Cl:33][C:31]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2)=[C:23]([O:22][CH2:21][CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[CH:32]=1
Reactant: Cc1ccc2c(OCCBr)cc(Cl)cc2n1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cc(Cl)cc2n1

Procedure:
The title compound was prepared from 8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-chloro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]=[CH:16][C:15]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: O=CC(=O)O
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O
Product: O=C(O)C=NNc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a mixture of 5.0 g of 4-(trifluoromethyl)phenylhydrazine (28.4 mmol), 31 ml of water and 3.1 ml of concentrated hydrochloric acid was added 2.9 g of glyoxylic acid-hydrate (31.4 mmol), and the mixture was stirred for one hour at room temperature. The precipitates thus separated out was collected by filtration, washed with water and dried over phosphorus pentoxide to give 6.26 g of 4-(trifluoromethyl)phenylhydrazonoacetic acid (95%) as a pale yellow powder.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](Cl)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9]>>[NH:1]([C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CS)C(=O)O
Product: CCCCCCCCCC(=O)N[C@@H](CS)C(=O)O

Procedure:
20 g of L-cysteine (0.1652 mol) are reacted with 28.2 g (0.1487 mol) of capric acid chloride analogously to Stage 6.1 to form decanoyl-Cys; m.p. 57°-58°, Rf =0.21 (CHCl3 :methanol=85:15), [α]D20 =-15° (c=0.814, CHCl3 :MeOH=1:1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:18][CH2:19][O:20][C:21]([CH2:23]P(OCC)(OCC)=O)=[O:22].[H-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)/[CH:8]=[CH:23]/[C:21]([O:20][CH2:19][CH3:18])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.3 g of the aldehyde prepared above in THF (1 mL) was added to a solution of sodium triethylphosphonoacetate prepared by combining triethylphosphonoacetate (0.37 g, 1.2 eq.) and NaH (0.1 g, 50% dispersion, 1.5 eq.) in THF (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour and then quenched with saturated ammonium chloride and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated to give ethyl trans-3, 5-di-t-butylcinnamate as a yellow oil used directly for the next step.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C(Cl)Cl>[CH3:10][S:11]([O:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCC2(CC2)O1
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane (116 mg, 0.9 mmol) and Et3N-(183.8 mg, 1.82 mmol, Shantou Xilong chemical factory) in dry CH2Cl2 (6 mL) at −10° C. under N2, was added MsCl (203 mg, 1.4 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe. After stirring for 2 hrs at rt, the reaction was quenched with water ice (3 mL), and the water phases were extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to give ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate as pale yellow oil.