Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]([CH3:14])([CH3:13])[CH:6]=1)([O-])=O.C(Cl)(Cl)[Cl:16]>C(O)C.[Pd]>[ClH:16].[CH3:11][C:9]1([CH3:12])[CH2:8][C:7]([CH3:13])([CH3:14])[CH2:6][CH:5]([CH2:4][NH2:1])[CH2:10]1
Reactant: ClC(Cl)Cl
Reactant: CC1(C)C=C(C[N+](=O)[O-])CC(C)(C)C1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(CN)CC(C)(C)C1
Product: Cl
Yield: 50 %

Procedure:
A solution of 1-nitromethyl-3,3,5,5-tetramethylcyclohexene (6) (1.1 g, 5.63 mmol) in a mixture of ethanol (140 ml) and chloroform (2.8 ml) was hydrogenated over 10% Pd/C (280 mg) at 5 atm for 20 h, filtered and evaporated. The crude product was treated with ether, filtered and washed with ether to give 0.57 g (50%) of amine 5-26.
Reaction SMILES: CC1C(C)=C2C(CCC(CCCC(CCCC(CCCC(C)C)C)C)(C)[O:9]2)=C(C)C=1O.N1C=CC=CC=1.[CH3:38][O:39][C:40]1[CH:50]=[CH:49][C:43]([CH:44]=[CH:45][C:46](Cl)=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:50]=[CH:49][C:43]([CH:44]=[CH:45][C:46]([OH:9])=[O:47])=[CH:42][CH:41]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)O)cc1
Yield: 88 %

Procedure:
4.3 g of dl-α-tocopherol (0.010 mol) and 1.34 g of pyridine (0.017 mol) are placed in 20 ml of CH2Cl2 while gassing with argon in a 100 ml 4-necked sulphonation flask provided with a temperature, a 20 ml dropping funnel, a magnetic stirrer and a reflux condenser. A solution of 0.95 g of 4-methoxycinnamic acid chloride (0.015 mol) in 15 ml of CH2Cl2 is added dropwise within 10 minutes. The reaction mixture is heated to reflux temperature for 3 hours. The solution is washed in succession with 10 ml of water, 10 ml of 5% HCl and 10 ml of 5% NaHCO3. After drying (Na2SO4) the solvent is concentrated on a rotary evaporator. The crude product (6.3 g) is chromatographed (toluene) on 150 g of silica gel (0.040-0.063 mm) under 0.5 bar pressure. There are obtained 5.2 g of yellowish d,l-α-tocopherol ester of p-methoxycinnamic acid (yield 88%).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])N=1.CC(C)=[O:16]>>[CH3:12][C:6]1([CH3:13])[NH:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4](=[O:16])[CH2:3]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
17.2 g of acetonine hydrate, 30 g of acetone and 0.5 g of ammonium chloride are heated in a sealed tube for 6 hours at 45° C. After this period of time, it is shown by gas-chromatographical analysis that at least 95% of the employed acetonine has been reacted to form triacetoneamine, which is then isolated by distillation.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]2.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][C:2]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[CH2:3]2)([O-:18])=[O:17]
Reactant: O=C1NC(=O)C2(Cc3ccccc3C2)N1
Reactant: O=[N+]([O-])O
Product: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1

Procedure:
A solution of (±)-spiro[imidazolidine-4,2′-indane]-2,5-dione (3.0 g, 14.8 mmol, described in Intermediate 13) in conc. nitric acid (33 mL) was stirred at ambient temperature for 1 h. The reaction was then poured onto crushed ice and the resultant solid was isolated by filtration. The crude material was recrystallized from ethanol to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[C:19](=[O:34])[CH2:20][C:21]1[NH:26][C:25](=[O:27])[CH:24]=[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:22]=1.O.ClCCl>C(Cl)(Cl)Cl>[Cl:1][C:24]1[C:25](=[O:27])[NH:26][C:21]([CH2:20][C:19]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][C@@H:10]2[CH3:9])=[O:34])=[N:22][C:23]=1[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
37.6 mg of N-chlorosuccinimide are added to a solution of 100 mg of 2-{2-[(2S)-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one in 4 ml of chloroform. The reaction medium is stirred at ambient temperature for 2 hours. 5 ml of water and 20 ml of dichloromethane are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 99/01 then 98/02 then 97/03 dichloromethane/methanol, so as to give 69 mg of 5-chloro-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[C:14]([N:16]=[C:17]([NH2:19])[NH2:18])#[N:15].[OH-].[K+]>COCCO.O>[NH2:15][C:14]1[N:16]=[C:17]([NH2:19])[N:18]=[C:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([S:3][C:2]([F:12])([F:1])[F:13])[CH:5]=2)[N:8]=1
Reactant: N#CN=C(N)N
Reactant: N#Cc1cccc(SC(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: Nc1nc(N)nc(-c2cccc(SC(F)(F)F)c2)n1

Procedure:
2.9 g of m-trifluoromethylthiobenzonitrile (b.p. 86°-88° C./40 mm Hg) and 1.4 g of dicyanodiamide are dissolved in 3 ml of methylcellosolve and the mixture is then combined with 0.3 g of caustic potash and refluxed for 5 hours. After cooling, the mixture is diluted with water and extracted with ether, and the extract, after evaporation, is recrystallized from methanol. Melting point of the obtained material: 172°-174° C.; yield: 2.4 g.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:14][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.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>[CH:22]1([C:3]2[C:4]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:30]=2[CH:28]=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cn1c(-c2ccc(OC)cc2C=O)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 57 %

Procedure:
tert-Butyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., prepared as described in Example 1, Step 3) and 2-formyl-4-methoxyphenylboronic acid (1.5 eq.) were dissolved in dioxane (0.1 M) and treated with 2 M Na2CO3 solution (2 eq.). The solution was degassed by bubbling argon through it and Pd(PPh3)2Cl2 (0.1 eq.) was added. The reaction mixture was heated to reflux for 20 min. After cooling down to RT, the mixture was diluted with EtOAc and washed with 1 N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo and the residue purified by chromatography (PE:EtOAc, 9:1) to afford the pure title compound (57%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 9.64 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.41-7.38 (m, 2H), 4.92 (d, J 18.0, 1H), 4.73 (d, J 18.0, 1H), 3.90 (s, 3H), 3.50 (s, 3H), 2.14-2.09 (m, 1H), 1.73-1.19 (m, 10H), 1.54 (s, 9H). MS (ES+) m/z: 534 [M+Na]+.
Reaction SMILES: C([C:3]1[N:4]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[CH:8][C:7](=[O:13])[C:6]1[CH:14]=[C:15]([F:25])[C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:17][C:5]2=1)C.[OH-:26].[Na+].[CH2:28]([OH:30])C>C(O)(=O)C>[F:25][C:15]1[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)=[CH:17][C:5]2[N:4]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:3]3)=[C:8]([C:28]([OH:30])=[O:26])[C:7](=[O:13])[C:6]=2[CH:14]=1
Reactant: [OH-]
Reactant: CCc1cccc2cc(=O)c3cc(F)c(N4CCN(C)CC4)cc3n12
Reactant: CCO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2ccccn23)CC1
Temperature: 25 °C

Procedure:
A mixture of 0.38 g of ethyl 8-fluoro-9-(4-methyl-1-piperazinyl)-6-oxo-6H-benzo[c]quinolizine, 25 ml of 0.1N sodium hydroxide and 5 ml of ethyl alcohol was refluxed for 18 hours. The mixture was cooled to room temperature and the pH adjusted to 6 with acetic acid. Most of the volatiles were removed under vacuum to give 0.31 g of water washed and dried desired product, mp 264°-266° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]([N:13]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([Br:23])=[C:19]([CH3:22])[CH:20]=2)[CH:15]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14]1)(=[O:12])[CH3:11]>CC(O)=O>[C:10]([N:13]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([Br:23])=[C:19]([CH3:22])[C:20]=2[N+:6]([O-:9])=[O:7])[CH:15]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)CCC1CN(C(C)=O)c2cc(C)c(Br)c(C)c21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CN(C(C)=O)c2c1c(C)c(Br)c(C)c2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mixture of AcOH (10 ml), conc. sulfuric acid (10 ml) and nitric acid (0.55 ml) was added by portions 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-4,6-dimethylindoline (3.0 g) at 0° C., and the mixture was stirred at the same temperature for 5 hr. The reaction mixture was poured into ice water and extracted with CHCl3 (100 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 2.7 g of 1-acetyl-5-bromo-3-(2-ethoxycarbonylethyl)-4,6-dimethyl-7-nitroindoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>ClCCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
3-fluoro-4-methylphenol (3.66 g, 29.0 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. HNO3 70% (3.7 mL, 58 mmol) was diluted with H2O (33 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture, which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.83 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 6.85 (d, J=11.0 Hz, 1H), 2.13 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:28])[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>ClCCl>[CH2:25]([N:22]([CH2:23][CH3:24])[C:21](=[O:27])[C:18]1[CH:17]=[CH:16][C:15]([C:14]([Br:28])=[C:11]2[CH2:12][CH2:13][N:8]([CH2:6][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:9][CH2:10]2)=[CH:20][CH:19]=1)[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(Br)=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Compound 6, prepared in Example 1 (v) above (6.122 g, 13.4 mmoL), was treated with TFA (13 mL) in dichloromethane (80 mL) at room temperature. After 2 h, the reaction mixture was washed with 2M sodium hydroxide (25 mL) and the organic layer was separated. The organic layer was dried (MgSO), filtered and concentrated. The residue was dissolved in dichloromethane (120 mL), cooled to 0° C. and benzyl bromide (1.8 mL, 15.1 mmol) and triethylamine (5.7 mL, 41.0 mmol) were added. The reaction was gradually warmed to room temperature and after 20 hours the reaction was washed with water (1×100 mL). The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography, eluting 50 to 60% ethyl acetate in hexanes gave 3.80 g of product (64% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][N:10]1[C@H:9]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:4][C:3]([C:2]4[CH:3]=[CH:4][CH:5]=[C:6]5[C:11]=4[N:10]=[CH:9][CH:8]=[CH:7]5)=[CH:2][C:19]=3[CH2:20][CH2:8]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: Brc1cccc2cccnc12
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc5cccnc45)cc3CC[C@@H]12
Yield: 38 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 8-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 88 mg (38%) of the title compound as a tan solid. mp 205°-207° FDMS: m/e=356 α[D]589 =+76.28 (c=0.47, chloroform).
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([NH:17][C:18]1[C:23]([C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])=[CH:22][N:21]=[C:20]2[NH:30][N:31]=[CH:32][C:19]=12)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[CH2:10]([NH:17][C:18]1[C:23]([C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])=[CH:22][N:21]=[C:20]2[N:30]([CH2:1][CH3:2])[N:31]=[CH:32][C:19]=12)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCI
Reactant: CON(C)C(=O)c1cnc2[nH]ncc2c1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(NCc3ccccc3)c(C(=O)N(C)OC)cnc21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Ethyl iodide (1.52 gm, 9.63 mmol) and potassium carbonate (2.214 gm, 16.05 mmol) were added to the solution 4-(benzylamino)-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (1 gm, 3.21 mmol) (example 6a) in dimethylformamide and the reaction mixture was stirred at 60° C. for about 5 hours. It was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over silica gel column.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)=O.C(O)(=O)C.[OH:26][C@H:27]1[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[CH2:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([N:29]2[CH2:30][C@@H:31]([OH:32])[C@H:27]([OH:26])[CH2:28]2)[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: O=S(=O)(Oc1cccc(Cc2ccccc2)n1)C(F)(F)F
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 6 h
Yield: 55.6 %

Procedure:
To a mixture of 11.3 g of 2-benzyl-6-pyridyl trifluoromethanesulfonate, 11.3 g of (3R,4R)-3,4-dihydroxypyrrolidine acetate (synthesized from D-tartaric acid as a starting material, Angew. Chem. Int. Ed. Engl., 23(6), 435, 1984) and 10 ml of N-methylpyrrolidone was added dropwise 11 ml of 1,8-diazabicyclo[5.4.0]-7-undecene under nitrogen atmosphere in an oil bath at 100° C., followed by heating under stirring for 6 hours. After standing to cool, the reaction mixture was extracted with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate), to give 5.35 g of the title compound.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]([F:12])([F:11])[F:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[Br:1][C:5]1[CH:4]=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:8]=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: FC(F)(F)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cccc(Br)c1
Reaction time: 0.25 h

Procedure:
3280 g of bromine are added to a mixture of 6046 g benzotrifluoride, 68 g FeCl3 and 2 g SiO2 at about 20° C. within ca. 2 hours. The reaction temperature is then slowly rised within ca. 7 hours to ca 40° C., 300 g water and 130 g Na2S2O3 are added and stirred for ca. 15 minutes. The phases are separated and the organic phase is destilled resulting in 4160 g bromo-benzotrifluoride (isomeric ratio 3:4=96:4) and 3290 g benzotrifluoride which is recycled.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:13]([C:10]2[CH:11]=[CH:12][C:7]3[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=3)[CH:9]=2)[OH:14])=[CH:18][CH:17]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)c1nnc2ccc(C=O)cn12
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(C(O)c3ccc(F)cc3)cn12
Reaction time: 20 h

Procedure:
To a solution of 3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine-6-carbaldehyde (404.6 mg, 2.13 mmol) in THF (8 mL) at ambient temperature was added 4-fluorophenylmagnesium bromide (3 mL, 1.0 M in THF). The resulting reaction was stirred for 20 hours, then quenched with water, followed by saturated NaHCO3. The reaction mixture was extracted with ethyl acetate, the organics dried over sodium sulfate, and concentrated to give the above named compound (591.3 mg, 97%).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2O)=[CH:10][CH:9]=1.[CH3:21][C:22]([C:25]([CH2:27]Cl)=[O:26])([CH3:24])[CH3:23]>C(C(C)=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:2][CH2:27][C:25](=[O:26])[C:22]([CH3:24])([CH3:23])[CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 84.7 %

Procedure:
280 g (2 mols) of powdered potassium carbonate were suspended in 2 l of methyl ethyl ketone. 409 g (2 mols) of 4' -chlorohydroxybiphenyl were added and the mixture was heated to the boil. Thereafter 269 g (2 mols) of α-chloropinacolone were added dropwise over the course of 1 hour and the mixture was heated for 15 hours under reflux. After cooling, the solid residue was filtered off, washed and recrystallized from ligroin. 513 g (79% of theory) of 1-[4-(4-chlorophenyl)phenoxy]-3,3-dimethylbutan-2-one of melting point 90° C were obtained.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(O)C.[N+]([NH:31][C:32](N)=[O:33])([O-])=O>O>[NH2:31][C:32]([N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:33]
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
A mixture of 4.89 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, 50 ml of 95% ethanol and 2.1 g of nitrourea was refluxed at 70° C. until the evolution of gas had ceased. After refluxing for an additional 30 minutes, the mixture was cooled, treated with 200 ml of water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 3.5 g (64.81%) of 1-aminocarbonyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 155°-160° C.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:31])[C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=3)=[CH:11][S:12][C:8]=2[C:7]([C:34]2[CH:38]=[CH:37][S:36][C:35]=2[CH:39]=[O:40])=[CH:6][N:5]=1>CN(C)C=O.C(Cl)Cl>[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:31])[C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=3)=[CH:11][S:12][C:8]=2[C:7]([C:34]2[CH:38]=[CH:37][S:36][C:35]=2[CH2:39][OH:40])=[CH:6][N:5]=1
Reactant: COc1cc(-c2csc3c(-c4ccsc4C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(-c4ccsc4CO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
Sodium borohydride (9.4 mg, 0.223 mmol) was added to a mixture of N-{4-[4-amino-7-(2-formylthien-3-yl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (40.0 mg, 0.0743 mmol) in N,N-dimethylformamide (5 mL) under an atmosphere of nitrogen gas. The solution was stirred for 20 hours at room temperature after which it was diluted with methylene chloride and was washed with water (10 mL) and brine (10 mL). The organics were dried over magnesium sulfate and the solvent was removed in vacuo. The product was purified via flash chromatography to furnish the title compound as a yellow powder (12.0 mg, 0.0222 mmol). LCMS (Conditions a): (MH+)=541.0, RT=3.70 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.60 (d, J=5.1 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 7.35-7.32 (m, 2H), 7.24 (d, J=5.1 Hz, 1H), 7.21 (d, J=1.56 Hz, 1H), 7.13 (m, 1H), 7.09 (dd, J=8.2, 1.56 Hz, 1H), 5.58 (br, 2H), 4.57 (d, J=5.5 Hz, 2H), 4.02 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17]COCC.[N+](=C)=[N-].C(O)(=O)C>C(OCC)(=O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:17])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCCCC(=O)O)cc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CCCOc1ccc(C(C)=O)cc1

Procedure:
4-(p-Acetylphenoxy)butyric acid (4.1 g.) was suspended in ethyl acetate (80 ml.), and to the suspension was added dropwise an ether solution of diazomethane with stirring under ice-cooling until a color of the diazomethane was appeared. After the stirring was continued at the same temperature for additional half an hour, a small amount of acetic acid was added to the reaction mixture, and then the solution was stirred for a while. This solution was evaporated to dryness under reduced pressure and the residue was treated with a mixture of isopropyl ether and n-hexane (1:1 by volume) to give methyl 4-(p-acetylphenoxy)butyrate (3.83 g.).