Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].N1C=CC=CC=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1c(F)cc(Br)cc1F
Yield: 83.6 %

Procedure:
252 g (1.95 mol) of 2,6-difluoroaniline and 170 g (2.15 mol) of anhydrous pyridine were dissolved in 780 cm3 of chloroform, and a solution of 328 g (2.05 mol) of bromine dissolved in 390 cm3 of chloroform was added dropwise for 2 hours on an ice water bath while stirring, after which it was stirred for 2 hours at room temperature. After washing the reaction solution with water, the chloroform was removed, the residue was distilled under reduced pressure (b. p. 100° C./30 mmHg), and the crystals obtained were recrystallized from hexane to obtain 340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-n2cccn2)cc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-n2cccn2)cc1O

Procedure:
A trifluoroacetic acid (5 mL) solution of the obtained tert-butyl 2-(2-hydroxy-4-(1H-pyrazol-1-yl)benzamido)-4-phenylbenzoate was stirred at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure, and methanol was added to the obtained residue. The solid substance was collected by filtration to obtain 0.056 g of 2-(2-hydroxy-4-(1H-pyrazol-1-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:25]
Reactant: CSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled (ice/water) solution of 5.21 g. of 2-methylthio-4,5-diphenyl-oxazole pre-dissolved in 50 ml. of chloroform is added in portions over 5 minutes, 4.35 g. of m-chloro-peroxybenzoic acid dissolved in 50 ml. of chloroform. After stirring the reaction mixture for 20 minutes, the ice/water bath is removed and the reaction mixture stirred at room temperature for an additional 60 minutes. The precipitated m-chloro-benzoic acid is filtered off, washed with chloroform and the combined chloroform solution is washed with a 10% solution of sodium carbonate, dried, evaporated in vacuo to dryness, and the residue recrystallized from benzene/ligroin to yield 2-methylsulfinyl-4,5-diphenyl-oxazole, m.p. 75°-78° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[N:29]1[N:30]([CH2:38][C:39](O)=[O:40])[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12>>[N:29]1[N:30]([CH2:38][C:39]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([C@@H:19]([CH3:28])[CH2:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[CH:11]=3)=[O:9])[CH:3]=2)=[O:40])[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12
Reactant: O=C(O)Cn1nc2ccccc2n1
Reactant: C[C@@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: C[C@@H](COC1CCCCO1)n1cc(C(=O)c2cncc(NC(=O)Cn3nc4ccccc4n3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 1 using (5-aminopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (see Preparation 33) and benzotriazol-2-yl-acetic acid to afford the title compound as a yellow solid in 72% yield, 70 mg.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH:15][C:16]1[C:24]([CH:25]=[O:26])=[CH:23][C:19]2[CH2:20][CH2:21][O:22][C:18]=2[C:17]=1[O:27][CH3:28]>O1CCOCC1>[OH:15][C:16]1[C:24]([CH:25]=[O:26])=[CH:23][C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]=1[O:27][CH3:28]
Reactant: COc1c(O)c(C=O)cc2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1c(O)c(C=O)cc2ccoc12

Procedure:
A solution of 817 mg. (3.6 mmole) of DDQ in 10 ml. of dioxane was added to 582 mg. (3 mmole) of 2,3-dihydro-6-hydroxy-7-methoxy-5-benzofuran-carboxaldehyde in 15 ml. of dioxane and the resulting mixture was heated under reflux for 7 hours, cooled and the formed solid removed by filtration. The precipitate was thoroughly washed first with benzene, then with CHCl3. The washings were combined with the initial filtrate and the total concentrated in vacuo to a residue which was chromatographed first on a 20 ml. dry silica gel column (E. Merck 7734) with CHCl3 elution followed by conventional chromatography over 20 g. of silica (E. Merck 7734) packed in benzene-ethyl acetate (95:5) and elution with this solvent mixture provided, after workup, a yellow solid, m.p. 60°-62°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]=[O:28].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]=[O:28]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccccc4c3C=O)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-naphthoaldehyde (231 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (24 mg, yield 15%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].C(N(CC)CC)C.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][S:22]([N:21]([CH3:26])[CH3:20])(=[O:24])=[O:23]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NCC1COc2ccccc2O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCC1COc2ccccc2O1
Reaction time: 3 h

Procedure:
Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL) and cooled in an ice bath as dimethylsulfamoyl chloride (1.44 g, 10 mmol) was added. The reaction mixture was then stirred for 3 hr with continued cooling. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate solution was washed with brine, dried (MgSO4) and evaporated in vacuo to yield an oil. The oil was purified using flash column chromatography (ethyl acetate:Heptane—1:1) to yield a white solid, which was recrystallized (ethyl acetate/Hexane) to yield the title compound as a white floccular solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].C(O)C.[OH-].[Na+]>O.[Zn]>[CH3:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(N)c1C
Reaction time: 0.5 h

Procedure:
To a 125 mL round bottom flask 2.20 g of 2,3-dimethyl-6-nitro-aniline (13.2 mmol) was added. Then 15 mL of ethanol was added to the flask followed by the addition of 4 mL of 20 wt % NaOH in water. Then 2.0 g of zinc dust was added to the flask. The flask was fitted with a condenser and was left to reflux with stirring. After about 0.5 hours the mixture became very pale-brown. After refluxing for 18 hours the mixture was filtered hot to give a pale filtrate which quickly became dark red. C8H12N2, fw=136.19. Yield 1.78 g, 98.7%. Mp: 60° C. (melt). 1H NMR (300 MHz, CDCl3): δ 6.54 (s, 2H), 3.46 (br s, 2H), 3.21 (br s, 2H), 2.22 (s, 3H), 2.11 (s, 3H). Rf=0.68 (ethyl acetate/silica).
Reaction SMILES: [C:1]1([C:7]2([CH2:14][NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:17])[CH2:12][CH2:11][C:10](=[CH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.[Pd]>[CH3:13][CH:10]1[CH2:11][CH2:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:17])[CH2:8][CH2:9]1
Reactant: C=C1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C)CC1
Reaction time: 2.5 h

Procedure:
A mixture of 1-phenyl-1-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-4-methylidenecyclohexane (Example 165, 38 mg, 0.11 mmol) and Pd/C (10%, 16.7 mg) in 15 mL of EtOAc was shaken under 50 psi of H2 for 2.5 h. The mixture was filtered through a plug of celite, concentrated and the residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 2.0/8.9 mL/min) to afford the two isomers of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14](=[O:15])[C:13]2[N:12]=[C:11]([CH:16]=O)[CH:10]=[CH:9][C:8]=2[C:7](=[O:18])[CH:6]=1)(=[O:3])[CH3:2].[CH2:19]([O:24][C:25](=[O:38])[C@H:26]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:27])[CH2:20][CH:21]([CH3:23])[CH3:22]>C1(C)C(C)=CC=CC=1>[CH3:23][CH:21]([CH2:20][CH2:19][O:24][C:25]([C:26]1[CH:28]=[C:29]2[C:30](=[C:16]([C:11]3[CH:10]=[CH:9][C:8]4[C:7](=[O:18])[CH:6]=[C:5]([NH:4][C:1]([CH3:2])=[O:3])[C:14](=[O:15])[C:13]=4[N:12]=3)[N:27]=1)[NH:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:37]2=1)=[O:38])[CH3:22]
Reactant: CC(C)CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Solvent: Cc1ccccc1C
Product: CC(=O)NC1=CC(=O)c2ccc(-c3nc(C(=O)OCCC(C)C)cc4c3[nH]c3ccccc34)nc2C1=O
Yield: 429 %

Procedure:
7-Acetamido-2-formylquinoline-5,8-dione (23) (prepared as described in Example 23) (244 mg, 0.1 mmol), L-tryptophan isoamyl ester (37) (prepared as described in Example 37) (239 mg, 1 mmol) and xylene (64 ml) were mixed. The mixture was stirred and slowly heated in an oil bath from room temperature to 110° C. over a one-hour period, and then from 110° C. to 140° C. over a 3-hr period. The hot reaction mixture was filtered to remove the brown impurity. The filtrate was evaporated under vacuum. The residue was treated with ethylacetate/hexane to give an orange solid (213 mg, 42% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=2)[N:10]=1
Reactant: COc1cc2[nH]c(=O)ccc2cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2nc(Cl)ccc2cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 7-methoxy-6-nitro-1H-quinolin-2-one (0.13 g) and phosphorus oxychloride (1 mL) was heated at 110° C. for 2 hours. The resulting mixture was then cooled and poured into ice. The solid which formed was collected by filtration and dried under vacuum to afford 0.119 g of 2-chloro-7-methoxy-6-nitro-quinoline as a brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-:26]>C1COCC1.O>[C:18]([O:17][C:15]([NH:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:11][C:12]([CH3:24])([CH3:23])[C:13]([OH:26])=[O:22])=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution (S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-3,3-dimethyl-2-oxopyrrolidine-1-carboxylate (2.7 g, 7.56 mmol) in THF (27 mL) and water (3 mL) was added LiOH (1 N, 15.2 mL, 15.2 mmol). The reaction mixture was stirred at RT overnight and concentrated. The residue was dissolved in water (20 mL), acidified with 10% citric acid to pH 6-7, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanoic acid (2.6 g, 91.7%), which was used without further purification. LRMS (M-Boc+H+) m/z 276.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[CH2:13]([O:12][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1)[CH3:14]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-chloro-2-methyl-3-nitropyridine (2.15 g) in ethanol (25 mL) was added sodium ethoxide (4.88 mL) solution at room temperature. The reaction mixture immediately turned dark purple and was refluxed for 2 hours. The reaction mixture was allowed to cool down to room temperature, concentrated in vacuo, and poured into ice. The precipitated solids were collected by filtration to provide the title compound (1.88 g) having the following physical data.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:31]([OH:46])[CH2:32][C@H:33]([C:35](=[O:45])[NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[CH3:34])[CH2:10][C@@H:11]([CH:28](C)C)[CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=O)(C)(C)C.[ClH:47]>O1CCOCC1>[ClH:47].[ClH:47].[NH2:8][C@H:9]([C@@H:31]([OH:46])[CH2:32][C@H:33]([C:35](=[O:45])[NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[CH3:34])[CH2:10][C@H:11]([CH3:28])[CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCN1CCOCC1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C)C[C@H](N)[C@@H](O)C[C@@H](C)C(=O)NCCN1CCOCC1

Procedure:
A solution of (2S,4S,5S,7R)-N-{4-(tert-butoxycarbonyl)amino-5-hydroxy-2-isopropyl-7-[(2-morpholin-4-ylethyl)-carbamoyl]-octyl}-2-(3-methoxypropoxy)-benzamide (105 mg) in 4N hydrochloric acid solution in dioxane (4 ml) is stirred at 0° C. for one hour. The reaction mixture is then lyophilised. (2S,4S,5S,7R)-N-[4-Amino-5-hydroxy-2-methyl-7-[(2-morpholin-4-ylethyl)-carbamoyl]-octyl}-2-(3-methoxypropoxy)-benzamide dihydrochloride is obtained in the form of a beige powder: Rf (dichloromethane-methanol 8:2)=0.28. HPLC Rt =7.73 min. MS(FAB) m/e 551 (M+ +1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1.[Na+].[Cl-]>[CH2:18]([O:17][C:15]([N:12]=[S:10]([CH3:13])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:11])=[O:16])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8.50 g (42.5 mmol) of (RS)—S-(4-nitrophenyl)-S-methyl sulfoximide in 400 ml of pyridine is mixed drop by drop at room temperature with 18.8 ml (197.2 mmol) of ethyl chloroformate. The batch is stirred for 4 hours at room temperature and then added in dilute NaCl solution. It is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1). 8.94 g (32.8 mmol, corresponding to 77% of theory) of the product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[CH3:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Product: CNC(=O)C=Cc1ccc(OCc2ccc(C)cc2)cc1
Yield: 44 %

Procedure:
The title compound is prepared in analogy to example 11 b) from 3-(4-hydroxy-phenyl)-N-methyl-acrylamide and 1-bromomethyl-4-methyl-benzene. Yield=44%.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])(=O)C>CCO>[OH:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
Sodium hydroxide (5M; 12.1 mL; 60.3 mmol; 3 eq.) was added to a solution of methyl 2-[(acetyloxy)methyl]-2′-methylbiphenyl-4-carboxylate (6 g; 20 mmol; 1 eq.) in EtOH (180 mL) and the reaction mixture was stirred at 60° C. for 2 hours. After concentration in vacuo, the residue was taken up in water (500 mL) and washed with EtOAc (2×100 mL). The aqueous phase was acidified to pH 2 with conc. HCl and extracted with EtOAc (2×100 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow solid (3.46 g, 71%). 1H NMR (DMSO-d6, 300 MHz) δ 12.97 (br s, 1H), 8.20-8.19 (m, 1H), 7.87-7.84 (dd, J=8.0 Hz, 1.86 Hz, 1H), 7.37-7.06 (m, 5H), 5.23-5.19 (m, 1H), 4.25-4.09 (m, 2H), 2.01 (s, 3H). LC/MS (Method A): 241.2 (M−H)−. HPLC (Method A) Rt 3.77 min (purity 96.1%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3]C(C)(C)C)=[O:2].C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([OH:3])=[O:2])[CH2:13][CH2:12]1)=[O:28]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 1-Boc-piperazine (0.50 g, 2.7 mmol) and diisopropylethylamine (1.75 g, 13.5 mmol) in dichloromethane at 0° C. was added a solution of 2-trifluoromethylbenzoyl chloride (0.626 g, 3.0 mmol). The resulting mixture was stirred at room temperature for 20 h and then quenched with water (25 mL). The organic phase was washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tent-butyl ester as a pale brown oil (0.948 g, 98% yield). 1H NMR (300 MHz, CDCl3) δ 7.69, 7.54, 7.30, 3.77, 3.51, 3.33, 3.14, 1.45.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: Nc1ccc(F)cc1F
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 46.4 %

Procedure:
A mixture of 3-chloro-4-nitrobenzonitrile (5 g), 2,4-difluoroaniline (17.7 g), cupric oxide (0.5 g) and potassium carbonate (4.5 g) was stirred for 5 hours at 200° C. To the mixture were added water (100 ml) and ethyl acetate (200 ml). The organic layer was separated, washed with 3N hydrochloric acid and water, dried, and evaporated to dryness. The oil (10 g) was purified by column chromatography on silica gel (200 g) eluting with toluene to give red crystals of 3-(2,4-difluorophenylamino)-4-nitrobenzonitrile (3.5 g).
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH:34][C:42](=[O:44])[CH3:43])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
(2S)-2-(N,N-dibenzylamino)-5-amino-1,6-diphenyl-4-hexene-3-one (100.0 g, 214.1 mmol) was dissolved in toluene (500 ml), to which pyridine (10 ml, 124.3 mmol) was added under a nitrogen stream. Acetyl chloride (25.7 g, 321.1 mmol) was slowly added to the resultant mixture while chilling with ice water so as not to raise the temperature above 10° C. The reaction mixture was further stirred at 50° C. for 5 hours and 25° C. for 16 hours. The mixture was then washed twice with a small amount of a 10% aqueous solution of sodium carbonate and with an aqueous sodium chloride, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from methanol (1000 ml), thereby obtaining the title compound (97.5 g, 89.4%) as pale yellow crystals.