Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[C:28](=[O:30])[CH3:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[C:28](=[O:30])[CH3:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32]
Reactant: COc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)c(C(C)=O)c1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
[2-(7-Benzyloxy-6-methoxyquinolin-4-yloxy)-5-methoxyphenyl]-ethanone (intermediate 3) (2.52 g) was suspended in a mixed solution composed of methanesulfonic acid (3.0 ml) and trifluoroacetic acid (50 ml), and the suspension was stirred at 70° C. for 0.5 hr. The solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with sodium hydrogencarbonate powder. The mixture was then extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (1.23 g, yield 62%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCO[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:23]([O:22][C:20]([C:14](=[CH:13][NH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:21])[CH3:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ncccc1N
Product: CCOC(=O)C(=CNc1cccnc1OC)C(=O)OCC
Temperature: 60 °C
Yield: 82.6 %

Procedure:
3-amino-2-methoxypyridine (12.0 g) was reacted with diethyl ethoxymethylene malonate (23.0 g) at a temperature of 120° C. to 130° C. for 30 minutes while distilling ethanol produced during the reaction. After completion of the reaction, the reaction mixture was cooled to 60° C., and poured into petroleum ether (200 ml) and cooled to 0° C. The resulting precipitates were filtered to give 23.5 g (82%) of the titled compound.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH2:2]>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH3:2]
Reactant: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
To a suspension of palladium (II) hydroxide on activated carbon (20% by wt, 1.2 g) in 10 mL of ethanol was added tert-butyl (2R)-2-vinylpyrrolidine-1-carboxylate (2.0 g, 10 mmol)as a solution in 15 mL of ethanol and the mixture was placed under 12 psi of H2 on a parr hydrogenator overnight. The resultant mixture was then filtered and concentrated to give tert-butyl (2S)-2-ethylpyrrolidine-1-carboxylate (1.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1O
Temperature: 60 °C

Procedure:
2-Hydroxy benzoic acid (1 g, 7.2 mmol) is dissolved in DCM (14 mL). To this mixture, thionyl chloride (1.57 mL, 22 mmol) and a catalytic amount of dry DMF are added. The resulting mixture is heated to 60° C. overnight, after which the resulting mixture is evaporated to give the desired product that is used as such.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1>CC(O)CC>[CH3:15][CH:14]([O:17][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1)[CH2:13][CH3:12]
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CCC(C)O
Product: CCC(C)Oc1cc(C(=O)Nc2ccc(O)cc2C)ncn1

Procedure:
Following the general method as outlined in Example 26, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and 2-butanol (Fluka), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH2:20].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:20][O:19][CH3:18])[CH2:10][CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 21 mmol) and O-methylhydroxylamine hydrochloride (2.7 g, 32.8 mmol) in chloroform (100 ml) containing triethyl-amine (5.5 g, 55 mmol). The reaction mixture was then stirred at ambient temperature over-night, prior to removal of solvent. The resultant crude reaction mixture was dissolved in ethyl acetate (150 ml) and washed rapidly with 1N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.3 g, 94%) was isolated as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH3:16])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH2:7][N:8]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[C:24]1=[S:25])[CH:2]=[CH2:3]
Reactant: C=CCNCCCNc1cc(Cl)ccc1C
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To an ice-cold solution of the diamine of Step C (3.4 g) and triethylamine (4.0 mL) in dry chloroform (50 mL) was added dropwise under nitrogen thiophosgene (1.1 mL). After 30 minutes at ambient temperature, additional triethylamine (1.0 mL) and thiophosgene (0.28 mL) were added. After 15 minutes, no starting material remained. The reaction was quenched with water, the pH adjusted to 8 with triethylamine, and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 10% ethyl acetate in hexane provided a yellow solid which was triturated with diethyl ether to give the title compound (1.69 g, 42.4%) as a white solid, m.p. 71-72° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][CH:3]=1.N.[CH:16](Cl)(Cl)Cl>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC[C@@H]2CCCN2)cn1
Reactant: ClC(Cl)Cl
Agent: N
Product: Cc1ccc(OC[C@H]2CCCN2C)cn1

Procedure:
The title compound was prepared from the compound of step 36a in a manner similar to compound 18b TLC Rf =0.17 (10%MeOHI/CHCl3). MS (DCI/NH3) and 1H NMR (CDCl3,300 MHz) are similar to the compound of step 18b
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].I[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:3]#[C:2][C:1]([NH2:5])=[O:4]
Reactant: C#CC(N)=O
Reactant: Ic1cccs1
Product: NC(=O)C#Cc1cccs1
Yield: 54.5 %

Procedure:
According to preparation 4, propiolamide (1.68 g, 24.45 mmol) was coupled with 2-iodothiophene (3.2 g, 15.67 mmol) to provide 1.29 g (55%) of product. NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:18])([F:17])[CH2:13][C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH2:13][C:12]([F:18])([F:17])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (10.0114 g; 56.5520 mmoles) and 3,3,3-trifluoro-propionic acid (7.5 mL; 84.9 mmoles) were combined with 6N HCl (20 mL; 120 mmoles) and heated to 108° C. for 18 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and water (200 mL), then sodium bicarbonate (15.15 g; 180.3 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×60 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid. A sample of the crude brown solid was purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light brown solid.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])=O)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[C:28]([O:27][C:25]([N:14]1[C:15]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](=[O:18])[NH:11][CH2:12][CH2:13]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(CCNC(=O)OCc1ccccc1)c1c(F)cccc1C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC(=O)c2cccc(F)c21

Procedure:
A solution of 2-[(2-benzyloxycarbonylaminoethyl)-tert-butoxycarbonylamino]-3-fluorobenzoic acid from Example 20B (390 mg, 0.87 mmol), 10% palladium/carbon (˜100 mg) and acetic acid (1.0 ml) in methanol (25 ml) was hydrogenated at atmospheric pressure for 1.5 h. The mixture was filtered, evaporated in vacuo and azeotroped with toluene. The residue was taken up in a mixture of IPA and acetic acid (90:10, 35 ml) and heated at reflux for 4 h. The mixture was cooled, evaporated in vacuo and azeotroped with toluene to give a white solid; yield 250 mg, 100%.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[Li+].[F:5][C:6]([F:12])([F:11])[S:7]([O-:10])(=[O:9])=[O:8].[CH3:13][N:14]([C+:16]([N:18]([CH3:20])[CH3:19])Cl)[CH3:15]>C(#N)C>[F:5][C:6]([F:12])([F:11])[S:7]([O-:10])(=[O:9])=[O:8].[CH3:13][N:14]([CH3:15])[C:16](=[N+:2]([CH3:3])[CH3:1])[N:18]([CH3:20])[CH3:19]
Reactant: C[N-]C
Reactant: CN(C)[C+](Cl)N(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
0.225 g (4.41 mmol) of lithium dimethylamide are added at room temperature to 1.26 g (4.42 mmol) of bis(dimethylamino)chlorocarbenium trifluoromethanesulfonate in 20 ml of acetonitrile. The reaction mixture is stirred for 12 hours, and LiCl is subsequently filtered off. The solvent is distilled off, and the residue is washed with 20 ml of diethyl ether and subsequently dried under reduced pressure (8.0 Pa), giving 1.25 g of hexamethylguanidinium trifluoromethanesulfonate, corresponding to a yield of 96.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].Br[CH2:26][C:27]#[CH:28]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH2:28][C:27]#[CH:26])=[O:5]
Reactant: C#CCBr
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)[O-])c(Cl)cc3F)c1=O)CCC2
Agent: [Na+]
Product: C#CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl

Procedure:
using sodium 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and 3-bromo-1-propyne there is obtained 2-propynyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 193°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[H-].[Na+].[NH2:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[C:25]([N:30]2[CH2:54][CH2:53][C:33]3([CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH:35]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:34]3)[CH2:32][CH2:31]2)[N:24]=1>C1COCC1>[NH2:22][C:23]1[N:28]=[C:27]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[C:9]([F:12])([F:11])[F:10])[N:26]=[C:25]([N:30]2[CH2:54][CH2:53][C:33]3([CH2:37][N:36]([C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:39])[CH:35]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:34]3)[CH2:32][CH2:31]2)[N:24]=1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(N)nc(Cl)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(CCN(c3nc(N)nc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (380 mg, 1.3 mmol) in 10 mL of THF was added NaH (60 mg, 1.4 mmol) and the reaction was stirred at RT for 30 min. After this time, 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product from Step 1, Example 39a) (570 mg, 1.2 mmol) was added and the reaction was heated to 50° C. for 12 h. After this time, the reaction was cooled to RT, quenched with methanol and concentrated in vacuo. Normal phase silica gel chromatography (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][C:4]=1[N+:26]([O-])=O>[Pd].CO.C(Cl)Cl>[NH2:26][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:3]=1[NH:2][CH3:1])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc(NC)c(N)c1

Procedure:
Prepared analogously to Example 1c from ethyl 3-[1-(4-methylamino-3-nitro-benzyl)-1H-benzimidazol-2-yl]-propionate and palladium on activated charcoal in methanol/methylene chloride.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+].C(OCC)(=O)C.[Cl-].[Na+]>CN(C=O)C.O>[N:27]([CH:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)NC1N=[N+]=[N-])c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.2 %

Procedure:
To a solution of 0.380 g of (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine in 1 ml of DMF is added a solution of 0.079 g of sodium azide in 1 ml of water and the mixture is stirred at room temperature for 15 hours. After addition of ethyl acetate and saturated aqueous sodium chloride solution, the organic layer is separated and washed with aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Purifying the residue on a silica gel column (ethyl acetate:CHCl3 :CH3OH=4:4:1) yields 0.201 g of (3S)-4-azido-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino-acetamido]-2-oxoazetidine(syn-isomer, cis-trans mixture).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]=[CH2:21])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:23]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:23][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C=COCCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: CCOCC
Solvent: ICI
Product: Clc1ccc(Br)cc1Cc1ccc(CCCOC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(3-(vinyloxy)propyl)benzyl)benzene (0.75 g, 2.04 mmol) and Et2Zn (5.11 mL, 5.11 mmol, 1.0 M in hexane) in dry ethyl ether (10 mL) was added diiodomethane (0.41 mL, 5.11 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and then with brine (20 mL), and then dried over sodium sulfate. The residue was concentrated and purified by preparative TLC (eluent EA:PE=1:40) to obtain intermediate DH (0.64 g) as a light yellow oil. 1H NMR (CDCl3, 400 MHz): δ 7.32˜7.25 (m, 3H), 7.15 (d, 2H), 7.11 (d, 2H), 4.05 (s, 2H), 3.53 (t, J=6.4 Hz, 2H), 3.31˜3.26 (m, 1H), 2.68 (t, J=7.2 Hz, 2H), 1.93˜1.86 (m, 2H), 0.61˜0.45 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[N:10][OH:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2].ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:25]=[C:26]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:27]=[C:28]([Cl:30])[CH:29]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2([C:33]([F:36])([F:34])[F:35])[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=3)[CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: CCc1ccc(C=NO)cc1[N+](=O)[O-]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
In dimethylformamide (40 mL), 2-ethyl-5-hydroxyiminomethylnitrobenzene (4.30 g) and N-chlorosuccinimide (2.97 g) were dissolved, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, and thereto was added 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1-propene (3.5 g), followed by triethylamine (1.7 g), and then the mixture was stirred for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-ethylnitrobenzene (5.74 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)[CH3:14])[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[N:3][C:4]([C@@H:13]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][NH:20]3)[CH3:14])=[CH:5]2
Reactant: CN1CCNCC1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(Cl)n1
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(N2CCN(C)CC2)n1
Temperature: 25 °C

Procedure:
To a mixture of (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine 38 (300 mg, 0.84 mmol, 1 eq) in 1,4-dioxane (10 mL) at RT, 1-methylpiperazine (167 mg, 1.68 mmol, 2 eq) was added and the resulting mixture was stirred at reflux for 8 h. The mixture was allowed to cool to RT, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, (S)—N-(1-(8-chloro-1-(4-methylpiperazin-1-yl)isoquinolin-3-yl)ethyl)-9H-purin-6-amine 46. ESI-MS m/z: 423.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].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.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](C(N)=O)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)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: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of trans-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (119 mg, 0.333 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (133 mg, 0.402 mmol), Na2CO3 (88.3 mg, 0.833 mmol), Pd(PPh3)4 (23.1 mg, 0.0200 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 22 h. To the cooled reaction solution was added water (10 mL), the mixture was extracted with EtOAc (3×15 mL), the combined organic layers were washed with water (2×10 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as light yellow solid. Chromatography of the mother liquor on silica gel (8 g, eluting with 2%→4%→6%→8%→10% MeOH in CH2Cl2) gave an additional batch. Both batches contained a small amount of the corresponding cis isomer (see below for its independent synthesis). 1H NMR (CDCl3, 400 MHz): δ=2.70-2.78 (m, 2H), 2.97-3.08 (m, 2H), 3.21-3.26 (m, 1H), 5.66-5.72 (quintet, 1H, J=8.4 Hz), 6.54 (brs, 2H), 7.08 (s, 1H), 7.59 (s, 1H), 7.68-7.78 (m, 3H), 7.94-7.98 (m, 1H), 8.12 (s, 1H), 8.26-8.28 (d, 1H, J=8.4 Hz), 8.32-8.37 (m, 3H), 8.48-8.53 (m, 2H), 8.66-8.68 (d, 1H, J=8.8 Hz). MS (ES+): 435.2 [MH+]. HPLC: tR=2.3 min (polar—5 min).