Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].OS(O)(=O)=O.O>CC(O)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:8]([OH:11])=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-tert-Butyl-2-trifluoromethyl-phenol (70 mg, 0.32 mmol) was dissolved in 3 mL AcOH/1.5 mL water and cooled to 0° C. HNO3 (1.5 mL) and catalytic H2SO4 were added and the reaction was allowed to warm to room temperature. Stirring was continued overnight, after which water was added and the compound was extracted into EtOAc. The organic layer was dried over MgSO4 and concentrated to yield 34 mg of final compound. Calculated mass =263. Observed mass=264
Reaction SMILES: [CH3:1]/[C:2](=[CH:12]\[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[Na].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2](=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([S:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Reactant: Sc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=CSc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
To a suspension of 0.8 g (3 mmol) of (E)-2-methyl-N-phenyl-3-(phenylthio)-2-propenamide in toluene (4 ml) was added 0.62 g (3 mmol) of phosphorus pentachloride and the mixture was stirred at room temperature for 4 hours. After concentration of the mixture under vacuum, the residue was dissolved in 35 ml of N,N-dimethylformamide [DMF] and then 793 mg (6 mmol) of a benzenethiol sodium salt was added portionwise under ice cooling. The mixture was stirred at room temperature for 2 hours. After dilution with tert-butyl methyl ether, the mixture was washed sequentially with water (three times) and saturated NaCl solution, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 0.4 g of phenyl 2-methyl-N-phenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 1).
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:34]=[CH:35][CH:36]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([NH:29][C:30](=[O:33])[CH2:31][SH:32])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:10][C:9]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([Br:8])[N:4]=2)[S:32][C:31]=1[C:30]([NH:29][C:24]1[CH:23]=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:34]=[CH:35][CH:36]=[C:16]([C:13]([C:11]#[N:12])([CH3:14])[CH3:15])[CH:17]=2)[CH:27]=[CH:26][C:25]=1[CH3:28])=[O:33]
Reactant: N#Cc1nc(Br)cnc1Br
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2ncc(Br)nc2c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a solution of 3,6-dibromopyrazine-2-carbonitrile 15 (286 mg, 1.089 mmol) and 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4-methylphenyl)benzamide 16 (400 mg, 1.089 mmol) in ethanol (5 mL) was added potassium carbonate (211 mg, 1.524 mmol). The reaction was stirred 1 h at rt and 2 h at 50° C. Quenched in cooled 1N HCl solution (aq), the resulting precipitate was collected and dried to give crude compound 17 (588 mg). Purification by chromatography (0-10% EtOAc in CH2Cl2) gave pure 7-amino-2-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 17 (463 mg, 77%). 1H-NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.21 (s, 3H), 7.09 (br s, 2H), 7.27 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.81 (br s, 1H), 7.95 (d, J=7.0, 1H), 8.05 (s, 1H), 8.93 (br s, 1H), 9.58 (br s, 1H), 10.32 (br s, 1H). (m/z)=549 and 551 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=4)[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cn4)CC3)nc2)c1

Procedure:
6-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-nicotinic acid was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 6-chloro nicotinic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C26H29N5O3 (m/e) 459, obsd 460 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:34][CH:36]4[O:38][CH2:37]4)=[CH:25][CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=Nc3ccc(O)cc3)n(C)c(=O)n2C)cc1OC
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(=Nc3ccc(OCC4CO4)cc3)n(C)c(=O)n2C)cc1OC

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(4-hydroxyphenylimino)-2(1H)-pyrimidinone (1.5 g) in acetone (30 ml) was added potassium carbonate (0.56 g) and epichlorohydrin (0.32 ml). After the mixture was refluxed for 7 hours, an additional epichlorohydrin (1.6 ml) was added thereto, and further the mixture was refluxed for 38 hours. The resulting mixture was evaporated and chromatographed on silica-gel eluting with chloroform to give crude 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-[4-(2,3-epoxypropoxy)phenylimino]-2(1H)-pyrimidinone, which was recrystallized from diethyl ether.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[Cl:18].[CH:19](=[O:21])[CH3:20]>CCOCC>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[CH:19]([OH:21])[CH3:20]
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a mixture of 65.2 ml of n-butyllithium (1.61M in hexane) and 100 ml of anhydrous ether was added dropwise 29.3 g of 4-bromo-3,5-dichlorobenzotrifluoride (3) in 30 ml of anhydrous ether at -78° C., followed by stirring for 20 minutes. Subsequently, 6.2 ml of acetaldehyde in 50 ml of anhydrous ether was added dropwise to the mixture at the same temperature, followed by stirring at 0° C. Ice waster was added to the reaction mixture, followed by extraction with ether, drying over anhydrous magnesium sulfate and concentration under reduced pressure to give 23.5 g of the desired product in the form of a colorless oil (crude yield 90.7% ).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[NH:22][C:23]2[C:24]3[C:31]([CH3:32])=[C:30]([C:33]([OH:35])=O)[S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.N>C1COCC1.O1CCOCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[NH:22][C:23]2[C:24]3[C:31]([CH3:32])=[C:30]([C:33](=[O:35])[NH2:37])[S:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[2-((1S,3S)-3-tert-butoxycarbonylamino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (115 mg), TBTU (81 mg) and DIPEA (88 μl) in THF (15 ml) was stirred at rt for 30 minutes. After the addition of 0.5 M ammonia in dioxane (458 μl) and DMF the mixture was stirred at rt overnight. The reaction mixture was concentrated, diluted with water and extracted with DCM. The organic layer was concentrated and the crude was purified by chromatography to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([CH3:24])=[CH:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CN(C=O)C.Cl.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]Cl>C1(C)C=CC=C(C)C=1>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15]([CH3:24])=[CH:14]2)(=[O:11])=[O:12])=[CH:3][C:2]=1[NH:1][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31]
Reactant: CN(C)CCCl
Reactant: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(N)c1
Agent: Cl
Solvent: Cc1cccc(C)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(NCCN(C)C)c1
Temperature: 25 °C

Procedure:
1-(3′-Amino-4′-methoxy benzenesulfonyl)-5-methoxy-3-methyl-1H-indole (600 mg, 1.7 mmol) (obtained from preparation 2) was taken into a 25 mL two necked round bottom flask containing DMF (3 mL) and m-Xylene (3 mL). Added 2-dimethylamino ethyl chloride hydrochloride (490 mg, 3.4 mmol) and heated at 135° C.-138° C. for a period of 10 hours and the progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was cooled to room temperature, quenched into chilled water (25 mL) and pH adjusted to 9.0 to 10.0 with 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (2×50 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude compound. The obtained technical product was purified by column chromatography, eluent being ethylacetate and triethylamine (99:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16](O)=[O:17])=[N:9][NH:8][C:7]2=[O:23].[CH2:24]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[C:15]([C:16]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH2:24][CH3:25])[CH2:28][CH2:29]3)=[O:17])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: CCOC1CCNCC1
Reactant: O=C(O)c1cc(F)cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC1CCN(C(=O)c2cc(F)cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Reaction time: 1 h

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-fluorobenzoic acid (128), 4-ethoxypiperidine and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate were dissolved in DMF (10 mL), to this was added DIPEA and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam (130 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 2.00-1.38 (4H, m), 3.29-3.05 (1H, m), 3.57-3.34 (5H, m), 4.08-3.91 (1H, m), 4.68 (2H, s), 6.90 (1H, d), 6.97-6.94 (2H, m), 7.67 (1H, t), 7.80 (1H, d), 8.50 (1H, dd); NH missing; m/z (LC-MS, ESI+), RT=2.06 (M+H 444).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[SH:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[OH-].[K+]>C(O)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[S:7][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: Sc1nc2ccccc2o1
Reactant: O=C(O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCSc1nc2ccccc2o1
Yield: 58.2 %

Procedure:
Ethanol (EtOH) (35 ml), 3-bromopropanoic acid (1.53 g, 10 mmols) and 2-mercaptobenzoxazole (1.51 g, 10mmols) were added in that order to an aqueous (15 ml) solution of potassium hydroxide (KOH) (1.0 g, 17.8 mmols), and heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and this was made acidic (pH=1) with 1N HCl added thereto. The precipitate formed was taken out through filtration, and crystallized in acetone-ether-hexane to obtain 1.3 g (58%) of 3-(benzoxazol-2-ylthio)propanoic acid as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:27]([S:28]C2C=CN=CC=2)=[CH:26][CH:25]=[N:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[N:24]1[CH:25]=[CH:26][C:27]([S:28][O:9][C:8](=[O:10])[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[CH:22][CH:23]=1
Reactant: c1cc(Sc2ccncc2)ccn1
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)OSc2ccncc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
31.0 g of 6-chloro-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoic acid, 22.0 g of 4,4'-dipyridylsulfide and 26.2 g of triphenylphosphine were suspended in 250 ml of toluene, and were violently stirred at room temperature for 2 hours. The reaction mixture was filtered, and the toluene was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to obtain 36.0 g of the above identified compound as a white crystal (yield 90%).
Reaction SMILES: C([O-])=O.[Na+].[OH-].[Na+].Cl[C:8]1[CH:9]=[CH:10][C:11]([NH2:18])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Pd]>[NH2:18][C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=1[C:14]([F:15])([F:16])[F:17]
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Agent: [Pd]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C[O-]
Solvent: O
Product: Nc1ccccc1C(F)(F)F
Yield: 60.3 %

Procedure:
To a solution of sodium formate (38 parts) in water (100 parts) are added sodium hydroxide liquor (32%; 13.5 parts), benzyl triethylammonium chloride (1.0 parts), 3% palladium on charcoal (50% paste; 6.0 parts) and 5-chloro-2-aminobenzotrifluoride (19.6 parts). The mixture is stirred rapidly at the boil under reflux for 4 hours and then steam distilled. The distillate is extracted with chloroform (2 × 50 parts), the extract dried over magnesium sulphate and then the solvent removed to give 9.7 parts (60.3%) of 2-aminobenzotrifluoride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@H:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][C@@H:11]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O1CCOCC1.O>S(=O)(=O)(O)O>[O:14]=[C:13]1[CH2:12][C@H:11]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:19][CH2:18]1
Reactant: O=C(N[C@H]1CC2(CC[C@@H]1c1cc(F)c(F)cc1F)OCCO2)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of benzyl [(7S,8R)-8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-yl]carbamate (315 mg, 0.75 mmol) in sulfuric acid (15 mL, 1:1 in water) was added 1,4-dioxane (30 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (70 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to yield the title compound. LC/MS 378.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:27]([CH2:26][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])=[N:8]2)[CH:32]=1
Reactant: Clc1ccc(OCc2ccccc2)c(CBr)c1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(174 mg, 0.78 mmol) was dissolved in DMF (2.5 ml). Sodium iodide (33 mg, 0.22 mmol) and potassium carbonate (164 mg, 1.19 mmol) were added followed by 2-(bromomethyl)-4-chloro-1-[(phenylmethyl)oxy]benzene (synthesised according to WO2006066968) (233 mg, 0.75 mmol) washed in with further DMF (2.5 ml). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then stirred and heated to 80° C. for 3 h under a nitrogen atmosphere and allowed to cool. Further 2-(bromomethyl)-4-chloro-1-[(phenylmethyl)oxy]benzene (51 mg) was added, and the reaction was stirred and heated to 80° C. under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated in vacuo. The crude material was treated with water (50 ml) and extracted with EtOAc (3×50 ml). The extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified on silica (50 g) using 0-100% EtOAc-cyclohexane. Appropriate fractions were concentrated in vacuo to give the title compound as a colourless gum (20 mg);
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:28][CH:27]=2)=[N:24][CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(OC1C=CC([Li])=CC=1)CCCCCCC.BrCCCCCCCC>C(Cl)Cl.N1C=CC=CC=1>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:28][CH:27]=2)=[N+:24]([O-:9])[CH:25]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)cn2)cc1
Agent: [Li]c1ccc(OCCCCCCCC)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCCCCBr
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c[n+]2[O-])cc1
Yield: 65.2 %

Procedure:
A solution of 3.03 g (12.3 mmol) of 3-chloroperbenzoic acid in 30 ml of methylene chloride is added dropwise at a temperature of 0° to 5° C. to 3.23 g (8.2 mmol) of 5-octyl-2-(4-octyloxyphenyl)pyridine (prepared, for example, analogously to C. S. Giam, J. Staut, J. Chem. Soc., Chem. Commun. 478 (1970) from pyridine, 4-octyloxyphenyllithium and 1-bromooctane) in 30 ml of methylene chloride. After a reaction time of 3 hours at room temperature, the mixture is washed once with 5% sodium carbonate and twice with sodium chloride solution, the organic phase is dried over sodium sulfate, filtered off, and the solvent is removed by distillation. Purification of the residue by chromatography (silica gel, 8:2 methylene chloride/ethyl acetate) gives 2.20 g of 5-octyl-2-(4-octyloxyphenyl)pyridine N-oxide. ##STR13##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C[Si](C)(C)[C:11]#[C:12][CH3:13].C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Cu]I.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>[Br:1][C:2]1[CH:7]=[C:6]([C:11]#[C:12][CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Brc1cc(I)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC#Cc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-bromo-4-iodopyridine (2 g, 7.04 mmo, copper(I) iodide (0.080 mL, 2.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.407 g, 0.35 mmol) in toluene (85 mL) was added 1-(trimethylsilyl)-1-propyne (1.054 mL, 7.04 mmol), triethylamine (3.24 mL, 23.25 mmol) and tetrabutylammonium fluoride (1 M in THF, 7.04 mL, 7.04 mmol) and the resulting mixture was stirred under an argon atmosphere at r.t. overnight. The mixture was concentrated and the resulting residue was partitioned between water (10 mL) and DCM (10 mL) and poured into a phase separator. The organic phase was collected, and the aqueous phase was extracted once with DCM (10 mL). The combined organics were concentrated and purified by flash chromatography using 0% to 30% EtOAc in heptane to give the title compound (1.195 g, 87% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 2.11 (s, 3 H), 7.42 (dd, 1 H), 7.65 (s, 1 H), 8.35 (dd, 1 H); MS (ES+) m/z 196 [M+H]+; MS (APCI+) m/z 196 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[O:21]([C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)Oc1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Oc4ccccc4)cc23)CC1
Yield: 91 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 7.2 mg (0.0458 mMol) phenyl chloroformate, 13.9 mg (91%) of the title compound were recovered.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O1CCCC1.C(OC(Cl)=O)C(C)C.[CH:27]1[C:32]([NH2:33])=[CH:31][CH:30]=[C:29]([OH:34])[CH:28]=1>O.N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:33][C:32]2[CH:27]=[CH:28][C:29]([OH:34])=[CH:30][CH:31]=2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(O)cc2)cc1

Procedure:
A solution of p-acetamidobenzoic acid (12.5 g.) in 250 ml. of tetrahydrofuran is treated with triethylamine (11.1 ml.). The mixture is then treated with isobutylchloroformate (10.4 ml.) and, after 5 min. at about 25° C., with p-aminophenol (13.3 g.) in 80 ml. of dry pyridine. After 40 min. the crude product is obtained by addition of 2 liters of water. The product is recrystallized from 500 ml. of hot methanol by dilution with 300 ml. of water as white crystals, 5.9 g., m.p. 275.0°-277.0° C.