Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (2 mL) were added triethylamine (60.7 mg) and methanesulfonyl chloride (68.7 mg) under ice-cooling, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, distilled water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (161 mg).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([CH2:20][OH:21])[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH2:13][NH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]1[O:24][CH2:23]1>O.C(O)(=O)C>[OH:24][CH2:23][CH2:22][N:12]1[CH2:13][CH:14]([OH:19])[CH:15]([OH:18])[CH:16]([OH:17])[C:11]1([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][OH:21]
Reactant: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccccc1
Reactant: C1CO1
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCC1(CO)C(O)C(O)C(O)CN1CCO)c1ccccc1
Reaction time: 24 h

Procedure:
4.44 g of 2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine (Preparation example 3) are dissolved in 65 ml of water and, after adding one drop of acetic acid, 6 ml of ethylene oxide are added at about 5° C. After stirring the mixture for 24 hours, the reaction has ended. The mixture is concentrated, the residue is dissolved in about 40 ml of methanol/water 2:1 and the solution is discharged onto a column 20 cm long and 3 cm wide which contains Amberlite® IR 120, H+ form. The column is washed thoroughly with methanol/water 2:1 and then eluted with 0.1% strength ammonia. The individual fractions are investigated by thin layer chromatography to determine their content and the fractions containing the desired product are concentrated. 2.4 g of N-hydroxyethyl-2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine are obtained in the form of a solid foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O1CCOCC1>[C:14]([NH:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)c1ncc(Cl)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(Cl)cc1NC(C)=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of ethyl 3-amino-5-chloropicolinate (107) (2.0 g, 10 mmol) in 10 mL of 1,4-dioxane was added 4 mL of acetic anhydride. The resulting solution was allowed to stir at 50° C. for 24 hr. Solvent was evaporated and water (10 mL) was added to the residue. The mixture was neutralized by saturated sodium bicarbonate solution to pH=7. A pale yellow solid was collected by filtration and dried in vacuo, giving 2.0 g (83%) of the product. mp 98°-100° C. 1H NMR (CDCl3): δ1.476 (t, J=7.2 Hz, 3H), 4.45 (q, J=7.2 Hz, 3H), 8.352 (d, J=2.1 Hz, 1H), 9.218 (d, J=2.1 Hz, 1H), 11.087 (s, 1H).
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2ccncc12
Product: Brc1cccc(Nc2ncnc3ccncc23)c1
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 4-methylthiopyrido[4,3-d]pyrimidine (171 mg, 0.96 mmol), (see previous experimental) and 3-bromoaniline (1 mL) is heated to 100° C. for 2 h. A solid precipitates on cooling and is collected by vacuum filtration and then recrystallized from EtOH to yield 4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (30 mg, 10%). 1H NMR (DMSO) δ 10.33 (1H, s), 9.86 (1H, s), 8.84 (1H, d, J=5.8 Hz), 8.79 (1H, s), 8.22 (1H, s), 7.89 (1H, d, J=7.2 Hz), 7.69 (1H, d, J=5.8 Hz), 7.40 (2H, dt, Jd=8.0 Hz, Jt=1.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate (350 mg, 1.28 mmol) and 1-phenylpiperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU (195 mg, 1.28 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:13]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(F)c(Br)cc2s1
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1cc2ccsc2cc1Br
Yield: 87.5 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25c above, 6-bromo-5-fluoro-benzo[b]thiophene-2-carboxylic acid (I-27c: 250 mg 0.89 mmol) in DMA (4 mL) and DBU (550 mL, 3.6 mmol) were heated in microwave to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 180 mg of the product (86% yield).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](Cl)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>ClC(Cl)C.C(O)(C)(C)C>[Br:1][C:2]1[S:10][C:9]2[C:8]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ncnc2cc(Br)sc12
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Temperature: 25 °C
Yield: 121.7 %

Procedure:
6-Bromo-4-chloro-thieno[3,2-d]pyrimidine (7.73 g, 31 mmol) was dissolved in 50 mL of dichloroethane and 50 mL of t-butyl alcohol, and 5-aminoindole (4.09 g, 31 mmol) were added. The reaction mixture was refluxed for 14 hours, cooled to room temperature, and concentrated in vacuo to afford 13.02 g of (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine. The crude material was used without further purification (83% purity). 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.62 (s, 1H), 8.38 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.35 (m, 2H), 7.10 (d, 1H), 6.40 (s, 1H); LC-MS: 345, 347 (MH+); HPLC RT: 3.77 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34].[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(Br)cc2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3ccc(F)cc3)cc2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 500 mg (0.91 mmol) of the bromide from Example 11A, reaction in analogy to general method [D] with 152.27 mg (1.09 mmol) of 4-fluorophenylboronic acid, 31.83 mg (0.05 mmol) of bis(triphenylphosphine)palladium(II) chloride and 115.34 mg (1.09 mmol) of sodium carbonate in 10 ml of 1,2-dimethoxyethane and 0.5 ml of water results in 370.7 mg (72% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:17]([O:20][C@@H:21]([C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1)[CH3:22])(=[O:19])[CH3:18].C(N(CC)CC)C>C(O)(C)C>[C:17]([O:20][C@@H:21]([C:23]1[N:24]=[C:25]([N:12]2[CH2:11][CH2:10][C:9]3[C:14](=[CH:15][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=3)[CH2:13]2)[CH:26]=[CH:27][N:28]=1)[CH3:22])(=[O:19])[CH3:18]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNCC2
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 92 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid dimethylamide (prepared according to the method of Example 247, Step B, 210 mg, 0.88 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 175 mg, 0.88 mmol) followed by triethylamine (0.24 mL, 1.75 mmol). This mixture was stirred at room temperature for 1.75 h then heated to reflux for 1.5 h, cooled to room temperature, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give 327 mg (92%) of the title compound of Example 247, Step C as a white solid. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.68-7.58 (c, 2H), 7.47 (d, 1H), 6.44 (d, 1H), 5.72 (q, 1H), 4.86 (s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s, 3H), 1.62 (d, 3H); MS (TS) 431 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([S:10][CH3:11])[CH:3]=1.[Br:12]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:12][CH2:8][C:6]1[N:7]=[C:2]([NH2:1])[CH:3]=[C:4]([S:10][CH3:11])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CSc1cc(N)nc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1cc(N)nc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 0.10 g (6-amino-4-methylsulfanyl-pyridin-2-yl)-methanol in 6 ml dichloromethane was added 0.292 g tetrabromomethane and 0.231 g triphenylphosphin and the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by chromatography on silica gel with heptan:ethyl acetate=1:1 to yield 0.075 g of the title compound as white crystals MS (ISP): 232.9; 234.9 [M+H]+.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].C(Cl)Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20]>CCCCCC>[Br:12][C:13]1[CH:18]=[C:17]([N+:7]([O-:8])=[O:6])[C:16]([F:19])=[CH:15][C:14]=1[CH3:20]
Reactant: O=[N+]=O
Reactant: Cc1cc(F)ccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a mixture of nitronium tetrafluoroborate (11.6 g, 87.0 mmol) and CH2Cl2 (60.0 mL) was added 2-bromo-5-fluoro toluene (15.0 g, 10.0 mL, 79.0 mmol) over 5 minutes. After refluxing for 4.5 h, the mixture was cooled to room temperature and poured into ice water (150 mL). The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give 18.3 g of crude product. The crude product was treated with hexane and cooled to −70° C. then the hexane was decanted away from the resulting solid to give the desired product as a semi-solid (9.77 g, 53% yield). The mother liquors were evaporated and purified by column chromatography (silica gel, 2% EtOAc in Hexane) to give 1.0 g of the desired product. 1H NMR (CDCl3) δ 8.26 (d, J=6.9 Hz, 1H), 7.20 (d, J=11.7 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=O)[NH:25][CH:26]=[C:20]2[C:19]1=[O:29]>N1CCCCC1.C(O)C>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])[NH:25][CH:26]=[C:20]2[C:19]1=[O:29]
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCc2c(c[nH]c2C=C2C(=O)Nc3cccc(C4CCNCC4)c32)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 57.1 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (58.4 mg, 0.27 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (48 mg, 0.27 mmol) and piperidine (1 drop) in ethanol (1 mL) was stirred at room temperature for 7 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 58 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:7]=1[NH2:8].[F:14][B-:15]([F:18])([F:17])[F:16].[H+]>O>[F:14][B-:15]([F:18])([F:17])[F:16].[Br:13][C:10]1[CH:11]=[CH:12][C:6]([CH3:5])=[C:7]([N+:8]#[N:1])[CH:9]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1[N+]#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium nitrite (0.56 g) in water (2.0 mL) was slowly added to a mixture of 2-methyl-5-bromoaniline (1.50 g) in tetrafluoroboric acid (6.0 mL) and water (4.0 mL) at 0-5° C. After addition, the reaction was stirred at room temperature for 30 min. The mixture was cooled to 0° C., filtered, washed with cold water, cold methanol and ether. The mixture was then dried to provide the product 5-bromo-2-methylphenyldiazonium tetrafluoroborate (1.90 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Butyryl chloride (0.26 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.139 g, 60%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.02 (d, J=9 Hz, 1 H), 7.54 (d, J=9 Hz, 1 H), 7.02 (d, J=9 Hz, 1 H), 5.74 (d, J=9 Hz, 1 H), 5.72-5.64 (m, 1H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3 H), 2.33-2.25 (m, 2H), 1.64-1.50 (m, 2 H), 1.47 (d, J=6 Hz, 3 H) and 0.92 (t, J=8 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=3)[CH:11]=2)=[CH:4][N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[Br:33]N1C(=O)CCC1=O>CN(C)C=O>[Br:33][C:4]1[N:3]=[CH:2][O:1][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[CH:11]=1
Reactant: CC(C)c1nnc2ccc(-c3cnco3)cn12
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3ocnc3Br)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A clean, dry, 1 liter 4 neck round bottom flask equipped with mechanical stirrer, temperature probe, and purged with nitrogen, was charged with 6-[oxazol-5-yl]-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine (45.2 grams 0.198 moles) and dimethylformamide (271 ml). The pot was cooled below −60° C. with a dry ice/acetone bath. Lithium bis(trimethylsilyl)amide, 1 molar solution in tetrahydrofuran (198 ml 0.198 moles), was added, keeping the temperature below −60° C. After the addition was complete, the pot was further cooled to below −70° C. and stirred for 1 hour. While stirring, a solution of N-bromosuccinimide (35.24 g 0.198 moles) and dimethylformamide (105 ml), were stirred in a separate 500 ml round bottom flask under nitrogen. After the one hour stir at −70° C., the solution of N-bromosuccinimide and dimethylformamide was slowly added to the anion keeping the temperature below −70° C. After the addition, the reaction was continued for one hour below −70° C. The batch was then warmed to room temperature and quenched into methylene chloride (452 ml) and 1N sodium hydroxide (452 ml). The organic layer was then separated. The aqueous layer was extracted a second time with methylene chloride (135 ml). The combined organic phase was washed with 1N sodium hydroxide (452 ml) and saturated brine solution (452 ml). The organic phase was then dried over magnesium sulfate (50 grams) and concentrated/displaced with isopropyl ether (226 ml) to a temperature of 42° C. A thick slurry formed upon cooling. The solids were granulated at 20 to 25° C. for two hours, filtered, washed with isopropyl ether (50 ml), and dried to afford 53.0 grams of light yellow solids, 96.4% purity (HPLC), 87% of theory.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(C=O)c3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (500 mg) potassium carbonate (638 mg), 3-formylphenylboronic acid (166 mg) and bis(triphenylphosphine)palladium(II) chloride (64.8 mg) were added to a 20 ml microwave vial. Ethanol (9 ml) and toluene (9 ml) were added to the vial and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated and the residue was chromatographed (0-10% methanol:DCM) to give (S)-2-(6-(4-chlorophenyl)-8-(3-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide as a light brown solid (287 mg). LCMS (formate): MH+ 498/500, RT 0.99 min
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:12]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]([CH2:29]O)[CH2:27][OH:28])=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O>[CH2:12]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH:26]2[CH2:27][O:28][CH:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[O:11][CH2:29]2)=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CCCCCCc1ccc(CCC(CO)CO)cc1
Solvent: O
Product: CCCCCCc1ccc(CCC2COC(c3ccc4c(c3)OCO4)OC2)cc1

Procedure:
By reaction of benzo[1,3]dioxole-5-carbaldehyde with 2-[2-(4-hexylphenyl)ethyl]propane-1,3-diol with acid catalysis on a water separator.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][CH:6]([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C:7](Cl)=[O:8].C(N(CC)CC)C>C1CCCCC1>[Cl:5][C:6]1([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C:2]([CH3:4])([CH3:3])[CH2:1][C:7]1=[O:8]
Reactant: O=C(Cl)C(Cl)CC(Cl)(Cl)Cl
Reactant: C=C(C)C
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C1(Cl)CC(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 60.2 %

Procedure:
In an autoclave, 280 g of isobutylene are added under pressure to 122 g (0.5 mole) of 2,4,4,4-tetrachlorobutyryl chloride in 600 ml of cyclohexane. A solution of 51 g (0.5 mole) of triethylamine in 500 ml of cyclohexane is then pumped in at 65° C. The reaction mixture is then kept for 3 hours at 65° C. The precipitated hydrochloride of triethylamine is collected by filtration and the filtrate is concentrated. The resulting crystals are collected by filtration, affording 79.4 g of 2-chloro-2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutan-1-one with a melting point of 75°-76° C. (60% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:19]1([CH:25]=[CH:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:19]1([CH:25]=[CH:26][CH2:27][NH:28][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: NCC=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
120 mg (0.450 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 71.9 mg (0.540 mmol) of 3-phenyl-2-propene-1-ylamine were dissolved in 10 ml of DMF. 129 mg (0.675 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.