Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([S:9]([NH:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[CH3:24])[CH:15]=1)(=[O:11])=[O:10])[CH2:5][CH2:6][CH2:7][CH3:8].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][S:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])=[O:34])=[CH:15][C:16]=1[N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:24]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N(C)Cc2ccc(Cl)cc2Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc(N)c(N(C)Cc2ccc(Cl)cc2Cl)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 22.2 %

Procedure:
Four milliliters of ethanol and 4 ml of tetrahydrofuran were added to 0.605 g of N-(n-pentanesulfonyl)-3-(N-methy-2,4-dichlorobenzylamino)-4-nitrobenzamide, and subsequently 10 ml of an aqueous solution containing 3.10 g of sodium hydrosulfite was added thereto. The mixture was stirred at 80° C. for 20 minutes and then extracted with water and ethyl acetate. The organic layer was washed with water and concentrated. The resulting residue was crystallized from ether, filtrated, and dried to obtain 0.126 g of 4-amino-3-(N-methyl-2,4-dichlorobenzylamino)-(N-(n-pentanesulfonyl))benzamide (32).
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3](OCC)=O.[OH-].[Na+].[N+:14]([C:17]1[CH:18]=CC(Cl)=[N:21][CH:22]=1)([O-:16])=[O:15].Cl>CN(C)C=O>[N+:14]([C:17]1[CH:18]=[CH:3][C:2]([CH3:1])=[N:21][CH:22]=1)([O-:16])=[O:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cn1
Reaction time: 0.25 h

Procedure:
206 g (1.29 mol) of diethyl malonate are added to 600 ml of dimethylformamide, and 51.2 g (1.28 mol) of freshly powdered NaOH are introduced, with cooling. The mixture is subsequently stirred after 15 minutes and a solution of 94.8 g (0.6 mol) of 5-nitro-2-chloropyridine in 600 ml of dimethylformamide is then added dropwise at room temperature. The deep red solution formed is stirred until the reaction is complete, 36% strength HCl is then added dropwise until the color changes to orange and the mixture is evaporated to dryness in vacuo. The residue is taken up in 400 ml of CHCl3, washed with 500 ml of water and evaporated again. The residue is now dissolved in a mixture of 1,200 ml of 36% strength HCl and 870 ml of water and the solution is boiled under reflux until the evolution of gas has ended. Thereafter, it is evaporated in vacuo, the residue is dissolved in 500 ml of water, the solution is extracted with methylene chloride and the organic phase is washed again with water. After the solvent has been stripped off, 72 g (87%) of 5-nitro-2-picoline remain.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1F
Yield: 82 %

Procedure:
To a solution of 2-fluoro-3-methyl benzoic acid (3.57 g, 23 mmol) in MeOH (40 mL) was added concentrated sulfuric acid (2.3 mL), and the reaction mixture was heated at reflux for 12 h. The reaction mixture was cooled, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with a saturated solution of NaHCO3 and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford methyl 2-fluoro-3-methylbenzoate as a yellow oil (3.2 g, 82%): 1H NMR (300 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.39-7.34 (m, 1H), 7.08 (t, J=8 Hz, 1H), 3.98 (s, 3H), 2.31 (d, J=3 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH3:22][C:23](O)=[O:24]>CCO.[Pt]>[C:23]([NH:1][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[CH:8][CH:9]=1)(=[O:24])[CH3:22]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CCO
Product: CC(=O)Nc1cccc(C2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 0.33 h
Yield: 35 %

Procedure:
4A (870 mg, 3.0 mmol) was hydrogenated in EtOH (12 mL) and HOAc (0.7 mL) with Pt/C (5% wt, 250 mg) using a H2 balloon for 2 days. After filtration and evaporation of solvent, the crude product was stirred in acetic anhydride (8.0 mL) for 20 min. After removal of acetic anhydride under high vacuum, the intermediate tert-butyl 2-(3-acetamidophenyl)pyrrolidine-1-carboxylate (316 mg, 35% yield for 2 steps) was obtained by chromatography (EtOAc/hexanes=1/1). This intermediate (310 mg, 1.0 mmol) was stirred in EtOAc (1.0 mL) and 4.0 N HCl/dioxane (4.4 mL, 18 eq) at rt for 1.0 h. After removal of solvent, 4B was obtained as HCl salt. 1H NMR (400 MHz, Methanol-d4) δ ppm 2.14 (s, 3H) 2.24 (m, 3H) 2.48 (m, 1H) 3.45 (m, 2H) 4.61 (m, 1H) 7.22 (d, J=7.47 Hz, 1H) 7.40 (t, J=7.69 Hz, 1H) 7.49 (m, 1H) 7.84 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C1CCN2C(=NCCC2)CC1.CCCCCC.[C:30](OCC)(=[O:32])C>CO.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[CH3:12][S:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:32][CH3:30])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Nc1ccccc1Br
Reactant: CCOC(C)=O
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Solvent: CO
Product: COc1ccccc1NS(C)(=O)=O
Yield: 82 %

Procedure:
2.50 g of 2-bromo-1-methanesulfonylaminobenzene was added to a solution containing 1.52 g of DBU, 85 g of cupric chloride dihydrate, and 90 mg of 1,10-phenanthroline in 40 ml of methanol, and the mixture was heated under reflux for 5 hours. After the temperature was brought to room temperature, the reaction mixture was treated in a usual manner, and crystallization was effected from n-hexane/ethyl acetate, to produce 1.64 g (yield: 82%) of the desired compound.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](O)=[O:29])[N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O.C(#N)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][C:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:20])[F:21])=[CH:9][CH:8]=4)=[CH:11][CH:12]=3)[CH2:17]2)=[O:29])[N:23]=1
Reactant: O=C(O)c1cccnn1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC#N
Product: O=C(c1cccnn1)N1CCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a suspension of 7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 mgs, 0.16 mmol), pyridazine-3-carboxylic acid (30 mgs, 0.24 mmol), HATU (91 mgs, 0.24 mmol), in DMF (1.0 mL) was added NMM (0.05 mL, 0.48 mmol) and the resulting solution was stirred at 23° C. for 16 h. The reaction mixture was then diluted with water/acetonitrile (10:1) and the solid formed was then washed with water, diethylether and dried to give the title compound. MS found for C21H16F3N3O as (M+H)+ 384.1 1H NMR (400 MHz, dmso-d6): mixture of rotomers (˜1.5:1): major rotomer: δ 8.93 (m, 2H), 7.96-7.91 (m, 3H); 7.91-7.55 (m, 6H); 7.32 (m, 1H); 4.90 (s, 2H); 3.44-3.41 (m, 2H); 2.86-2.848 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][S:12](=[O:15])[CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[CH:18][CH:17]=2)[CH2:10]1)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].C1(C)C=CC=CC=1>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:11]2[S:12](=[O:15])[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CCN1CCS(=O)C(c2ccc(Oc3ccccc3Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)CCN1CCS(=O)C(c2ccc(Oc3ccccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{2-[4-(2-Chloro-phenoxy)-phenyl]-1-oxo-thiomorpholin-4-yl}-propionic acid tert-butyl ester (0.19 g; 0.42 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The resulting mixture was stirred, at RT, overnight'treated with toluene, and concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo to afford 3-{2-[4-(2-Chloro-phenoxy)-phenyl]-1-oxo-thiomorpholin-4-yl}-propionic acid trifluoroacetic acid salt as an oil (0.17 g). 1H NMR (400 MHz, DMSO-d6) □ ppm 2.83 (t, J=8 Hz, 2H), 2.92-3.13 (m, 1H), 3.21-3.34 (m, 2H), 3.34-3.44 (m, 2H), 3.44-3.61 (m, 2H), 3.86 (t, J=12 Hz, 1H), 4.44 (d, J=12 Hz, 1H), 7.04 (m, 2H), 7.23 (d, J=8 Hz, 1H), 7.33 (m, 1H), 7.40 (dd, J=8 and 2 Hz, 1H), 7.47 (m, 2H), 7.69 (dd, J=8 and 2 Hz, 1H), 11.00-13.00 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:17]=[CH:16][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:9]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:8]=2)[N:6]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:17]=[CH:16][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:9]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:8]=2)[N:6]=1)(=[O:29])[CH3:28]
Reactant: CS(=O)(=O)Nc1ccc(-c2csc(N)n2)cc1Oc1ccc(F)cc1F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)c(Oc3ccc(F)cc3F)c2)cs1

Procedure:
A solution of 4'-(2-amino-4-thiazolyl)-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.2 g) in acetic anhydride (3 ml) was stirred for 30 minutes at 80° C. The mixture was concentrated, and then evaporated with xylene and ethanol. The residue (1.4 g) was purified by column chromatography on silica gel (30 g) eluting with a mixture of toluene and ethyl acetate (1:1), and recrystallized from ethanol to afford pale brown crystals of 4'-(2-acetamido-4-thiazolyl)-2'-(2,4-difluorophenoxy)methanesulfonanilide (0.82 g).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20]([OH:34])([C:23]([NH:25][CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>ClCCl>[OH:34][C:20]1([C:23]([NH:25][CH:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27])=[O:24])[CH2:21][CH2:22][CH:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:18][CH2:19]1
Reactant: CC(NC(=O)C1(O)CCC(N)CC1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2cocn2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C1(O)CCC(NS(=O)(=O)c2ccc(-c3cocn3)cc2)CC1)c1ccccc1

Procedure:
4-Oxazol-4-yl-benzenesulfonyl chloride (Intermediate 26, 71.5 mg) was added to solution of 4-amino-1-hydroxy-N-(1-phenylethyl)cyclohexanecarboxamide (Intermediate 92, 70 mg) and diisopropylethylamine (0.103 ml) in dichloromethane (2.7 ml). After 16 hours the reaction was diluted with dichloromethane, rinse once using 1N hydrochloric acid followed by once using saturated aqueous sodium bicarbonate. The organics were dried over sodium sulfate, filtered and concentrate to 126 mg crude solid. The title compound was isolated by preparative basic reverse-phase chromatography to yield two isomeric samples of 1-hydroxy-4-(4-(oxazol-4-yl)phenylsulfonamido)-N-(1-phenylethyl)cyclohexanecarboxamide. Yield 4.5 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.Br[CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1.COC1C=CC(C2NC(C(N)=O)=C(C3C=CC(OC)=CC=3)N=2)=CC=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Agent: [Pd]
Agent: COc1ccc(-c2nc(-c3ccc(OC)cc3)c(C(N)=O)[nH]2)cc1
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CCNCC2)cc1

Procedure:
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide with benzyl 4-(bromomethyl)piperidine-1-carboxylate according to the procedure described in example S-1, step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 20° C., 0.05M in MeOH). NMR (DMSO) δ 1.30-1.50 (2H, m), 1.85 (2H, d), 1.90-2.10 (1H, m), 2.71-2.81 (2H, m), 3.21 (2H, d), 3.92 (2H, d), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 3.13 min; m/z (ES+) 414.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[NH2:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN>C1COCC1>[NH2:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:3][CH3:1])=[O:17]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(F)c1N
Reaction time: 18 h
Yield: 80.2 %

Procedure:
1,1′-Carbonyldiimidazole (1.946 g, 12.00 mmol) was added in one portion to 2-amino-3-fluorobenzoic acid (1.551 g, 10 mmol) in THF (25 mL) at room temperature and the resulting suspension stirred for 18 hours. A 2N solution of methylamine in THF (7.50 mL, 15.00 mmol) was added and the resulting solution stirred at room temperature for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (100 mL). The solution was washed sequentially with water (2×50 mL) and a saturated solution of NaCl (50 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was dissolved in EtOAc (100 mL) and the mixture washed sequentially with a 2M solution of NaOH (50 mL), water (50 mL), and then with a saturated solution of NaCl (50 mL). The organic layer was dried over MgSO4 and then evaporated to afford 2-amino-3-fluoro-N-methylbenzamide (1.349 g, 80% yield); 1H NMR spectrum: (300 MHz, CDCl3) δ 2.91 (3H, d), 5.52 (2H, s), 5.97 (1H, s), 6.49 (1H, td), 6.93-7.04 (2H, m); Mass spectrum: m/z (ESI+) (M+H)+ =169.34.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29]O)[C:22](=[O:28])[NH:23]2>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=1)[C:22](=[O:28])[NH:23]2
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Reactant: O=C1Nc2cccc(F)c2C1=CO
Product: O=C1Nc2cccc(F)c2C1=CNc1ccc(OCCCN2CCCCC2)cc1

Procedure:
In a manner similar to that described in Example 231, 4-(3-piperidin-1-yl-propoxy)-phenylamine (610 mg, 1.3 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (360 mg, 2 mmol, 1 equiv.) are converted to the named compound as a yellow solid (625 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14](I)[C:13]([Cl:17])=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(N(CC)CC)C.[Pd].[Cu]I>[Cl:1][C:2]1[CH:15]=[C:14]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Cl:17])=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: CCN(CC)CCOc1cc(Cl)c(I)cc1Cl
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1cc(Cl)c(C#Cc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.9 %

Procedure:
To a solution of 19.4 g (0.05 mole) of 1-(2,5-dichloro-4-iodophenoxy)-2-diethylaminoethane and 5.2 g (0.053 mole) of phenylacetylene in 250 ml of triethylamine are added, under nitrogen, 200 mg of the palladium complex PdCl2 [P(C6H5)3 ]2 and 100 mg of copper(I) iodide. After the weakly exothermic reaction has subsided, the reaction mixture is stirred for 15 hours at room temperature, then concentrated, and the residue is taken up in water. After extraction with 200 ml of ether, the combined ethereal phases are washed 4 times with water, dried and evaporated to dryness. The crude product is chromatographed on silica gel, affording 14.3 g (79%) of 1-(2,5-dichloro-4-phenylethynylphenoxy)-2-diethylaminoethane with a refractive index of nD25 :1.6173.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1.C(O)(C(F)(F)F)=O.[I:24]N1C(=O)CCC1=O.[NH4+].[OH-]>C(O)(=O)C>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([I:24])[C:8](=[O:11])[NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1ccc(Cc2ccc(F)cc2F)c[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cc(Cc2ccc(F)cc2F)cc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2,4-difluorobenzyl)pyridin-2(1H)-one 3 (1.89 g, 8.5 mmol) in acetic acid (34 ml) was added TFA (2.2 ml), followed by N-iodosuccinimide (2.02 g, 8.5 mmol). The red homogeneous solution was allowed to stir overnight at room temperature, poured onto ice and neutralized with cone. NH4OH. The solid was collected by filtration, rinsed with water, treated with methanol/dichloromethane, dried over sodium sulfate, and evaporated. The resulting brown solid was purified by flash column chromatography on silica gel (hexanes:ethyl acetate, 50:50). Yield 2.57 g (87%). 1H NMR (CDCl3, 500 MHz): δ 13.20 (s, 1H), 7.98 (d, 1H, J=2.2 Hz), 7.26-6.81 (m, 4H), 3.70 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 162.5, 161.9, 160.5, 151.9, 133.5, 131.2, 121.8, 120.0, 111.6, 104.3, 91.6, 29.9.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl>[CH2:1]([NH:4][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of propargylamine and triethylamine (1.3 eq.) in DCM (3 M) at 0° C., it was added dropwise a solution of benzyl chloroformate (1.1 eq.) in DCM (5 M). The reaction mixture was stirred at RT for 2 h. After evaporation of the solvent the resulting residue was purified by flash column chromatography on silica (EtOAc/Petroleum ether 1:10) to yield (56%) the title compound. 1H NMR (300 MHz, CDCl3, 300K) δ 7.3 (5H, s), 5.29 (2H, s), 5.0 (1H, bs), 3.85 (2H, d, J=3.3 Hz), 2.21 (1H, m). MS (ES+) C11H11NO2 requires: 189, found: 190 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:17][C:16]3[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([OH:19])[C:11]=3[C:9](=[O:10])[CH2:8]2)=[CH:5][CH:6]=1.Cl.O.CO>CN(C=O)C.[Pd]>[CH2:8]1[C:9](=[O:10])[C:11]2[C:16](=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[OH:19])[O:17][CH:7]1[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C1C[C@@H](c2ccccc2)Oc2cc(O)cc(O)c21
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1CC(c2ccccc2)Oc2cc(O)cc(O)c21
Yield: 92 %

Procedure:
4.4 g of the benzyl protected pinocembrin in R-configuration obtained in Example 3 was dissolved in 100 ml of DMF, 20 ml of 10% aqueous HCl and 3.5 g of 10% Pd—C with a water content of 62.9% were added, and then a hydrogenation at normal pressure was performed. The reaction was monitored by TLC until completion (about 5 h). Then stopped stirring, the reaction mixture was filtered and extracted with ethyl acetate and water. The organic phase was collected, evaporated to remove solvent, and recrystallized with 95% ethanol to give a white solid of (S)-pinocembrin (3.0 g, yield 92%) with specific rotation [α]D20=−45.63° (c=0.515, methanol), and e.e %>99.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]2[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH:8]=1.Cl.O.[OH-].[Na+]>COCCO.O1CCOCC1>[Cl:20][C:19]1[CH:18]=[N:17][C:16]2[NH:1][C:2]3[CH:24]=[CH:23][CH:22]=[C:4]([CH:3]=3)[CH2:5][NH:6][C:7]3[CH:8]=[C:9]([NH:13][C:14]=1[N:15]=2)[CH:10]=[CH:11][CH:12]=3
Reactant: Nc1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Solvent: C1COCCO1
Product: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Yield: 10.2 %

Procedure:
To a solution of N-(3-aminobenzyl)-N′-(2,5-dichloropyrimidin-4-yl)benzene-1,3-diamine (900 mg, 2.0 mmol) in 2-methoxyethanol (18 mL) was added 4.00 M of hydrogen chloride in 1,4-dioxane (1.88 mL). The resultant mixture was heated at 150° C. in the microwave for 5 min. After cooling, water and NaOH (12 N) were added to neutralize the mixture to pH=7. The aqueous layer was extracted with EtOAc four times. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (66 mg, 8%). LCMS for C17H15ClN5 (M+H)+: m/z=324.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I.CCOC(C)=O.O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(O)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 90 °C

Procedure:
A mixture of 4-bromobiphenyl (1.16 g, 5 mmol), 4-methoxyphenol (413 mg, 3.33 mmol), Cs2CO3 (2.17 g, 6.66 mmol) in anhydrous dioxane (10 mL) was purged with nitrogen for 10 min. Then copper (I) iodide (18 mg, .096 mmol) and N,N-dimethylglycine.HCl (41 mg, 0.29 mmol) were added. Reaction was stirred at 90° C. over night. Reaction mixture was cooled and poured over 1:1 mixture of EtOAc/water. Organic layer was separated, washed with water, brine, dried over anhydrous MgSO4 and concentrated to give the crude product. It was used in next step without purification (1.26 g, 91%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:7]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Cl)=O>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:24]([CH2:23][Cl:22])=[N:14][N:13]=[C:11]3[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:7]=2[CH:21]=1
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCC(NN)=N2
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: CSc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(CCl)n1-2

Procedure:
According to the procedure of Preparation 2, 7-methylthio-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with chloroacetyl chloride in acetic acid to give 8-methylthio-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(OCC)(=O)C=C.O[CH:9]([CH2:15][CH:16](O)[CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)CC>[C:10]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:9]=[CH:15]/[CH:16]=[CH:17]/[CH3:18]
Reactant: CCOC(=O)C(O)CC(O)CC
Agent: C=CC(=O)OCC
Solvent: CCCO
Product: C/C=C/C=C/C(=O)OCC

Procedure:
For example, when n-propyl alcohol is allowed to react with ethyl acrylate, ethyl 2,4-dihydroxyhexanoate corresponding to Formula (4) and 4-ethyl-2-hydroxy-65-butyrolactone corresponding to Formula (6) are formed in addition to the target ethyl sorbate under some conditions.