Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from (5-methoxy-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M29) (254 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (96 mg).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27]C)=[O:26])=[N:23][CH:24]=2)=[CH:6][C:5]=1[F:29]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=2)=[CH:6][C:5]=1[F:29]
Reactant: COC(=O)c1ccc(-c2cc(F)ccc2CNc2ccc(Br)c(F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(F)ccc2CNc2ccc(Br)c(F)c2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.81 mL, 2.4 mmol) was added to a THF solution (13.7 mL) of methyl 5-(2-(((4-bromo-3-fluorophenyl)amino)methyl)-5-fluorophenyl)picolinate (350 mg, 0.8 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][CH:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]1=[O:13]>CCOCC.[Cu]I>[CH3:4][C:5]1([CH3:2])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]1=[O:13]
Reactant: CI
Reactant: CC1CCC(C)(C)CC1=O
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5.2 g of magnesium shavings are suspended in 100 ml of absolute ether and treated dropwise with 13.5 ml of methyl iodide. After the addition of 100 ml of ether, the mixture is boiled at reflux for a further 3 hours until all magnesium has dissolved. The mixture is cooled to 0° C. and treated with 20.7 g of finely powdered copper (I) iodide. After stirring at 0° C. for 15 minutes, a solution of 10 g of 3,6,6-trimethyl-2-cyclohexanone in 40 ml of ether is added dropwise thereto and the mixture is stirred at 0° C. for a further 4 hours. Thereafter, the yellow suspension is poured into ice/2N hydrochloric acid, extracted several times with ether, the organic phase is dried and evaporated. The residue is distilled in a water-jet vacuum. There are obtained 9 g of 2,2,5,5-tetramethylcyclohexanone as a colorless liquid, b.p. 71°-74° C./15 mm.
Reaction SMILES: [CH2:1]([C@@H:3]1[C:6](=[O:7])[O:5][C@H:4]1[CH2:8][C@@H:9]([O:27][C:28](=[O:45])[C@H:29]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:30][C:31](OCC1C=CC=CC=1)=[O:32])[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][CH2:25][CH3:26])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([C@@H:3]1[C:6](=[O:7])[O:5][C@H:4]1[CH2:8][C@@H:9]([O:27][C:28](=[O:45])[C@H:29]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:30][CH:31]=[O:32])[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][CH2:25][CH3:26])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CC)OC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
565 mg of N-[(benzyloxy)carbonyl]-L-leucine (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester were dissolved in 12 ml of THF. The mixture was hydrogenated at room temperature in the presence of 40 mg of 10% Pd/C. After the reaction was finished the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in 9 ml of THF and 71 μl of formic acid/acetic acid anhydride were added dropwise. The mixture was diluted with 5 ml of diethyl ether and washed twice with 2% sodium hydrogen carbonate solution and then with water. After drying over sodium sulfate it was filtered and evaporated. By chromatography on silica gel and recrystallization from n-pentane there was obtained N-formyl-(S)-leucine (S)-1-[[(2S,3S)-3-ethyl-4-oxo-2-oxetanyl]methyl]octadecyl ester of m.p. 60°-61° C.
Reaction SMILES: [CH3:1][C:2](O)([CH3:5])[CH2:3][NH2:4].O=S(Cl)Cl.[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[NH:4][CH2:3][C:2]([CH3:5])([CH3:1])[S:23]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)(O)CN
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCC(C)(C)S1

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:12]1([CH2:1][C:3]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1cccc(C(=O)O)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CN2CCCCC2)n1
Reaction time: 0.75 h
Yield: 103.5 %

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid (available from Chemstep Product List, 250 mg, 1.65 mmol) in dichloromethane (5.8 ml) was added piperidine (0.428 ml, 4.33 mmol) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 30 mins when sodium triacetoxyborohydride (459 mg, 2.17 mmol) was added and the mixture stirred for 45 mins. The mixture was loaded onto an aminopropyl cartridge (5 g) pre-eluted with dichloromethane. The cartridge was eluted with dichloromethane and methanol, and fractions containing product were combined and blown to dryness under a stream of nitrogen. The crude product was taken up in ethyl acetate (25 ml) and washed with sodium hydroxide solution (2M, 3×25 ml). The aqueous layer was acidified to pH6 using hydrochloric acid (5M) and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g), which had been pre-eluted with methanol (1 volume) followed by water (1 volume). The cartridge was eluted with water (1 volume) followed by methanol. Fractions containing product were combined and dried to give the title compound (376 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[N:23]([CH3:28])[N:24]=[CH:25][C:26]=3[Br:27])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl.CCOC(C)=O>C(O)C>[Br:27][C:26]1[CH:25]=[N:24][N:23]([CH3:28])[C:22]=1[C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Br)cnn1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(NC(=O)Nc2cccc(C(C)O)c2)cc1-c1c(Br)cnn1C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Compound 17 (30.2 mg, 0.07 mmol, see Example 1.24) was dissolved in ethanol (5 mL). Sodium Borohydride (3.1 mg, 0.08 mmol) was added under Argon gas. The reaction was stirred overnight and found to be complete by TLC and LC/MS. The mixture was worked up with 1N Hydrogen Chloride solution (10 mL) and EtOAc (2×15 mL). The organic layers were combined and washed with water, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was then purified by HPLC to afford 19.4 mg (63%) of Compound 94: LCMS m/z (%)=445 (M+H79Br, 25), 447 (M+H81Br, 25). 1H NMR (400 MHz, CDCl3) δ: 7.34 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 7.11 (d, J=8 Hz, 1H), 7.09 (s, 1H), 7.06 (t, 1H), 6.95 (d, J=4 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 4.65 (m, 1H), 3.59 (s, 3H), 3.49 (s, 3H), 1.27 (d, J=4 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[O:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Cl:23][C:19]1[C:18]([O:24][CH:25]([CH3:27])[CH3:26])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(Cl)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1c(Cl)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
The mixture of 2-(3-chloro-2-isopropoxy-benzoylamino)-indan-2-carboxylic acid ethyl ester (15) (122 mg, 0.30 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (16) as white solid (119 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1.B.[Na]>CO>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][CH:11]([OH:12])[C:5]=2[CH:4]=1
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccc(C(F)(F)F)cc21
Agent: B
Agent: [Na]
Solvent: CO
Product: OC1Cc2c(Cl)cccc2Sc2ccc(C(F)(F)F)cc21

Procedure:
To the mixture of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-one obtained in Example 40 and 10 ml of methanol was gradually added 0.2 g of sodium boron hydride with ice-cooling over a period of 5 minutes and the mixture was reacted at room temperature for 30 minutes and refluxed for 15 minutes. After the completion of the reaction, methanol was distilled off. After cooling, to the mixture was added water and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and freed of the solvent to obtain 0.5 g of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-ol as colorless crystals having a melting point of 130°-132° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[CH:26]=1)[NH2:23])(=[O:18])[CH3:17]>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:23][C:22]2[CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[CH:26]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[CH:21]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CC(=O)Nc1cc(N)cc(NC(C)=O)c1
Solvent: CO
Product: CC(=O)Nc1cc(NC(C)=O)cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
To a refluxing mixture of 0.96 g. (0.0045 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 35 ml. of methanol was added a solution of 1 g. (0.0045 mol) of 3,5-bis-acetamidoaniline (prepared as above) in 15 ml. of methanol. After three hours at reflux, the reaction mixture was cooled and filtered to yield 5-acetyl-4-hydroxy-3-[1-(3,5-bis-acetamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 265°-267° C. (dec.).
Reaction SMILES: ClC([O:4][CH:5]1[CH:12]2[CH2:13][CH:8]3[CH2:9][CH:10](C[CH:6]1[CH2:7]3)[CH2:11]2)=O.C1(CC[NH2:23])C=CC=CC=1>>[NH2:23][C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][OH:4]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Product: N[C@H](CO)Cc1ccccc1

Procedure:
The acid 6 is condensed with amines such as illustrated in Scheme X to produce final products, for example, condensation of 6 with phenylethylamine gives compound 13a with (S)-(-)-2-amino-3-phenyl-1-propanol gives compound 13b and with (R)-4-[[(2-amino-1-phenyl)ethyl]amino]-4-oxobutanoic acid benzyl ester to give 13c and 13d.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
To a solution of 20.9 g (64.5 mmol) of the azido compound obtained in Step B in 650 mL of THF, there are successively added 25.5 g (97.2 mmol) of triphenylphosphine and 157 mL of water. The batch is refluxed for 2 hours 30 minutes. The reaction mixture is then concentrated to dryness and the residue oil is then taken up in isopropyl ether. A white precipitate appears; it is filtered off and washed with isopropyl ether. The filtrate is then concentrated to dryness and then purified by chromatography over silica gel using dichloromethane and methanol as eluants. The title product is obtained in the form of an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.ClC[C:26]1[N:30]=[CH:29][O:28][N:27]=1.[C:31](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH2:31][C:29]3[O:28][N:27]=[CH:26][N:30]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3)cc2)cc1
Reactant: ClCc1ncon1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3Cc3ncno3)cc2)cc1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of (S)-2-[4-(4-chloro-phenoxy)-phenoxymethyl]-piperidine hydrochloride (218 mg, 0.615 mmol), 3-(chloromethyl)-1,2,4-oxadiazole (47 mg, 0.393 mmol), and potassium carbonate (87 mg, 0.629 mmol) in DMF (2.5 mL) was heated for 18 h at rt. The solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (65 mg, 51%): MS; m/z 400 (M+H):: LCMS (UV) 93%.
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH2:15]([N:22]1[CH2:31][CH2:30][CH:29]2[C:24](=[N:25][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:27][C:28]2=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:15]([N:22]1[CH2:31][CH2:30][C:29]2[C:28]([Cl:12])=[N:27][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:25][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1N=C(CN2CCOCC2)N=C2CN(Cc3ccccc3)CCC12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Product: Clc1nc(CN2CCOCC2)nc2c1CCN(Cc1ccccc1)C2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
N,N-Dimethylaniline (1.2 g, 10 mmol) and phosphorus oxychloride (12.2 g, 80 mmol) were added to the solution of 7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4(4aH)-one (˜10 mmol) in 1,2-dichloroethane (30 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 30 min. Reaction mixture was poured into ice, neutralized by solid sodium bicarbonate, extracted by ethyl acetate and dried over sodium sulfate. Solvent was removed in vacuo and the resulting brown oil was used directly in the next step.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][S:30]([CH2:33][CH2:34][C:35](O)=[O:36])(=[O:32])=[O:31])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[OH:15][C:8]1[C:9]2[NH:10][C:11](=[O:14])[S:12][C:13]=2[C:5]([CH2:4][CH2:3][NH:2][C:35](=[O:36])[CH2:34][CH2:33][S:30]([CH2:29][CH2:28][O:27][CH2:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)(=[O:31])=[O:32])=[CH:6][CH:7]=1
Reactant: O=C(O)CCS(=O)(=O)CCOCCc1ccc([N+](=O)[O-])cc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: Br
Product: O=C(CCS(=O)(=O)CCOCCc1ccc([N+](=O)[O-])cc1)NCCc1ccc(O)c2[nH]c(=O)sc12

Procedure:
Following the general method outlined in Example 20c) using 7-[2-aminoethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrobromide and 3-[2-[2-[4-nitrophenyl]ethoxy]ethylsulphonyl]propanoic acid [Example 13a)] gave the subtitled compound after purification by chromatography over silica using 8% ethanol in dichloromethane as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:41][C:40]([SH:42])=[N:39][N:38]=2)=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[O:41][C:40]([SH:42])=[N:39][N:38]=4)=[CH:35][CH:36]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc(-c2nnc(S)o2)cc1
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(-c5nnc(S)o5)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 19.6 %

Procedure:
A mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (100 mg, 0.245 mmol), 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol (53 mg, 0.27 mmol), EDCI (94 mg, 0.49 mmol) and DMAP (90 mg, 0.735 mmol) in 5 mL of DMF was stirred at room temperature for 40 hours. The mixture was poured into water and extracted with EtOAc (3×10 mL). The water layer was allowed to stand overnight then filtered to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)benzamide (28 mg, 19.5%) as white solid. 1H NMR (300 MHz, DMSO): δ 10.67 (s, 1H), 10.20 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 9.61 (d, 1H, J=7.8 Hz), 8.10 (d, 1H, J=8.1 Hz), 7.96-7.93 (m, 3H), 7.83-7.68 (m, 4H), 7.55 (d, 1H, J=6.6 Hz), 6.99 (d, 1H, J=9.0 Hz), 3.81 (s, 3H), 3.74 (s, 3H). LC-MS: 584 [M+H]+, 582 [M−H]−, tR=1.61 min. HPLC: 96.43% at 214 nm, 96.83% at 254 nm, tR=4.60 min.
Reaction SMILES: C(O[C:4](=[NH:16])[C:5](=[N:11][O:12][CH:13]1[CH2:15][CH2:14]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[Cl-:17].[NH4+:18]>CO>[ClH:17].[C:4]([C:5](=[N:11][O:12][CH:13]1[CH2:14][CH2:15]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[NH:16])[NH2:18]
Reactant: CCOC(=N)C(=NOC1CC1)C(=O)OCC
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: CCOC(=O)C(=NOC1CC1)C(=N)N
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.8 %

Procedure:
A mixture of ethyl 3-ethoxy-3-imino-2-(cyclopropyloxyimino)propionate (syn isomer)(9.6 g) and ammonium chloride (3.27 g) in methanol (70 ml) was stirred at ambient temperature for 3 days. The mixture was concentrated in vacuo and triturated with diethyl ether to give crude ethyl 2-amidino-2(cyclopropyloxyimino)acetate hydrochloride (syn isomer) (9.00 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[F:23][C:24]([F:32])([F:31])[C:25](N(OC)C)=[O:26]>C1COCC1>[C:19]([CH:16]1[CH2:15][CH2:14][CH:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:25](=[O:26])[C:24]([F:32])([F:31])[F:23])[CH:11]=[CH:10]3)[CH2:18][CH2:17]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(Br)ccc3c2)CC1
Reactant: CON(C)C(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(Oc2ccc3cc(C(=O)C(F)(F)F)ccc3c2)CC1
Temperature: -78 °C

Procedure:
To a solution of 2-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (2 g, 0.006 mol) in mL dry THF stirring at −78° C., was added dropwise. The reaction was then stirred at −78° C. for minutes, yellow color results. 2,2,2-Trifluoro-N-methoxy-N-methyl-acetamide (1.0 mL, 0.0083 mol) in 10 mL THF was then added dropwise while the reaction was stirred at −78° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.[CH2:39]([N:41]([CH2:58][CH3:59])[CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)[CH3:40]>>[CH2:27]([O:26][P:25]([CH2:24][C:23]1[CH:33]=[CH:34][C:20]([NH:19][C:11]2[N:10]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([C:47]4[CH:46]=[N:45][N:44]([CH2:43][CH2:42][N:41]([CH2:58][CH3:59])[CH2:39][CH3:40])[CH:48]=4)=[CH:3][C:4]=3[C:35](=[O:38])[NH:36][CH3:37])[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=2)=[CH:21][CH:22]=1)(=[O:32])[O:29][CH2:30][CH3:31])[CH3:28]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Reactant: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCN(CC)CC)c4)cc3C(=O)NC)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure of Example 97 using Diethyl(4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and N,N-diethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (Compound 175A). MS (ES+): m/z 703.45 (100) [MH+]; HPLC: tR=0.73 min (UPLC, purity).