Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.CO[CH:19](OC)[N:20]([CH3:22])C.[F:25][C:26]1[CH:32]=[CH:31]C(N)=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:20]([C:19]1[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=1)[CH:22]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]2=[O:15]
Reactant: CCOC(=O)CC(=O)c1cc(Br)ccc1F
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Temperature: 120 °C
Yield: 97.8 %

Procedure:
Compound C (2.87 g, 9.93 mmol, 1.00 eq) and N,N-dimethylformamide dimethyl acetal (1.87 mL, 14.9 mmol, 1.50 eq) were dissolved in DMF (33 mL) in a microwave vial and heated in a microwave reactor at 120° C. for 15 minutes. To this mixture was then added 4-fluoroaniline (1.41 mL, 14.9 mmol, 1.50 eq) and the reaction was heated in a microwave reactor at 150° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with water (2×). The aqueous layers were back-extracted with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using 0-45% hexanes/ethyl acetate afforded 3.79 g (98%) of the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.81 (dd, J=9.1, 2.4 Hz, 1H), 7.77-7.73 (m, 2H), 7.54-7.50 (m, 2H), 6.92 (d, J=9.0 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 390.2.
Reaction SMILES: N1([CH2:10][NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)C2C=CC=CC=2N=N1.[Cl:17][C:18]([Cl:27])=[C:19]([O:25][CH3:26])[O:20][Si](C)(C)C.B(F)(F)F.CCOCC>ClCCl>[CH3:26][O:25][C:19](=[O:20])[C:18]([Cl:27])([Cl:17])[CH2:10][NH:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: c1ccc2c(c1)nnn2CNC1CCCC1
Reactant: COC(O[Si](C)(C)C)=C(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(Cl)(Cl)CNC1CCCC1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 4.3 g (0.02 mole) of benzotriazol-1-ylmethyl-cyclopentyl-amine and 6.4 g (0.030 mole) of (2,2-dichloro-1-methoxy-vinyloxy)-trimethyl-silane in 140 ml of anhydrous dichloromethane was added dropwise 3.7 ml (0.030 mole) of boron trifluride diethyl etherate at 0 degrees. The reaction was stirred at 0 degrees for 1 hour and then at room temperature for 24 hours. The reaction was quenched by the addition of 10% aqueous sodium carbonate and extracted with dichloromethane. The organic layer was washed with saturated sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-85:15) gave 2.4 g of 2,2-dichloro-3-cyclopentylamino-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][CH2:12][CH2:13][CH3:14])[CH2:8][CH2:7][C:5]=2[N:6]=1.[C:15]([OH:24])(=[O:23])[C@@H:16]([C@H:18]([C:20]([OH:22])=[O:21])[OH:19])[OH:17]>CO>[CH3:14][CH2:13][CH2:12][NH:11][C@@H:9]1[CH2:10][C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH2:7][CH2:8]1.[C:20]([CH:18]([CH:16]([C:15]([O-:24])=[O:23])[OH:17])[OH:19])([O-:22])=[O:21]
Reactant: CCCNC1CCc2nc(N)sc2C1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Product: CCCN[C@H]1CCc2nc(N)sc2C1
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Yield: 56.4 %

Procedure:
5 g of (±)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole was dissolved in 25 ml of methanol and 4.0 g of L(+)-tartaric acid was added under stirring. The mixture was cooled and the white crystals were filtered off, washed with methanol and dried to yield 4.8 g of pramipexole tartrate. The crystals were dissolved in 10 ml of water and concentrated hydrochloric acid was added to dissolve the solid. The solution was cooled to 10° C. and a solution of 10 g of potassium hydroxide in 10 ml of water was added. The mixture was stirred for 30 minutes and the white crystals were removed by filtration and washed with cold water. The crystals were redissolved in 7 ml of ethanol and gaseous hydrogen chloride was bubbled through the solution at 10° C. After 1 hour of stirring, the precipitated solid was separated by filtration, washed with cold ethanol and dried to yield 2.1 g of white crystals. The product is identical with pramipexole dihydrochloride by NMR and has optical rotation [α](20,D)=−48,78° (c=1, MEOH)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])([CH2:30]OS(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:18][CH:17]=2)[C:12]1=[O:29])[CH3:10].[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]([OH:36])([CH2:30][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:18][CH:17]=2)[C:12]1=[O:29])[CH3:10]
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Yield: 58.5 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (3.6 g) was dissolved in 70 ml of dimethylformamide, to which 2.0 g of 1H-1,2,4-triazole and 7.8 g of potassium carbonate were added. The mixture was heated at 80° C. for 4 hours. The reaction solution was diluted with a mixture of 150 ml of ethyl acetate and 50 ml of diisopropyl ether, and washed with 150 ml of water, 1N-hydrochloric acid (100 ml×2) and 100 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=1:2 to ethyl acetate). The desired fraction was concentrated and the residue was recrystallized from diisopropyl ether to give 2.0 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 69%) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]1([C:18]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[N+:10]([C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([C:18]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:19])=[CH:25][CH:24]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:12])=[O:11]
Reactant: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(C(=O)N3CCCC3)cc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 178.9 %

Procedure:
To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol), 4-(pyrrolidine-1-carbonyl)phenylboronic acid (21.2 g, 96.7 mmol), and Pd(PPh3)4 (508 mg, 0.440 mmol) in toluene (200 mL) was added EtOH (40 mL) followed by Na2CO3 (70.0 mL, 140 mmol, 2 M aq solution) at room temperature. The resulting mixture was heated at 100° C. for 18 h. The reaction mixture was cooled to room temperature and the organic layer was separated. The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (500 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was combined with another batch of the crude material obtained from an additional run in the same reaction scale. The combined crude material was purified by silica gel flash column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to afford 51 g (90%) of 3-nitro-4′-(pyrrolidine-1-carbonyl)biphenyl-4-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].Cl[C:14](=O)[CH2:15][C:16]([O:18]CC)=[O:17]>CN(C)C(=O)C.C(OCC)C.O>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:14]([CH2:15][C:16]([OH:18])=[O:17])=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
2-Amino-5-iodo-benzenesulfonamide (2.0 g, 6.71 mmol) was dissolved in N,N-dimethylacetamide (5 mL) and diethyl ether (7 mL). Ethyl 3-chloro-3-oxo-propionate (0.916 g, 6.71 mmol) was added and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with diethyl ether (10 mL) and water (20 mL). Upon mixing vigorously, a precipitate formed. The solid was collected by vacuum filtration, rinsed with 1.0 M aqueous hydrochloric acid solution (2×10 mL) and dried in vacuo for 2 h. The solid was dissolved in 8% aqueous sodium hydroxide solution (50 mL) and stirred at 100° C. for 15 min. Upon cooling to 25° C., the solution was neutralized with 6.0 M aqueous hydrochloric acid solution. Additional 1.0 M aqueous hydrochloric acid solution (20 mL) was added and the desired product precipitated. The solid was collected by vacuum filtration, rinsed with 1.0 M aqueous hydrochloric acid solution (2×10 mL) and dried in vacuo for 16 h to afford the desired product, (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (2.0 g, 5.46 mmol, 81%) as a pale pink powder. 1H NMR (400 MHz, DMSO-d6) δ: 3.58 (3H, s), 7.13 (1H, d, J=8.5 Hz), 7.98 (1H, dd, J1=8.6 Hz, J2=1.7 Hz), 8.03 (1H, d, J=2.5 Hz), 12.33 (1H, bs), 13.05 (1H, bs). LC-MS (ESI) calcd for C9H7IN2O4S 365.92, found 366.95 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:13]OCC)[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=O)[CH3:2].[N+:18]([CH2:21][C:22]([NH2:24])=[O:23])([O-:20])=[O:19].C([O-])(=O)C.[Na+].Cl>C(O)C>[N+:18]([C:21]1[C:22](=[O:23])[NH:24][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:13]=1)([O-:20])=[O:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: NC(=O)C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 79.3 %

Procedure:
Diethyl(ethoxymethylene)oxalacetate (5.63 g. 0.023 mol) is dissolved under N2 atmosphere in 20 mL of absolute ethanol and cooled to 0° C. Nitroacetamide (2.00 g, 0.019 mol,) (S. K. Brownstein, 3. Org. Chem 23, 113 (1958)) and sodium acetate (1.56 g, 0.019 mol,) are added and the mixture is stirred at room temperature for 15 hours. The suspension is diluted with 15 mL of absolute ethanol and acidified to pH 2 with concentrated HCl. The inorganics are removed by filtration and the filtrate is concentrated to an oily solid which is gravity chromatographed, first with methylene chloride and then 2% methanol in methylene chloride. The fractions are combined and stripped to give 4.28 g of the title product as a yellow solid, 78.4% yield. melting point 144°-145° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH2:16])[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:12][N:11]=2)=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:29]1([CH2:35]Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:29]1([CH2:35][N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([C:10]3[N:15]=[C:14]([NH2:16])[C:13]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)=[CH:12][N:11]=3)=[N:2]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1nc(-c2n[nH]c3ncccc23)ncc1-c1ccncc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2nn(CC3CCCCC3)c3ncccc23)ncc1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.691 mmol) of 2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(pyridin-4-yl)pyrimidine-4-amine (preparation: see WO 03/097063, Example 35A) were dissolved in 5 ml of DMF, and 248 mg (0.760 mmol) of cesium carbonate and 136 mg (0.760 mmol) of cyclohexylmethyl bromide were added. The mixture was stirred at RT overnight. Water was added, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was fractionated by preparative HPLC (Method 5). The product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 29 mg (11% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:22](=[O:23])[N:21]([CH3:20])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:15][CH:14]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(-c2nc(-c3ccc(Cl)cc3)cs2)cc1
Product: CN(C(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)cs2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-[4-(4-chloro-phenyl)-thiazol-2-yl]-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (59%, white crystals). HPLC-MS m/z=421.1 (M+1), Rt: 5.85 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH3:20]>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:20]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1OC
Temperature: 40 °C

Procedure:
2-methoxy-5-nitro-phenol (508 mg, 3 mmoles) was dissolved in DMF (20 mL) under nitrogen atmosphere. K2CO3 (900 mg, 6.5 mmoles), KI (490 mg, 2.95 mmol) and ethyl bromide (0.250 mL, 3.3 mmoles) were added, and the suspension was heated to 40° C. for 28 hours. The mixture was diluted with AcOEt (60 mL) and extracted with 1N NaOH (40 mL) and water (40 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was employed in the next step without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH4+:10].[Cl-].C(Cl)(Cl)Cl.Cl[CH:17](Cl)[CH3:18]>>[NH2:10][CH2:17][CH2:18][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: [NH4+]
Reactant: CC(Cl)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: NCCc1c[nH]c2ccccc12
Reaction time: 0.25 h

Procedure:
To a solution of (S)-4b (30 mg) in dichloroethane (1 mL) cooled at −5° C. was dropwise added AgClO4. The resulting mixture was stirred for 15 min at the same temperature and added to a solution of indole (50 mg) in dichloroethane (1 mL) warmed in a reaction flask. The reaction mixture was stirred for 10 h at 50° C. and treated with saturated NH4Cl (mL), and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to the dryness. The residue was purified by silica gel (60-230 mesh) column chromatography eluted with 10% ethyl acetate in hexanes to afford 5. [α]26D=+190.3 (c=0.1, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[SH:33]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([S:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[Cl:25])[CH2:8][C@H:7]1[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(S)c(Cl)c1
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1COc1ccc(F)cc1
Product: CCOC(=O)[C@@H]1CC(Sc2ccc(F)cc2Cl)C[C@H]1COc1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 8 using (1R,2R)-2-(4-Fluoro-phenoxymethyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, example 143 and 144 step 3) and 2-chloro-4-fluorothiophenol. Yellow oil (56%). MS (EI): 378.3 (M+NH4)+.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][CH:5]=1>C(O)(=O)C.S([O-])(O)(=O)=O.[K+]>[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[S:12][C:13]([Br:1])=[CH:14][N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Brc1cccc(Nc2nccs2)n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: Brc1cccc(Nc2ncc(Br)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of bromine (1.1 mL, 20.9 mmol) in acetic acid (15 mL) was added dropwise to a solution of 2-[(6-bromo-2-pyridinyl)amino]thiazole (2.68 g, 10.46 mmol) in acetic acid (23 mL) at 40° C. After addition, the mixture was stirred at rt. for 3 h. The mixture was diluted with aqueous potassium hydrogen sulfate solution (60 mL) at 0° C. and stirred for several min. The precipitated solid was filtered, washed several times with water and dried in vacuo over P2O5 to obtain the titled compound (3.28 g, 94%) as an off-white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([O:17][C:16]([F:28])([F:27])[F:15])[CH:19]=2)=[O:22])=[CH:30]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: O=C(c1cccc(OC(F)(F)F)c1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-(3-trifluoromethoxy-phenyl)-methanone was prepared from phenanthridine, 3-(trifluoromethoxy)benzoyl chloride, and indole according to GP 2. Yield, 16%. 1H-NMR (DMSO-d6): δ=6.22 (d, J=2.0 Hz, 1H), 6.37 (s, br., 1H), 6.83 (t, J=7.5 Hz, 1H), 6.99-7.32 (m, 7H), 7.35-7.48 (m, 3H), 7.51-7.59 (m, 2H), 7.85 (“d”, J≈7 Hz, 1H), 7.98 (dd, J=7.8 Hz, J=1.0 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 10.72 (s, 1H); (+)-ESI-MS: m/z=485 [M+H]+, 368 [M-indole+H]+; (−)-ESI-MS: m/z=483 (M−H)−.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[CH2:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][CH3:11].Cl>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:9][CH2:10][CH3:11])=[CH:13][C:14]=1[C:5](=[O:6])[CH3:7]
Reactant: CC(=O)Cl
Reactant: CCCc1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1ccc(OC)c(C(C)=O)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A suspension of 10.6 g of AlCl3 in 150 ml of dichloromethane is cooled to −10° C. 5.7 ml of AcCl and 6 g of 4-propylanisole are added. The medium is stirred at −10° C. for 30 min, and then poured into a beaker containing ice mixed with 35% HCl. After separation by settling out, the aqueous phase is extracted 3 times in dichloromethane, and the combined organic phases are washed with water and with a saturated NaCl solution, dried over MgSO4 and then evaporated, to give 7.86 g of a brown oil (quant.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[S:23]1[CH:27]=[C:26]([CH2:28][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:28]\[C:26]2[N:25]=[CH:24][S:23][CH:27]=2)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C(=C\c1cn(-c2ccccc2)nc1OCc1ccccc1)\c1cscn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.3 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.70 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (3.64 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:3, v/v) to give 4-{(Z)-2-[3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a colorless oil (0.82 g, yield 37%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OCC1C=CC(O)=CC=1.BrCC1C=CC=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: BrCc1ccccc1
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccccc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 1-benzyloxy-4-chloromethyl-benzene prepared from 4-hydroxymethyl-phenol and 4-bromomethyl-benzene in the manner analagous to Examples 14A and 14B. MS m/z 435 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:6]([N:8]3[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]3[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:18])=[O:7])=[CH:31][CH:32]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Reactant: NCC(O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 3′,4′-dichloro[1,1′-biphenyl]-4-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=527.