Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[C:3]=1[F:16].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[C:3]=1[F:16]
Reactant: CN1CCc2[nH]c3ccc(Cl)c(F)c3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3c(F)c(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-9-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[CH:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[C:16][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nccc(C#Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
Into a 250 mL round-bottomed flask was charged 1-(benzyloxy)-4-ethynylbenzene (2.0540 g, 9.86 mmol) and tetrahydrofuran (49.3 ml). 2,4-Dichloropyrimidine (1.469 g, 9.86 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.346 g, 0.493 mmol), copper(I) iodide (0.033 ml, 0.986 mmol), and triethylamine (4.12 ml, 29.6 mmol) were added. The reaction was heated to 45° C. overnight. Silica gel (approx. 15 g) was added, and the reaction concentrated. The reaction was purified by flash chromatography (10% ethyl acetate:hexanes for 10 minutes, then to 30% ethyl acetate:hexanes over 30 minutes, then to 50% ethyl acetate in hexanes over 5 minutes, then to 100% ethyl acetate over 5 minutes.) to provide the title compound. MS (ESI) m/e 321 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21]C=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:31]([CH3:34])[CH:32]=[O:33])C=CC=CC=1.[C:47]1(C)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[C:4]=1[CH2:21][CH:47]=[C:31]([CH3:34])[CH:32]=[O:33]
Reactant: Cc1ccccc1
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Yield: 83 %

Procedure:
[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde (70 mg, 0.21 mmol) in toluene (2 mL) was heated at 100° C. with 2-(triphenyl-phosphanylidene)-propionaldehyde (72.9 mg, 0.23 mmol) overnight. A second portion of 2-(triphenyl-phosphanylidene)-propionaldehyde (33 mg, 0.11 mmol) was added and the reaction mixture was heated for an additional day. After concentration, the residue was purified by silica gel chromatography to provide 54 mg (83%) of the desired product as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (S, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16 (s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][C:9]=1O)([O-:3])=[O:2].CC[N:18]([CH2:21][CH3:22])CC.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CCOC(C)=O.CCCCC>[CH2:38]([NH:45][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([NH:18][CH2:21][C:22]2[CH:4]=[CH:9][CH:8]=[CH:7][CH:11]=2)[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCN(CC)CC
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(O)cc(C(F)(F)F)nc1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 160.3 %

Procedure:
A second batch of 3-Nitro-6-trifluoromethyl-pyridine-2,4-diol (11.06 g, 49.4 mmol) was dissolved in DCM (100 mL) and Et3N (13.8 ml, 98.7 mmol) was added. The mixture was cooled to 0° C. and Tf2O (16.2 ml, 98.7 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in THF (100 ml). BnNH2 (16.2 ml, 148 mmol) was added and the mixture was stirred at 50° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with water (100 ml) and extracted with EtOAc (200 ml). The extract was washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give the crude (53 g). The two crudes were combined. Column chromatography through silica eluting with 95:5→90:10 Pentane:EtOAc gave the title compound (15.93 g) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C@:11]1([CH3:32])[C@H:16]([CH2:17][CH2:18][OH:19])[S:15](=[O:21])(=[O:20])[C:14]([CH3:23])([CH3:22])[C:13]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:12]1.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH3:23][C:14]1([CH3:22])[S:15](=[O:20])(=[O:21])[CH:16]2[CH2:17][CH2:18][O:19][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[C@@:11]2([CH3:32])[N:12]=[C:13]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)[C@H](CCO)S(=O)(=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
A solution of crude tert-butyl ((5R,6S)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (250 mg, 0.528 mmol) in THF (5 ml) and DMF (0.5 ml) was treated portionwise with NaH (60% suspension in mineral oil) (52.8 mg, 1.320 mmol). After initial gas evolution the reaction mixture became dark red. The mixture was stirred at RT for 10 min. The mixture was quenched with NH4Cl solution and diluted with EtOAc. Water was added to dissolve solids, and the organic layer was separated, washed with brine and concentrated. The residue was purified by FC on 12 g RedSep Gold column using 10-100% EtOAc in heptane. All the fractions containing both epimers were combined and concentrated to afford tert-butyl ((11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (196 mg, 0.432 mmol, 82% yield) as a mixture of epimers at C4. Ratio by NMR 2:1 favoring trans-isomer.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[CH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:4]2[N:3]=1.O.[NH2:24][NH2:25].[CH2:26](O)[CH3:27]>>[CH3:19][C:18]1[CH:17]=[C:16]([CH:4]=[CH:26][CH:27]=1)[CH:15]=[N:24][NH:25][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[CH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:4]2[N:3]=1
Reactant: Clc1cc(N2CCOCC2)n2ncc(-c3ccccc3)c2n1
Reactant: CCO
Reactant: NN
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3ncc(-c4ccccc4)c3n2)c1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-7-morpholin-4-yl-3-phenyl-pyrazolo[1,5-a]pyrimidine (42.1 mg, 0.134 mM) and then hydrazine monohydrate (65.0 μL, 1.34 mM) was added to the suspension. This suspension was stirred at 150° C. for 20 minutes under the irradiation with microwaves, the solvent was then distilled off, the resulting residue was diluted with a saturated aqueous common salt solution and extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, and the solvent was then distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (2.0 μL, 0.035 mM) and 3-methyl-benzaldehyde (15.8 μL, 0.134 mM) were added to the suspension and the mixture was stirred at room temperature for 2 hours and a half.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]([N:14]1[CH:19]=[CH:18][C:17](=[O:20])[CH2:16][CH:15]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:13].[OH:28]OS([O-])=O.[K+].[OH2:34]>CO.C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([CH3:10])(=[O:28])=[O:34])=[CH:4][C:3]=1[NH:11][C:12]([N:14]1[CH:19]=[CH:18][C:17](=[O:20])[CH2:16][CH:15]1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)=[O:13]
Reactant: O
Reactant: CSc1cc(NC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(Br)cc1Cl
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CS(=O)(=O)c1cc(NC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4-chloro-5-methylsulfanyl-phenyl)-amide (0.050 g, 0.106 mmol) in methanol (2 ml) and acetonitrile (2 ml) was added oxone (0.131 g, 0.213 mmol) and water (0.3 ml). The mixture was stirred at room temperature for two hours. Water was added and the mixture was extracted with EtOAc. The organic extract was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (EtOAc) gave 2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4-chloro-5-methanesulfonyl-phenyl)-amide (0.009 g) as a white foam. MS (M+H) 502.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([NH:36][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:17]=3[Cl:24])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCC1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a solution of 5-(2,6-Dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfonyl chloride (1.3 grams, 3.2 mmol) in methylene chloride (30 mL) at 0° C. was added triethylamine (0.58 mL, 4.1 mmol) followed by cyclobutylamine (0.27 mL, 3.2 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with 1N hydrochloric acid (25 mL) and extracted with methylene chloride (3 times 15 mL). The combined organic extracts were washed with 1N HCl (20 mL), saturated aqueous NaHCO3 (2 times 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (30% ethyl acetate in hexane) to afford the title compound (531 mg). 1H NMR (400 MHz, CDCl3) δ8.28 (s, 2H), 7.28 (d, 1H), 7.07-7.04 (dd, 1H), 6.98 (d, 1H), 5.26 (d, 1H), 3.96 (s, 3H), 3.71-3.69 (m, 1H), 1.99-1.92 (m, 2H), 1.74-1.68 (m, 2H), 1.57-1.48 (m, 2H). MS (APCI−) Calc: 446.1, Found: 445.2 (M−1).
Reaction SMILES: I[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([F:16])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[C@H:5]([OH:17])[C@@H:4]1[OH:18].C(NC(C)C)(C)C>C(O)C.C(O)(C)C.[Pd]>[F:16][C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:6]1[O:7][C@H:3]([CH3:2])[C@@H:4]([OH:18])[C@H:5]1[OH:17]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F
Agent: [Pd]
Solvent: CC(C)NC(C)C
Solvent: CCO
Solvent: CC(C)O
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reaction time: 14 h
Yield: 89 %

Procedure:
To a suspension of 20 g (0.053 m) of 5′-deoxy-5′-iodo-5-fluoro uridine in a mixture of 60 ml of ethanol and 40 ml of isopropanol, 15.2 ml (0.108 m) of diisopropylamine are added, then 3 g of 5% Pd/C are added thereinto and the mixture is hydrogenated at about 1-bar pressure for 14 hours. After removal of the catalyst by filtration, the solution is concentrated under vacuum until a solid residue is obtained, which is crystallized with a mixture ethanol/isopropanol=60/40 v/v; after 8 hours the product is filtered, washed with said mixture and dried at 45° C. for 15 hours. Thus, 11,6 g (yield—89% of the theoretical) of 5′-deoxy-5-fluorouridine M.p.=187÷188° C., puritya (HPLC)=99,75% and [α]D=+18.2° (c=0.42, H2O).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6](/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])/[C:9]#[N:10])=O)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH:30]([F:32])[F:31])=[CH:27][C:28]#[N:29].C(O)(=O)C>CC(O)C>[F:31][CH:30]([F:32])[C:26]1[NH:25][C:6]([C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[C:8]([C:9]#[N:10])[CH:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])[C:27]=1[C:28]#[N:29]
Reactant: N#CC=C(N)C(F)F
Reactant: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(F)cc3)cc12
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(c4ccc(F)cc4)NC(C(F)F)=C3C#N)cc12
Reaction time: 6 h

Procedure:
A mixture of 200 mg (0.569 mmol) (2E)-2-(4-fluorobenzoyl)-3-(6-fluoro-3-methyl-1H-indazol-5-yl)-prop-2-enenitrile (Example 5A) and 69 mg (0.569 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Then, acetic acid (1.5 ml) was added, and stirring at reflux was continued for 6 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 80:20 v/v) to yield 36 mg (15% of th.) of the racemic title compound.
Reaction SMILES: [C:1]([C:3](=[C:9](OC)[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH3:17]>C1COCC1>[NH2:17]/[C:9](/[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[C:3](/[C:1]#[N:2])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N
Reactant: CCOC(=O)C(C#N)=C(OC)C(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C(C#N)=C(\N)C(CC)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 10° C., 52 g (0.23 mol) of ethyl 2-cyano-3-methoxy-4-ethyl-2-hexenoate were initially charged in THF, and 20 g (0.3 mol) of 25% strength ammonia solution were added. After 2 h of stirring at 25° C., the solution was concentrated, the residue was taken up in n-hexane/diisopropyl ether (1:1) and the precipitate was filtered off with suction.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH2:22][CH3:23])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43](Cl)=[O:44].O>ClCCl>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH2:22][CH3:23])=[CH:24][CH:25]=1)=[O:44]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cn1c(CC)c(Cc2ccc(N)cc2)c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(CC)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-ethyl-1H-indol-1-yl]acetate (288 mg, 0.86 mmol) was added, and dissolved in 7 mL dichloromethane. Triethylamine (0.36 mL, 2.59 mmol) was added, in an ice bath a dichloromethane solution 2 mL dissolving 2-naphthoyl chloride (163 mg, 0.86 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 1 h, and stirred at room temperature overnight. Water was added into the system, extracted with dichloromethane, rotate evaporated to dryness to obtain a crude. It was washed again with a small amount of acetonitrile to obtain the yellow product 340 mg, at a yield of 80.2%.
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[Cl:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[C:28]([F:29])([F:30])[F:31])[O:27][CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 167 mg, 0.47 mmol) in dimethylsulfoxide (2 mL) was added 2-chloro-4-hydroxybenzotrifluoride (92 mg, 0.47 mmol) followed by addition of potassium carbonate (129 mg, 0.94 mmol). The reaction was left to stir at room temperature for 18 hours. The reaction was diluted with dichloromethane (20 mL) and washed with aqueous potassium hydrogen sulfate (5 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (30 mL) and filtered through a phase separation cartridge. The solvent was removed under reduced pressure and the crude product purified by reverse phase preparative HPLC. The correct fractions were combined and reduced to dryness to afford the title compound as white solid (23 mg, 10%).
Reaction SMILES: ClC(Cl)(Cl)[S:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]C(Cl)(Cl)Cl)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.ClC(Cl)C>C(O)C>[SH:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(SC(Cl)(Cl)Cl)cc1)c1ccc(SC(Cl)(Cl)Cl)cc1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(S)cc1)c1ccc(S)cc1
Reaction time: 6 h

Procedure:
10 g said 4,4′-di(trichloro methyl sulfenyl)benzophenone obtained in step 2, 30 g dichloroethane and 10 g ethanol are added into a 100 ml reaction flask. The solution is heated to react under reflux with nitrogen protection, and is cooled after reacting for 6 hours to precipitate solids. Filtering, and washing with ethanol to obtain 4.4 g white flake crystals, the yield is 85%, and the melting point is 179-182.3° C. 1H-NMR data (solvent CDCl3): δ3.6369 ppm, s, 2H; δ7.3168, 7.3435 ppm, d, 4H; δ7.6384, 7.6650 ppm, d, 4H.
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].C1(=O)O[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>C(OC(C)C)(=O)C.O>[OH:15][CH2:16][CH2:17][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: O=C1OCCO1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: O=Cc1cccc(OCCO)c1

Procedure:
To a 5 L flask equipped with an internal temperature probe and a mechanical stirrer was added dimethyl sulfoxide (500 mL), 3-hydroxybenzaldehyde (100.0 g, 0.819 mol), ethylene carbonate (108 g, 1.23 mol), and potassium carbonate (136 g, 0.983 mol). The resulting mixture was stirred at 110 to 125° C. until all 3-hydroxybenzaldehyde starting material was consumed. (Additional portions of ethylene carbonate may be added to drive the reaction to completion). The reaction mixture was then cooled to below 25° C. and diluted with isopropyl acetate (1.0 L) and water (1.5 L). The mixture was stirred until the residual potassium carbonate was completely dissolved. The layers were separated and the organic layer was washed with an additional portion of water (1.5 L). Additional isopropyl acetate was added (1.0 L), and then distilled off to leave a final volume of ˜1 L of dry organic solution of 3-(2-hydroxyethoxy)benzaldehyde.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:15](P(C(C)(C)C)C(C)(C)C)(C)([CH3:17])[CH3:16].C#CC>O1CCOCC1.CCOC(C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:16]([C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1)#[C:15][CH3:17]
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Agent: Cl[Pd]Cl
Agent: C#CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: N#Cc1ccccc1
Product: CC#Cc1coc2ccc(C(=O)OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 226 %

Procedure:
Methyl 3-bromobenzofuran-5-carboxylate (750 mg, 2.94 mmol) is combined with bis(benzonitrile)palladium dichloride (169 mg, 0.44 mmol), cuprous iodide (19 mg, 0.10 mmol), tri-t-butylphosphine ((10% in hexane) 1.92 ml, 0.95 mmol), and propyne (2 ml, 35 mmol) in 7 ml dry dioxane in 15 ml screw cap pressure tube under nitrogen. The mixture is treated with DIA (494 μL, 3.6 mmol), is stirred overnight at RT, and is diluted with 50 ml EtOAc. The reaction is washed with 4×25 ml 1:1:0.1 H2O/brine/conc. NH4OH, the organic layer is dried (MgSO4), and the volatiles are removed in vacuo. The crude material is chromatographed over 50 g silica gel (230-400 mesh) eluting with 12% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 460 mg (73%) of methyl 3-prop-1-ynyl-1-benzofuran-5-carboxylate as a pale solid. MS for C13H10O3 (EI) m/z (rel. intensity): 214 (M)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:9]([C:3]2[C:2]([CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:8])=[C:1]([OH:7])[CH:6]=[CH:5][CH:4]=2)[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:10]1([CH:9]([C:2]2[CH:3]=[C:4]([CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:8])[CH:5]=[C:6]([CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:8])[C:1]=2[OH:7])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccccc1
Reactant: Oc1ccccc1
Product: CC(c1ccccc1)c1cc(C(C)c2ccccc2)c(O)c(C(C)c2ccccc2)c1
Product: CC(c1ccccc1)c1cccc(O)c1C(C)c1ccccc1
Reaction time: 20 h
Yield: 27 %
Yield: 56 %

Procedure:
A suspension of 94 parts of phenol, 208 parts of styrene and 5 parts of ion exchange resin is prepared in a stirred reactor at 80° C. and 1 bar pressure, the mixture being stirred at 700 rpm. The ion exchange resin is a sulfonated styrene/divinylbenzene copolymer resin, which has been dehydrated under reduced pressure for 20 hours at 100° C. before being used; it has a gel structure and its particle size is from 20 to 150 micrometers. The suspension is then stirred constantly in the reactor at 700 rpm. After 10 hours, 4.7 parts of phenol and 10.4 parts of styrene are introduced per hour at 80° C. and 1 bar pressure and correspondingly 15.1 parts per hour of suspension are filtered through a suction line equipped with a metal filter (pore diameter 10 micrometers) and are subjected to fractional distillation. After 100 hours' operation, 248 parts of 4-mono-(α-phenylethyl)-phenol (13% of theory, based on starting material II) of boiling point 182°-189° C./13 millibars, 845 parts (56% of theory, based on starting material II) of 2,4-di-(α-phenylethyl)-phenol of boiling point 231°-235° C./6 millibars and 366 parts (27% of theory, based on starting material II) of 2,4,6-tri-(α-phenylethyl)-phenol of boiling point 260°-268° C./6 millibars are obtained. The conversion is 98%, based on phenol, or 97%, based on starting material II.