Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:6]C(O)=O)([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([CH:5]1[CH2:10][CH2:11][C:12](=[O:13])[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(CCCO)CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(=O)C1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A suspension of the 3-tert-butyl-6-hydroxyhexanoic acid (1 g, 4.95 mmol), anhydrous NaOAc (0.321 g, 3.91 mmol) and acetic anhydride was refluxed for 5 hours during which time the solution mixture turned black. After the reaction mixture was cooled to room temperature, the formed acetic acid and remaining acetic anhydride were removed on a rotary evaporator and then under high vacuum. The residue was then dissolved in ethyl acetate, filtered through a plug of celite to remove the precipitate NaOAc, and concentrated in vacuo to give the crude product of 3-tert-butylcyclopentanone (0.557 g, 58%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH3:22])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[Cl:3][CH2:6][CH:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH3:22])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1cc(Cl)ccc1OC(CO)C(=O)C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1OC(CCl)C(=O)C(C)(C)C
Yield: 82.5 %

Procedure:
50 g (0.42 mole) of thionyl chloride were slowly added dropwise at room temperature to a solution of 106 g (0.39 mole) of 1-hydroxy-2-(2-methyl-4-chlorophenoxy)-4,4-dimethylpentan-3-one in 400 ml of methylene chloride, while stirring and using reflux cooling, and the mixture was stirred at room temperature overnight. It was then distilled under reduced pressure. 93 g (82% of theory) of 1-chloro-2-(2-methyl-4-chlorophenoxy)-4,4-dimethyl-pentan-3-one of boiling point 113°-117°C/0.2 mm were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([O:5][CH2:6][C@@H:7]1[C@@H:11]([OH:12])[CH2:10][C@H:9]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[O:8]1)=[O:4].[ClH:37].CC(O)C>>[ClH:37].[NH2:1][CH:2]([CH:34]([CH3:35])[CH3:36])[C:3]([O:5][CH2:6][C@@H:7]1[C@@H:11]([OH:12])[CH2:10][C@H:9]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[O:8]1)=[O:4]
Reactant: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](COC(=O)[C@@H](N)C(C)C)O4)c(=O)nc3o2)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](COC(=O)C(N)C(C)C)O4)c(=O)nc3o2)cc1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
The above reaction mixture from Example 14 was cooled to 5-10° C. and was added with 20% of HCl IPA solution until pH 2˜3. The mixture was stirred for additional 1 h and was filtered. The filter cake was washed with 140 mL of dichloromethane. 12.2 g of desired crude product were obtained. The overall yield from Example 11 was 71.1% and the purity was 97%. The crude product was recrystallized with methanol/dichloromethane/MTBE to give the desired pure product:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[F:20])[O:6][CH:7]=1.C([O-])(=[O:23])C.[Na+]>C(O)(=O)C>[F:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:5]1[O:6][CH:7]=[C:3]([CH2:2][OH:23])[N:4]=1
Reactant: CC(=O)[O-]
Reactant: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(CCl)co1
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2F)n1
Temperature: 25 °C

Procedure:
A solution of 4-chloromethyl-2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazole (1.000 g, 3.27 mmol) and sodium acetate (0.536 g, 6.54 mmol) in acetic acid (10 ml) is refluxed for 55 h. The reaction mixture is cooled to r.t., concentrated in vacuo and the resulting residue is dissolved in ethanol (5 ml) and 7M potassium hydroxide (KOH) (12 ml). The solution is refluxed for 5 h and cooled to r.t. Saturated ammonium chloride (NH4Cl) is added and the mixture is extracted with ethyl acetate (3×). The extract is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:1) yielding {2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl}-methanol as a colorless solid. Yield 0.791 g (84%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1.O>C(O)C>[CH:18]1([CH2:17][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCC1
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(OCC2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A mixture of 4-(hydroxymethyl)phenol (3.20 g, 25.8 mmol), potassium carbonate (7.12 g, 51.6 mmol) and (bromomethyl)cyclobutane (3.75 mL, 33.6 mmol) in ethanol (50 mL) was stirred at 70° C. overnight. Water was added thereto, ethanol was evaporated under reduced pressure, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=19:1 to 13:7), and then purified by basic silica gel chromatography (hexane:ethyl acetate=19:1 to 13:7), and the solvent was evaporated to give the title compound (1.17 g, yield 23%) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH2:26][CH2:25]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([N:33]3[CH2:34][CH2:35][CH:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH2:31][CH2:32]3)=[CH:37][CH:38]=2)=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 55.1 %

Procedure:
A mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (400 mg), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (374 mg), trifluoroacetic acid (209 μL), and N-methylpyrrolidone (2.8 mL) was heated at 150° C. for 16 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration, and then dried. The obtained solid was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1) to obtain 6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (383 mg) as a brown solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:21])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[NH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[C:11]1=[O:20].O.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[CH3:21][N:7]([CH3:6])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]2[NH:16][C:17]([CH:27]=[O:28])=[C:18]([CH3:19])[C:12]=2[C:11]1=[O:20]
Reactant: Cc1c[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A stirred solution of N,N-dimethylformamide (2 ml) was added dropwise slowly with phosphorus oxychloride (104 μl, 1.1 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 5-(2-dimethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (221 mg, 1 mmol) in 1.2 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (15 ml), stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (15 ml×6). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (105 mg, 38%) as a pink oil which was used as such.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 31.7 %

Procedure:
To a suspension of 8.66 g (50 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 100 ml of DMF was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 13.14 g (50 mmol) of N-(3-bromopropyl)phthalimide. The mixture was stirred for 7 hours at 100° C. After cooling, the reaction mixture was poured into water, which was subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and, the solvent was then distilled off. The residue was crystallized from methylene chloride--ethanol to give 5.72 g of the desired compound (31.7%, pale brown solid substance).
Reaction SMILES: [F:1][C:2]([CH3:17])([CH3:16])[CH:3]([NH:8]C(=O)OC(C)(C)C)[C:4]([NH:6][CH3:7])=[O:5].[ClH:18].C(OCC)C>ClCCl>[ClH:18].[NH2:8][CH:3]([C:2]([F:1])([CH3:17])[CH3:16])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)F
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)C(N)C(C)(C)F
Reaction time: 2 h

Procedure:
Intermediate 66B (306 mg, 1.23 mmol) was dissolved in dichloromethane (5 mL) and was treated with 2M hydrochloric acid solution in diethyl ether (6.18 mL, 12.4 mmol). The resulting mixture was stirred for 2 hour then was concentrated under reduced pressure. The oily residue was dried overnight in a 40° C. vacuum oven to provide intermediate 66C as an off-white solid in quantitative yield. 1H-NMR (400 MHz, (CD3)2SO) δ: 1.38 (d, 3H), 1.43 (d, 3H), 2.67 (d, 3H), 3.97 (d, 1H), 8.51 (broad s, 3H), 8.76 (q, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[CH:29].C(N(CC)CC)C>C1COCC1.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.[Cu]I>[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[C:29][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: C#CCN(C)C
Reactant: Ic1cnccc1OCc1nnc2ccc(-c3ccccc3)nn12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1cnccc1OCc1nnc2ccc(-c3ccccc3)nn12
Temperature: 75 °C
Reaction time: 1.25 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.5 μmol) was added to a suspension of 3-((3-iodopyridin-4-yloxy)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (107 mg, 249 μmol) and 1-dimethylamino-2-propyne (80.4 μl, 748 μmol) in THF (0.6 mL) and triethylamine (591 μl, 4238 μmol) at RT. Copper(i) iodide, 99.999% (4.75 mg, 24.9 μmol) was added and the reaction mixture was stirred at 75° C. (oil bath) for ˜75 min. The reaction mixture was cooled at RT, concentrated in vacuo. Purification by MPLC (ISCO, CH2Cl2/MeOH: 100/0 to 90/10) afforded the title compound. MS m/z=385.1 [M+H]+. Calc'd for C, 22; H, 20; N, 6; O, : 384.44
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:20]([OH:22])=O)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8])[CH3:6]>CN(C)C=O>[CH2:5]([S:7]([C:10]1[CH:11]=[C:12]([C:20]([Cl:3])=[O:22])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Yield: 99.7 %

Procedure:
243 g of thionyl chloride, a few drops of dimethyl formamide and 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated and then the thionyl chloride in excess was distilled off under vacuum. 148 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 146°-147° C.; yield: 100%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20]>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:24])=[N+:19]=[N-:20]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCCCCCNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a stirred ice cold solution of N-methylhexan-1-amine (4.69 mL, 1.0 equiv, 30.9 mmol) and DIEA (7.0 mL, 1.3 equiv, 40.2 mmol) in anhydrous DCE (150 mL) was added 3-azido-3-methylbutanoyl chloride (5.0 g, 30.9 mmol) in small portions over 5 min. The reaction was removed from the ice bath and stirred at room temperature for 1 h. The reaction mixture was poured into a separatory funnel and washed with 1 M HCl (3×100 mL) and saturated sodium hydrogen carbonate (2×100 mL). The organic layer was separate and dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a yellow oil (5.14 g, 72.0%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 3H), 1.2-1.35 (m, 6H), 1.47 (d, 6H), 1.47-1.66 (m, 2H), 2.51 (s, 2H), 2.94-3.04 (d, J=40 Hz, 3 H), 3.30-3.40 (m, 2H). LRMS (ESI+) for C12H24N4O (240.2); Found: 241 (MH+).
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][C:28]=1[Cl:40]>>[O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][NH:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][C:28]=2[Cl:40])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: c1ccc(OCCOCc2ccc(OCC3CO3)cc2)cc1
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(COCCOc4ccccc4)cc3)c(Cl)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-phenoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:37](B(O)O)[CH3:38]>>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:11]([CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH2:37][CH3:38])[CH:3]=2)[C:12](=[O:25])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([Cl:23])[C:14]=2[F:24])=[CH:28][CH:29]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Br)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1
Reactant: CCB(O)O
Product: CCc1cc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)ccc1F

Procedure:
The title compound was prepared in analogy to example 3, using N-[2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide (Example B178) and ethylboronic acid. 538.3 [ISP (M+H)+]
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][S:4][C:3]1=2.N1C2CCC3C=CC=CC=3C(=O)C=2S[CH:17]=1.IC>C1COCC1>[CH3:17][C:5]1[S:4][C:3]2[C:2](=[CH2:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: C=C1c2ccccc2CCc2ncsc21
Reactant: O=C1c2ccccc2CCc2ncsc21
Solvent: CI
Solvent: C1CCOC1
Product: C=C1c2ccccc2CCc2nc(C)sc21
Reaction time: 0.08 h

Procedure:
Add 1.2 equiv of n-BuLi-hexanes dropwise to a solution of 4-methylene-9,10-dihydro-4H-3-thia-1-aza-benzo[f]azulene (prepared from 9,10-dihydro-3-thia-1-aza-benzo[f]azulen-4-one (see Scheme XIII(b) as in Preparation 23) in THF (0.08 M) at −78° C. under Ar. Stir the resultant dark green solution for 5 min before adding 1.2 equiv of iodomethane in THF. Allow to warm and stir at room temperature for 18 h before quenching with excess water. Separate layers and extract the aqueous layer with diethyl ether (3×) and then dry (MgSO4) and concentrate the combined organic layers under reduced pressure. Use in the next step without further purification: 1H NMR (CDCl3, 400 MHz) δ 2.60 (s, 3 H), 3.03-3.13 (m, 4 H), 5.34 (s, 1 H), 5.53 (s, 1 H), 7.20-7.28 (m, 3 H), 7.33 (m, J=7.2 Hz, 1 H). TLC Rf=0.30 (10% EtOAc:hexanes).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26]/[C:27](=[N:58]\[OH:59])/[C@H:28]([NH:35][C:36]([CH:38]1[N:42]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)(=[O:45])=[O:44])[CH2:41][CH2:40][S:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:49]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:50]=[CH:51][C:46]([S:43]([N:42]2[CH2:41][CH2:40][S:39][CH:38]2[C:36]([NH:35][CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:27](/[NH:26][C:8](=[O:10])[CH2:7][CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:58]\[OH:59])=[O:37])(=[O:45])=[O:44])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OCCC(=O)O
Reactant: N/C(=N\O)[C@H](NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OCCC(=O)N/C(=N/O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Carboxylic acid, e.g., 3-tert-butoxypropionic acid (35 mg, 0.24 mmol), was dissolved in THF (2 mL). The resulting solution was cooled down to −15° C. NMM (84 μL, 0.76 mmol), followed by isobutyl chloroformate (33 μL, 0.25 mmol), were added. The mixture was stirred at −15° C. for 30 min. Intermediate Id, e.g. N-[(1R,2Z)-2-amino-2-(hydroxyimino)-1-phenylethyl]-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (108 mg, 0.22 mmol) in THF (2 mL) was added dropwise. The mixture was stirred overnight, letting the temperature increasing up to RT. Solvents were evaporated. The resulting oil was dissolved in AcOEt, and washed with sat NH4Cl and sat NaHCO3. Aqueous phases were extracted with two portions of AcOEt. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording intermediate Id′, e.g. 3-(biphenyl-4-ylsulfonyl)-N-[(2E)-2-[(3-tert-butoxypropanoyl)amino]-2-(hydroxyimino)-1-phenylethyl]-1,3-thiazolidine-2-carboxamide (118 mg, 86% yield), which was directly used in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH3:17])(=[O:14])=[O:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[C:34]1[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=1>>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:20]2[CH:21]=[CH:22][C:23]([C:2]3[C:3]([S:12]([NH:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=3)=[CH:24][C:19]=2[F:18])=[CH:35][N:36]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H16F4N4O2S, 440.09; m/z found, 441.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.56-8.53 (d, J=1.4, 2H), 8.34-8.31 (m, 1H), 7.99-7.95 (m, 1H), 7.63-7.59 (d, J=8.0, 1H), 7.59-7.53 (m, 1H), 7.36-7.34 (dd, J=7.1, 1.6, 1H), 7.34-7.32 (m, 1H), 2.97-2.71 (q, J=7.2, 2H), 1.15-0.84 (t, J=7.2, 3H).
Reaction SMILES: C(OC([C:11]1([NH2:32])[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[C:26](Br)[CH:27]=[CH:28][C:14]=2[N:13]([CH3:30])[C:12]1=[O:31])=O)C1C=CC=CC=1>[Pd].CO>[NH2:32][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]([CH3:30])[C:12]1=[O:31]
Reactant: CN1C(=O)C(N)(C(=O)OCc2ccccc2)N=C(c2ccccc2F)c2cc(Br)ccc21
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reaction time: 21 h

Procedure:
A flask was charged with 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1 eq.; Example 8-D, Step A) and 10% palladium on carbon. Methanol was added, and the flask was placed under a balloon of H2. The reaction was stirred for 21 hours. The mixture was filtered through celite washing with methanol. The filtrate was concentrated to a white solid.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH2:5][N:4]([CH3:17])[CH2:3]1.S(=O)(=O)(O)O>C(O)(=O)C.[C].[Pd]>[CH3:16][O:15][C:7]1[C:8]2[O:14][CH2:13][O:12][C:9]=2[CH:10]=[C:11]2[C:6]=1[CH2:5][N:4]([CH3:17])[CH2:3][CH2:2]2
Reactant: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1c2c(cc3c1OCO3)CCN(C)C2
Reaction time: 2 h
Yield: 93.1 %

Procedure:
1.19 g (5 mmol) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (6) was dissolved in 15 ml of acetic acid, and this solution was subjected to catalytic reduction for 2 hours at 75° C. by adding 0.33 ml (6 mmol) of 97% sulfuric acid and 500 mg of 5% palladium carbon. The catalyst was filtered off, and the filtrate was added with 2 ml of 25% aqueous solution of sodium hydroxide and 5 ml of water and then concentrated under reduced pressure. The residue was added with 10 ml of water, made basic with 25% aqueous solution of sodium hydroxide under ice cooling and extracted with 10 ml and then with 5 ml of methylene chloride successively. The extract layer was washed with 5 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.03 g of 8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline. Yield: 93%.