Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([OH:5])=O.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([N:38]([CH3:39])[CH3:37])=[O:5]
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of hydroxy-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (100 mg, 0.19 mmol), dimethylamine (2 N solution in THF, 0.19 mL, 0.38 mmol), diisopropylethylamine (49 mg, 0.38 mmol) in THF was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N,-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol). The resulting suspension was heated to 60° C. with stirring until all was dissolved dissolved. The solvent was evaporated and the residue was used in the next step reaction without further purification. MS: m/z 533 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:20]([C:19]3[CH:23]=[CH:24][C:16]([I:15])=[CH:17][CH:18]=3)=[O:21])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Yield: 95.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 1-(3,5-dimethylpyridin-2-yl)piperazine (3.8 g) described in Preparation Example 47 and 4-iodobenzoyl chloride (5.3 g), the title compound (8 g) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH3:26]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:25]([CH2:24][CH2:23][O:22][CH3:21])[CH3:26])=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CNCCOC
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: COCCN(C)CCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and N-(2-methoxyethyl)methylamine were converted to yield [2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-(2-methoxy-ethyl)-methyl-amine, MS: 422 (MH+, 1Br).
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH2:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([N:39]1[CH2:44][CH2:43][N:42]([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]2)=[O:22])[CH2:41][CH2:40]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CCOC(=O)N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 567 mg, 1.8 mmol) was dissolved in DMF (15 mL). DIPEA (0.52 mL, 3.0 mmol) and 4-benzyl-piperazine (0.296 mL, 1.7 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (40 mL) and washed with 1 M aq Na2CO3 solution (6×50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give 2-(4-methylpiperazin-1-yl)ethyl 4-benzylpiperazine-1-carboxylate (352 mg, 60% yield) as a colourless oil.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH2:8][C:9]([NH:11][C:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])([C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][OH:15])=[O:10]>CC(O)(C)C.C1COCC1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1([C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][O:15][CH2:8][C:9](=[O:10])[NH:11]1
Reactant: O=C(CCl)NC(CCO)(c1ccccc1F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C1COCCC(c2ccccc2F)(C(F)(F)F)N1
Yield: 76.1 %

Procedure:
To a refluxing solution of potassium tert-butylate (1.31 g, 11.29 mmol) in 43 ml t-BuOH was added dropwise a solution of 2-chloro-N-[1-(2-fluoro-phenyl)-3-hydroxy-1-trifluoromethyl-propyl]-acetamide (1.77 g, 5.64 mmol) in 35 ml THF over a period of 60 minutes. The reaction mixture was cooled down and quenched with 1N HCl. EtOAc was added and the organic layer was washed with brine, dried with MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 3/1->2.5/1 to give 1.19 g of the title compound as white crystals.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>>[F:13][C:12]1[C:7]([F:6])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:10][C:11]=1[B:22]([OH:27])[OH:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCOc1cccc(F)c1F
Agent: [Li]CCCC
Product: CCCCCCCOc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: n-butyllithium (20 cm3, 10.0M in hexanes, 0.2 mol), compound from Example 40 (45.5 g, 0.2 mol) and triisopropyl borate (74.4 g, 0.4 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=1Cl)[NH:6]2.[NH2:31][CH2:32][C@@H:33]([OH:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[CH3:43].CCN(CC)CC>CCO>[Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=1[NH:31][CH2:32][CH:33]([OH:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[CH3:43])[NH:6]2
Reactant: CN1CCC(N2C(=O)c3cc4[nH]c(-c5c(Cl)cc[nH]c5=O)nc4c(Cl)c3C2=O)CC1
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3c(Cl)c4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1

Procedure:
A solution of 4-chloro-2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (18 mg, 0.04 mmol), (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (12.0 mg, 0.06 mmol) and Et3N (0.2 mL, 1.43 mmol) in EtOH (2.0 mL) was heated at 100° C. for 19 h and then concentrated to result a residue which was subjected to HPLC purification to furnish the title compound in TFA salt form (3.98 mg, 14%). 1H NMR (DMSO-d6) δ 1.95 (m, 2H), 2.15 (s, 3H), 2.19 (s, 3H), 2.51 (m, 2H), 2.80 (s, 3H), 3.18 (m, 2H), 3.50-3.80 (4H), 4.02 (m, 2H), 4.15 (m, 1H), 4.30 (m, 1H), 5.50 (br s, 1H, NH), 6.25 (d, J=8 Hz, 1H), 6.80-6.94 (3H), 7.40 (m, 1H), 8.08 (s, 1H), 9.49 (br s, 1H), 10.90 (br s, 1H), 11.36 (d, J=6 Hz, 1H); ESI-MS m/z 605.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[I:8].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([C:5]1[C:6]([CH3:9])=[C:7]([I:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)c(Cc2ccccc2)c(C)c1I
Temperature: 25 °C
Yield: 68 %

Procedure:
0-Benzyl-3,5-dimethyl-4-iodophenol was prepared as follows: In a 500 ml round-bottom flask were placed 30.0 g (121 mmol) of 3,5-dimethyl-4-iodophenol, 190 ml acetone, 16.9 g (122 mmol) potassium carbonate and 20.7 g (121 mmol) benzyl bromide. The mixture was refluxed for 15 hours, cooled, filtered and the precipitate washed with acetone. The combined filtrate was evaporated under reduced pressure to yield an orange oil which slowly crystallized. This was dissolved in methylene chloride and water and the methylene chloride layer sequentially washed with 5% sodium hydroxide, saturated sodium bisulfite and water. After drying over magnesium sulfate and filtering, the methylene chloride was removed under reduced pressure. The resulting solid was recrystallized from hot methanol, cooled to room temperature and then in ice, collected and washed with cold methanol to yield 27.9 g (68% yield) of white plates, mp 56-57, which were identified as O-Benzy13,5-dimethyl-4-iodophenol. 1H NMR analysis indicated: (δ, CDCl3) 7.68 (m, 5H), 6.62 (s, 2H), 4.88 (s, 2H) and 2.39 (s, 6H). Mass spectrum analysis indicated: (m/e) 338 (M+) and 91.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:34]=[CH:33][C:28]([C:29](OC)=O)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[OH:15][CH2:14][C@H:9]1[C@H:8]([C:7]2[C:6]([O:16][CH3:17])=[CH:5][C:4]([O:18][CH3:19])=[C:3]3[C:2]=2[O:1][C:29]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:35])[F:36])=[CH:34][CH:33]=2)=[CH:21][C:20]3=[O:22])[CH2:12][CH2:11][N:10]1[CH3:13]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(C(F)(F)F)cc3)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (1.5 g, 4.84 mmol) in dry DMF (15 mL) was reacted with methyl 4-trifluoromethylbenzoate (3.27 g, 16.02 mmol) in the presence of NaH (50%, 1.2 g, 25 mmol) as described in example 16, to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH2:6])=[O:5])[CH3:2].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[CH2:1]([NH:3][C:4]([NH:6][C:14]([NH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])=[O:5])[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CCNC(N)=O
Solvent: C1COCCO1
Product: CCNC(=O)NC(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 55.5 %

Procedure:
In 50 ml of anhydrous dioxane, 3.5 g (0.04 mol) of ethyl urea was dissolved, and under stirring 4.8 g (0.04 mol) of phenylisocyanate was added thereinto. The reaction was carried out at a room temperature for 15 hours, then the solvent was removed by distillation under a reduced pressure. The residue thus obtained was recrystallized from ethanol-water to obtain 4.6 g (yield 55%) of 1-ethyl-5-phenylbiuret having a melting point of 80°-81.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[C:46]([OH:49])[CH:47]=3)[N:42]=[CH:41][N:40]=2)=[N:34]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:49][C:46]1[CH:47]=[C:48]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][N:40]=[C:39]2[NH:38][C:35]1[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=1
Reactant: CN(C)CCCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)CCCN(C)S(=O)(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
5,6-Dichloro-N-[3-(dimethylamino)propyl]-N-methylpyridine-3-sulfonamide (122 mg, 0.37 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred under a nitrogen atmosphere at 100° C. for 2.5 hours. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform/methanol (9:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate:chloroform to chloroform:methanol=2:4:1 to 100:2) to obtain the entitled compound (75 mg, yield: 68%) as a pale orange amorphous solid.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/[OH:6])=O.[F:7][C:8]([F:18])([F:17])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.C(OCC)(=O)C>C(OCC)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:4]=[N+:5]([O-:6])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([F:7])([F:18])[F:17])=[CH:10][CH:11]=2)[N:16]=1
Reactant: CC(=O)/C=N/O
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c[n+]([O-])n(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 23 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred solution of anti-pyruvic aldehyde 1-oxime (2.67 g, 30.7 mmol) in diethyl ether (50 mL) was added 4-(trifluoromethyl)phenylhydrazine (5.40 g, 30.7 mmol). The reaction mixture was stirred at 23° C. for 2 h, then concentrated under reduced pressure. The crude residue was dissolved in 15% aqueous pyridine (150 mL). A solution of copper(II) sulfate pentahydrate (15.31 g, 61.3 mmol) in water (75 mL) was added at once. The resulting mixture was stirred at reflux for 17 h, then cooled to 0° C. Ethyl acetate (100 mL) was added and the mixture was filtered through Celite® diatomaceaous filter aid. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with 1.0 M aqueous hydrochloric acid (3×50 mL). The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 0 to 50% ethyl acetate in hexanes, to afford the title compound (5.84 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:54])[CH2:24][C:25]1([CH2:28][CH2:29][CH:30](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[OH:53])[CH2:31][C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)[CH3:21]>C(#N)C>[CH2:20]([O:22][C:23](=[O:54])[CH2:24][C:25]1([CH2:28][CH2:29][CH:30](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[O:53][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:43][CH:44]=2)[CH2:26][CH2:27]1)[CH3:21]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(OC(F)(F)F)cc2)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1

Procedure:
118 mg (0.46 mmol) of 4-trifluoromethoxybenzyl bromide and 98 mg (0.71 mmol) of anhydrous potassium carbonate are added to a solution of 170 mg (0.36 mmol) of tert-butyl 4-[(3E)-2-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 3 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 155 mg (67% of theory) of a colorless oil.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[BH4-].[Na+]>C1COCC1.CO>[OH:1][CH:2]([CH3:16])[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)[C@H](C)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Under argon, 810 mg of benzyl [(2S)-3-oxobutan-2-yl]carbamate (Example 150A, 3.7 mmol, 1 equivalent) were initially charged in 12 ml of dry THF and 12 ml of methanol, and 208 mg of sodium borohydride (5.5 mmol, 1.5 equivalents) were added at 0° C. After 2 h at 0° C., the mixture was concentrated, water and saturated aqueous sodium bicarbonate solution were added to the residue and the mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. This gave 777 mg (90% of theory) of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccccc1CCBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-2-chlorobenzene and isolated as light yellow gum. MS (m/e): 421.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1.O>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])[O:12][CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(COc2ccc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethyl)phenol (110 mg, 0.56 mmol) in DMSO (5.0 mL) was added potassium carbonate (155 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 10 minutes, before addition of ethyl 4-(bromomethyl)benzoate (136 mg, 0.56 mmol). The resulting mixture was heated to 70° C. with stirring for 3 hours before cooling back to room temperature. Water (50 mL) and EtOAc (50 mL) were added and the layers partitioned. The aqueous layers were washed with EtOAc (2×50 mL) and the combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid as the title compound (198 mg, 99%).
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[Br:16]Br.O>C(O)(=O)C>[Br:16][C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccccc2Oc2sccc21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2Oc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 80.7 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (2 g) was suspended in acetic acid (30 ml) and a solution of bromine (1.5 g) in acetic acid (10 ml) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 35 minutes and poured into water. The precipitated crystals were collected by filtration and washed with water and diisopropyl ether to give 2-bromothieno[2,3-b][1,5]benzoxazepin-4(5H)-one (2.2 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:33]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[S:12][C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[N:15][CH:14]=2)=[CH:17][CH:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NCc3ccccc3)cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 200 mg) in DCM (6 ml) was added triethyl amine (0.417 ml, 5.0 equiv.) and benzyl bromide (308 mg, 3.0 eq) and the reaction mixture was stirred for 2 days at RT. The solvent was evaporated and the residue was purified by column chromatography using 1% ethylacetate in chloroform to give the title compound. Yield: 50 mg (20%). 1H NMR (CDCl3; 300 MHz): δ 7.87 (s, 1H), 7.66 (d, 1H), 7.44 (d, 2H), 7.38 (m, 5H), 7.32 (m, 1H), 6.68 (d, 2H), 4.74 (m, 1H), 4.40 (s, 2H), 3.79 (s, 3H), 2.34 (m, 1H), 1.05 (t, 6H); MS (ESI) m/z 424.2 [M+H]+, 446.1 [M+Na]+.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1nc(Cc2ccccc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoate (5.2 g, 21.1 mmole) in methanol (30 ml) was added 50 ml of 1N NaOH. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to PH=3-4 under ice bath, and extracted with EtOAc (3×). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to yield the desired product (4.8 g, 98%) as colorless oil. LCMS calculated for C12H13N2O3(M+H): 233.1, found 233.0.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C(O)(=O)C>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:1]#[N:2])[CH:10]=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: O=Cc1cccc(Cl)c1
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CC(O)c1cccc(Cl)c1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of KCN (5.04 g, 78 mmol) in methanol (20 mL) was added 3-chlorobenzaldehyde (7.0 g, 50 mmol) at 0° C. under nitrogen atmosphere. Then acetic acid (4.4 mL) was added dropwise at 0° C. After 30 minutes, the mixture was warmed to 15° C. and stirred for 5 hours. Then the reaction mixture was concentrated to dryness and extracted with ethyl acetate (200 mL). The organic solution was washed with water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:15) to afford (3-chloro-phenyl)-hydroxy-acetonitrile. (Yield 8.2 g, 97%). LC-MS: [M+Na]+ 190.