Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[N:26]>N1C=CC=CC=1>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:30]4[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=4)(=[O:35])=[O:34])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.026 g, 0.08 mmol), 4-cyanobenzenesulfonyl chloride (0.019 g, 0.10 mmol) and pyridine (0.40 ml) was stirred at room temperature overnight. Most of pyridine was removed under reduced pressure and the residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 25%-100% acetonitrile-0.1M ammonium acetate over 25 min, 21 ml/min) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxy-phenyl]-4-cyano-1-benzenesulfonamide as yellow solids (0.018 g, 0.04 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 9.91 (s, 1H), 8.13 (s, 1H), 8.05 (d, 2H), 7.89 (d, 2H), 7.44 (s, 1H), 7.27 (d, 1H), 7.00 (dd, 1H), 6.98 (d, 1H), 6.07 (broad, 2H), 5.07 (m, 1H), 3.49 (s, 3H), 2.11 (m, 2H), 1.88 (m, 4H), 1.69 (m, 2H); MH+489; TLC (ethyl acetate/methanol=9:1) Rf 0.49; RP-HPLC (Hypersil C18, 5 μm, 200 A, 25 cm; 25%-100% acetonitrile-0.1M ammonium acetate over 25 min, 1 ml/min) Rt 14.65 min.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:28]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)=O)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:28](/[C:20]1[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:30]1[O:31][C:32]([CH3:35])=[N:33][N:34]=1)[CH3:16]
Reactant: Cc1nnc(C(=O)c2cc(Br)cc(C(F)(F)F)c2)o1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1cc(Br)cc(C(F)(F)F)c1)c1nnc(C)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a suspension of NaH (60%, 1.13 g, 28.35 mmol) in dry THF (20 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (6.49 g, 28.35 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-trifluoromethyl-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanone (9.047 g, 27 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5 N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9 g of the desired product (Yield: 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]=O.N1C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:2]2[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)=[CH:12][CH:11]=1
Reactant: Nc1cccc(Br)c1
Reactant: Oc1ccc(F)cc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Nc1cccc(Oc2ccc(F)cc2)c1
Temperature: 210 °C

Procedure:
In a dry microwave vessel with stir bar, 3-bromoaniline (316 μL, 0.029 mol) and 4-flourophenol (716 mg, 0.064 mol) were added to anhydrous pyridine (10 mL) under nitrogen. To this was added potassium carbonate (1.6 g, 120 mol) and copper(II) oxide (1.2 g, 145 mol). The microwave vessel was sealed then heated in the microwave at normal absorbance at 210° C. for 40 min. The cooled reaction was filtered through a bed of Celite with ethyl acetate. The filtrate was then washed 3 times with concentrated aqueous NaHSO4 and twice with concentrated aqueous NaCl. The organic layer was then dried over magnesium sulfate, filtered and concentrated. Purification over silica using an eluent of hexane and ethyl acetate with a gradient of 0-23% ethyl acetate over 45 min gave 3-(4-fluoro-phenoxy)-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(Cl)(Cl)=O.CO[CH2:24][CH2:25][O:26]C>>[CH2:17]([C:25]1([OH:26])[CH2:8][CH2:9][N:10]([C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH2:2][CH2:24]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Reactant: COCCOC
Solvent: O=S(Cl)Cl
Product: O=C(c1cccnc1Cl)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-chloronicotinic acid (1.0 g), toluene (15 mL) and DME (5 mL) was added thionyl chloride (0.51 mL), and the mixture was stirred at 90° C. for 4 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in THF (15 mL), and triethylamine (0.97 mL) and 4-benzyl-4-hydroxypiperidine (1.1 g) were added thereto. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.9 g).
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:14]1(=[O:27])[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[CH2:17][CH2:16][CH2:15]1.[CH3:28][C:29]1[N:33](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:32]=[N:31][C:30]=1[CH:53]=O.S(=O)(=O)(O)O>C1COCC1.FC(F)(F)C(O)=O>[CH3:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1/[CH:53]=[C:15]1/[C:14](=[O:27])[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[CH2:17][CH2:16]/1
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCc2sc3ccccc3c21
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1[nH]cnc1/C=C1\CCc2sc3ccccc3c2C1=O
Reaction time: 1.5 h
Yield: 44.5 %

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) (1.5M in cyclohexane; 3.6 ml) was added dropwise to a solution of 3,4-dihydro-1(2H)-dibenzothiophenone (1.0 g) in dry THF (30 ml) at -65°. The resultant solution was stirred at -65° for 1 h and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (1.9 g) was then added. The reaction mixture was stirred for a further 1.5 h, whilst it was allowed to warm to 0°. The solution was quenched with acetic acid (6 ml) and the resultant suspension was treated with water (10 ml) and p-toluenesulphonic acid (10.2 g). The reaction mixture was heated at reflux for 17 h, added cautiously to 8% aqueous sodium bicarbonate (300 ml), and extracted with dichloromethane (2×120 ml). The combined organic extracts were dried and evaporated to give an oil which was heated at reflux in a mixture of trifluoroacetic acid (60 ml) and concentrated sulphuric acid (0.3 ml) for 40 min. The reaction mixture was concentrated in vacuo to ca. 10 ml, added cautiously to 8% aqueous sodium bicarbonate (300 ml) and the resultant suspension was extracted with dichloromethane (2×120 ml). The combined organic extracts were dried and evaporated to give a foam which was purified by FCC eluting with System A (100:5:0.5) to give the title compound (648 mg) as a solid, m.p. 220°-223°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.O.ON1C2C=CC=CC=2N=N1.[CH2:30]([N:37]1[CH2:41][CH2:40][C@@H:39]([NH2:42])[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O.C(N(CC)CC)C>[NH3:3].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:42][C@@H:39]1[CH2:40][CH2:41][N:37]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:38]1)=[O:18]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N
Product: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.5 %

Procedure:
Triethylamine (0.167 ml) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (100 mg) [see Preparation 3], 1-hydroxybenzotriazole hydrate (60.4 mg), (3R)-1-benzylpyrrolidin-3-ylamine (78.7 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85.4 mg) in dichloromethane (30 ml). The reaction mixture was stirred at room temperature for 18 hours, after which time the mixture was diluted with water and the organic layer was separated, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 50:50:0, changing to 25:75:0, changing to 20:80:1, by volume, hexane:ethyl acetate: 0.88 aqueous ammonia solution to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-[(3R)-1-benzylpyrrolidin-3-yl]-2-piperidinecarboxamide as a yellow oil (94 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[C:20]([F:33])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:25][N:26]([CH3:32])[C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[C:20]([F:33])[CH:19]=1
Reactant: CCCC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CCCC(=O)N(C)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A solution of 2,6-difluorobenzoylisocyanate (2.0 g) in a 1:1 mixture of toluene and petroleum ether (5 ml) was added at room temperature over 30 minutes to a stirred solution of the compound of Example 3 (4.4 g) in the same solvent (20 ml). After stirring at room temperature for 2 hours, the solid product was filtered off and recrystallised from a mixture of diethyl ether and petroleum ether to give 4.3 g of the desired product, melting point 136°-138° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1)[C:29]([C:42](O)=[O:43])=[CH:28]2.[NH2:45][CH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49]>C(Cl)Cl.O>[OH:49][CH2:48][C:47]([CH3:51])([CH3:50])[CH2:46][NH:45][C:42]([C:29]1[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=2)[C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([Cl:24])=[CH:33][CH:32]=2)=[O:43]
Reactant: CC(C)(CN)CO
Reactant: Cc1cccc(Cn2c(C(=O)O)cc3cc(Cl)ccc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(Cn2c(C(=O)NCC(C)(C)CO)cc3cc(Cl)ccc32)c1
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.14 g, 0.57 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (0.1 μg, 0.59 mmol) were added to a solution of 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid (0.20 g, 0.67 mmol) in DCM (10 ml). After stirring for 10 min, 3-amino-2,2-dimethylpropan-1-ol (0.083 g, 0.80 mmol) was added. After stirring for 17.5 h, water (10 ml) was added, the layers separated, the organic phase washed with water (3×15 ml) and dried with magnesium sulfate. Purification was achieved by silica chromatography using DCM:methanol (3:1) as eluent. Crystallisation of the crude product afforded 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid (3-hydroxy-2,2-dimethylpropyl)amide as a white solid (0.100 g, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.O.O.[I:22](O)(=O)(=O)=O.S([O-])(O)=O.[Na+]>O.C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([I:22])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: [O-][I+3]([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(c1)Cc1cc(I)ccc1-2
Temperature: 75 °C
Yield: 382.7 %

Procedure:
A mixture of 2-bromofluorene (compound 19) (25.0 g, 0.1020 mol), glacial acetic acid (250 cm3), concentrated sulphuric acid (3 cm3) and water (20 cm3) became homogeneous on heating to 75° C. Periodic acid dihydrate (H5IO6, 4.56 g, 0.0200 mol) and pulverised 12 (10.2 g, 0.0402 mol) were added. The initial deep-purple colour changed to a brown during 2 h of heating and stirring at 75° C. Upon dilution with sodium hydrogensulphite (2.50 g) in water (25 cm3), the colour changed to yellow. The solution was subsequently diluted with water (500 cm3) and cooled to 0° C. to give a yellow precipitate. The excess liquid was decanted and the solid filtered off, washed repeatedly with cold ethanol (4×50 cm3), aqueous NaOH (5% solution, 4×50 cm3) and with water (4×50 cm3) to leave a yellow powder. The product was recrystallised from a solvent mixture of DCM and ethanol to yield a yellow powder (28.4 g, 74.9%). Melting point/° C.: 185.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:16]=1>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(C#CCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(CCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
A mixture of 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)benzoyl]pyrazole (0.45 g, 1.0 mmol) [prepared as described in Example 1] and 5% Pd/C (0.07 g) in ethanol (20 ml) was stirred under hydrogen atmosphere. After 16 h, the reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (elution gradient, EtOAc-15% MeOH/EtOAc with 0.2% NH4OH). The product was converted to the hydrochloride salt and recrystallized from a mixture of methanol/ethyl acetate to give 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.HCl (0.3 g, mpt. 211.9-212.6° C.) as a solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]([CH2:33][CH2:34][C:35]1([C:41](=O)[CH3:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[O:15]([CH2:33][CH2:34][C:35]1([CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[Si:16]([C:29]([CH3:31])([CH3:30])[CH3:32])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)C1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OCCC1(CCN2CCOCC2)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 138.6 %

Procedure:
After adding sodium triacetoxyborohydride (0.63 g, 2.98 mmol) to a solution of 1-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]acetaldehyde (1.29 g, ca. 1.97 mmol), morpholine (0.26 mL, 2.98 mmol) and acetic acid (0.23 mL, 4.02 mmol) in 1,2-dichloroethane (5 mL), the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with chloroform. The organic layer was washed with saturated brine and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (1.31 g). This was used without purification for the following step.
Reaction SMILES: [CH2:1](O)COCCOCCO.C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH2:22]([OH:40])[CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39]>CCOC(C)=O>[CH3:1][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][OH:40]
Reactant: OCCOCCOCCO
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The following description refers to the scheme illustrated in FIG. 10. Non-polydispersed activated hexaethylene glycol monomethyl ether was prepared analogously to that of non-polydispersed triethylene glycol in Example 38 above. A 20% phosgene in toluene solution (35 mL, 6.66 g, 67.4 mmol phosgene) was chilled under a N2 atmosphere in an ice/salt water bath. Non-polydispersed hexaethylene glycol 50 (1.85 mL, 2.0 g, 6.74 mmol) was dissolved in 5 mL anhydrous EtOAc and added to the phosgene solution via syringe. The reaction mixture was kept stirring in the ice bath for one hour, removed and stirred a further 2.5 hours at room temperature. The phosgene, EtOAc, and toluene were removed by vacuum distillation, leaving non-polydispersed compound 51 as a clear, oily residue.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:17]2[CH:16]=[CH:15][C:14]([S:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)=[C:13]([NH:12][C:2]3[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)[CH:18]=2)=[CH:22][CH:23]=1
Reactant: Nc1cc(OCc2ccc(Cl)cc2)ccc1Sc1ccc(O)cc1
Reactant: Clc1ccnc2ncccc12
Product: Oc1ccc(Sc2ccc(OCc3ccc(Cl)cc3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with the product from Example 143a (107 mg, 0.30 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (50 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.14 (s, 2H) 6.31 (d, J=7.36 Hz, 1H) 6.64 (d, J=8.82 Hz, 2H) 7.05-7.40 (m, J=8.46 Hz, 4H) 7.46 (m, J=5.52 Hz, 3H) 7.93 (m, J=4.41 Hz, 1H) 8.48 (d, J=6.98 Hz, 1H) 9.17 (m, J=1.47 Hz, J=5.88 Hz, 3H) 9.79 (s, 1H) 11.15 (br s, 1H) 14.54 (br s, 1H); MS (ESI+) m/z, 486 (M+H−TFA)+; (ESI−) m/z, 484 (M−H−TFA)−.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:14])(=S)[NH2:2].F[B-](F)(F)F.C([O+](CC)CC)C.[Cl-:27].[NH4+:28]>>[ClH:27].[C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:14])(=[NH:28])[NH2:2]
Reactant: [NH4+]
Reactant: NC(=S)c1cccc2c1CCCC2=O
Reactant: [Cl-]
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: Cl
Product: N=C(N)c1cccc2c1CCCC2=O

Procedure:
Analogously to Example 29b), 8.6 g (42 mmol) of 5-thiocarbamoyl-1-tetralone are treated with 8.8 g (44 mmol) of triethyloxonium tetrafluoroborate and 2.6 g (49 mmol) of ammonium chloride. There is thus obtained the title compound in the form of slightly pink-colored crystals, MS (FAB): (M+H)+ =189.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]([C:18]([O:20]CC)=[O:19])[C:8](=[O:23])[NH:7]2)([O-:3])=[O:2].[OH-].[K+].O.Cl>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[C:8](=[O:23])[NH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nc2cc(C(F)(F)F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc2cc(C(F)(F)F)c([N+](=O)[O-])cc2[nH]c1=O
Yield: 92.9 %

Procedure:
To a solution of ethyl 3,4-dihydro-6-nitro-3-oxo-7-trifluoromethylquinoxaline-2-carboxylate (120 mg, 362 μmol) in ethanol (5 ml) was added 1N aqueous solution of potassium hydroxide (724 μl, 724 μmol), and the mixture was refluxed for 1 hour. After cooling, water was added and the pH value was brought to 2 with concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and then air-dried to obtain 102 mg of the title compound as colorless powder. Yield 88%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:19][NH:20][O:21][CH3:22]>>[CH:5]1[C:13]2[CH:12]([CH2:14][C:15]([N:20]([O:21][CH3:22])[CH3:19])=[O:16])[C:11]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc21
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)CC1c2ccccc2-c2ccccc21

Procedure:
In analogy to example 55, step 1, from fluorene-9-acetic acid (CAS RN: [6284-80-6]) and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as an off-white oil, MS (ESI+): m/z=268.1 ([M+H]+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([CH3:3])[CH3:2].CN(C)[CH:14]=[O:15].P(Cl)(Cl)(Cl)=O>>[CH:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[O:10][CH3:11])[CH:14]=[O:15])([CH3:3])[CH3:2]
Reactant: COc1ccccc1C(C)C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C=O)cc1C(C)C
Temperature: 80 °C
Yield: 84.5 %

Procedure:
A 5 L three-necked round bottom flask was equipped with mechanical agitation and provided with an inert gas blanket. The flask was charged with 1-isopropyl-2-methoxybenzene (859 g, 5.85 moles) and dimethylformamide (1584 mL, 20.46 moles), and the mixture was heated to 80° C. Phosphorus oxychloride (2690 g, 17.54 moles) was added to the reaction mixture over approximately 3 h while maintaining the temperature of the reaction mixture between 80° C. and 90° C. The addition of POCl3 caused an immediate color change with continuous darkening over the course of the reaction. The reaction mixture was maintained at 80° C. for approximately 16 h, then checked by HPLC for presence of unreacted starting materials. The reaction mixture was quenched by slow addition over approximately 2 h to icewater (8 kg total, 5 kg ice); alternatively the reaction mixture was added over approximately 3 h to deionized water (10 L) in a jacketed 30 L reactor whose cooling bath was maintained between 0° and 5° C. Ethyl acetate (12 L) was added to the quenched reaction with stirring. After settling, the layers were separated, and the aqueous layer was washed with additional ethyl acetate (4 L). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (4 L) and saturated aqueous sodium chloride (4 L). The ethyl acetate was removed by vacuum distillation to yield 3-isopropyl-4-methoxybenzaldehyde (881 g, 86.5%).