Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.CCO.C[C:10]([CH3:13])([O-:12])[CH3:11].[K+].Br[CH:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1.[Cl-].[Na+].O>[O:12]1[C:10]2[CH:13]=[CH:2][CH:1]=[CH:5][C:11]=2[CH:22]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A 3-neck round bottomed flask equipped with a mechanical stirrer, a dropping funnel, a gas inlet tube, and a thermometer is charged with 24.4 g (0.2 mol) of salicyl aldehyde (Aldrich) and 800 ml of THF-EtOH (19:1) under a nitrogen atmosphere. To this solution 150 ml (0.24 mol) of potassium t-butoxide in THF (1.6M) is added dropwise over 20 min at room temperature. A milky yellow precipitate is formed during the addition. The mixture is stirred at room temperature for one hr. A solution of 57.4 g (0.24 mol) of diethyl bromomalonate (Aldrich) in 20 ml of THF is added dropwise over 10 min. The mixture becomes grayish in color. After stirring for one hr at room temperature, another portion of potassium t-butoxide in THF (150 ml, 0.24 mol) is added dropwise over 40 min at room temperature. TLC shows no starting material remaining after an additional 40 min of stirring. The mixture is poured into 500 ml of brine mixed with crushed ice and extracted twice with ethyl acetate (1 L). The organic phase is washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration affords a deep brown oil. Vacuum distillation affords pure ethyl benzofuran-2-carboxylate (boiling point 88°-91° C./0.03 mm, 32.5 g, 85%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:17][OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[OH:18][CH2:17][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:19])=[O:2])=[CH:9][CH:8]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC(CO)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(CO)c1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
4-(1-Hydroxymethyl-heptyl)-benzoic acid methyl ester (3.46 g, 12.1 mmol) is dissolved in tetrahydrofuran (40 mL) and 5N sodium hydroxide (10 mL) is added. The reaction may be monitored by HPLC and is complete within 8 h. The reaction is neutralized with 5N HCl (10 mL), and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated to provide the title compound which is used without further purification. MS (ES): 249.3 [M+H]−.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[NH:9][C:8](=O)[C:7]=2[N:21]=1.O=P(Cl)(Cl)[Cl:24].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:24][C:8]1[C:7]2[N:21]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[C:15]2[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1nc(SC)ncc12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1nc(SC)ncc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
methyl 3-(methylthio)-5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 279 mg, 0.926 mmol) was suspended in toluene (2 ml). POCl3 (2 ml) and DIEA (0.5 ml) were added and the mixture stirred at 120° C. for 5 hours. The volatiles were removed in vacuo and CH2Cl2 was added. The organic phase was washed with saturated aqueous sodium bicarbonate, washed with water and dried over Na2SO4. The solution was filtered through a pad of celite and the solvents removed in vacuo. The material was triturated in hexanes and AcOEt, filtered and dried to provide methyl 5-chloro-3-(methylthio)pyrimido[4,5-c]quinoline-8-carboxylate as a beige solid (184 mg, 63% yield). LCMS (ES): >95% pure, m/z 320 [M+1]+, 322 [M+3]+.
Reaction SMILES: [F:1][C:2]([CH:5]([C:9]([F:11])=[O:10])[C:6]([F:8])=[O:7])([F:4])[F:3].C(N(CC)CC)C.Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>CCOCC>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][C:5]([C:2]([F:4])([F:3])[F:1])([C:6]([F:8])=[O:7])[C:9]([F:11])=[O:10]
Reactant: CC(C)=CCCl
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)=CCC(C(=O)F)(C(=O)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 16 %

Procedure:
To 17.6 g (0.10 mol) of trifluoromethylmalonyl fluoride and 50 ml of ether stirred at -80°C was added dropwise a solution of 9.2 g (0.09 mol) of triethylamine in 25 ml of ether. Then 12.5 g (0.12 mol) of 1-chloro-3-methyl-2-butene was added, and the mixture was stirred at 25°C until homogeneous. After standing at 25°C for 3 days, the mixture was distilled to give 3.9 g (16%) of (3-methyl-2-butenyl)-trifluoromethylmalonyl fluoride, bp 43°-45°C (20 mm); ir (CCl4): 3.31, 3.37 and 3.42 (CH), 5.36 (C=O) and 7.5-8.5 μ (CF).
Reaction SMILES: CC([N:5]([C@H:9]([CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]Br)=[CH:13][CH:12]=1)[C:6](=[O:8])[O-:7])(C)C.[Br:33][C:34]1[C:35]([NH2:40])=[N:36][CH:37]=[CH:38][CH:39]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:33][C:34]1[C:35]2[N:36]([CH:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][C@H:9]([NH:5][C:6](=[O:8])[O:7][C:11]([CH3:16])([CH3:12])[CH3:10])[CH2:21][N:22]4[C:23](=[O:32])[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:30]4=[O:31])=[CH:12][CH:13]=3)[N:40]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Nc1ncccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 1,1-dimethylethyl{(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (6.9 mmol), 3-bromo-2-pyridinamine (8.4 mmol), and sodium bicarbonate (10.4 mmol) in isopropanol (70 mL) were stirred at 80° C. for 18 h. The reaction was then cooled to RT and a precipitate formed which was filtered, washed with cold hexanes (3×100 mL), and dried to afford the title compound as light gray solid (72%). ESMS [M+H]+: 576.2.
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH2:2][CH3:3].[C:6]1([CH:12]=[C:13]2[C:18](=O)[C:17](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][S:15](=[O:27])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[C:6]1([CH:12]2[N:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:18]3[C:17](=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][S:15](=[O:27])[CH2:14][CH:13]23)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccccc2)CS(=O)CC1=Cc1ccccc1
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3)CS(=O)CC2C1c1ccccc1
Yield: 22.3 %

Procedure:
n-Propyl hydrazine (1.14g) is added to a suspension of 3.8g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one-1-oxide in 75ml of methanol and the mixture is heated at reflux temperature for 2 hours. The crystals which form on cooling are collected to give 1.0g of the title compound, melting point 176°-177.5°C. The mother liquor is concentrated in vacuo and the residue is crystallized from acetonitrile/water (2:1) to yield an additional 0.6g of the title compound, melting point 176.5°-178°C. (isomer A)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=3[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:18]2[C:19]([F:21])=[C:20]3[C:15]([C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12][N:11]3[CH:8]3[CH2:10][CH2:9]3)=[CH:16][C:17]=2[F:23])[CH2:3]1
Reactant: N[C@H]1CCCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 79.9 %

Procedure:
A suspension of (S)-3-aminopiperidine (4.0 g) obtained as described in the step (c) above 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(11.4 g) and triethylamine (8.4 g) in acetonitrile (250 ml) was refluxed for 3 hours with stirring. Then the mixture was cooled down and filtrationof the precipitated powder followed by treatment with a mixture of ethanol (550 ml) and water (250 ml) gave (S)-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.6 g) as colorless needles. m.p. 247.8° C. (decomposition).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C(Cl)Cl>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 7.81 g. (0.040 mol.) of 2-phenylbenzofuran and 7.0 g. (0.041 mol.) of p-anisoyl chloride in 100 ml. of methylene chloride is added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture is allowed to warm to ambient temperature, then stirred for two hours. Water is slowly added to the mixture and it is stirred an additional 30 minutes. The layers are separated and the organic phase is washed with water until the washings are neutral, dried (MgSO4) and concentrated to give 3-(4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Cl[C:19]1[N:24]=[C:23](Cl)[C:22]([C:26]#[N:27])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C.[C:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1>C(Cl)Cl.C(OCC)(=O)C>[C:37]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:19]2[N:24]=[C:23]([N:8]3[CH2:7][CH2:6][C:5]4([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]4)[CH2:10][CH2:9]3)[C:22]([C:26]#[N:27])=[CH:21][N:20]=2)[CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3nc(Nc4cccc(-c5ccccc5)c4)ncc3C#N)CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (69 mg, 0.287 mol) was added to a cooled solution of the 2,4-dichloropyrimidine-5-carbonitrile (50 mg, 0.287 mmol) and Hunig's base (50 uL, 0.287 mmol) in CH2Cl2 (1.5 mL) and the reaction mixture was stirred for 3 hours at 0° C. The solvent was removed under reduced pressure, then the mixture was diluted with CH3CN (2 mL) and the biphenyl-3-amine (97 mg, 0.575 mol) was added. The mixture was then heated to 80° C. overnight. Upon cooling, the reaction mixture was diluted with ethyl acetate, washed with H2O and then brine and the organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) provided a mixture of the two possible isomers which was separated by the reverse phase chromatography to afford tert-butyl 8-[2-(biphenyl-3-ylamino)-5-cyanopyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate. MS ESI calcd. for C30H35N6O2 [M+H]+ 511, found 511.
Reaction SMILES: [CH3:1][CH:2]([NH2:11])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[C:14](=[S:16])=[S:15]>>[CH3:1][CH:2]1[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[S:16][C:14](=[S:15])[NH:11]1.[CH3:1][CH:2]1[CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][C:14](=[S:15])[NH:11]1
Reactant: S=C=S
Reactant: CC(N)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC1NC(=S)OC1c1ccccc1
Product: CC1NC(=S)SC1c1ccccc1
Reaction time: 24 h

Procedure:
Carbon disulphide (27 ml) was added to a mixture of (1S,2R)-(+)-norephedrine (5.0 g) and aqueous sodium hydroxide (50 ml of 15% solution) and the mixture stirred for 24 hours. Excess carbon disulphide was evaporated under reduced pressure and the residue poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and evaporated. The residue was chromatographed on silica gel (eluent-ether/hexane; 1:1) to give 4-methyl-5-phenylthiazolidine-2-thione and 4-methyl-5-phenyloxazolidine-2-thione. A solution of the first of these thiones (0.80 g) in dimethylformamide was treated with sodium hydride (0.12 g of 80% dispersion in oil). When hydrogen evolution had ceased, intermediate A (1.2 g) was added, over one hour, and the mixture allowed to stand for 60 hours. The mixture was poured into water and extracted with ether. The extract was worked up in conventional manner to give methyl (E)-2- 2- (4-methyl-5-phenylthiazol-2-in-2-yl)thio!methyl!phenyl!-3-methoxy-2-propenoate, as a gum. (Compound 1)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]2[CH2:63][CH2:62][N:61]([C:64](=[O:73])[CH2:65][N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)[CH2:60][CH2:59]2)=[CH:54][CH:53]=1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:51][C:52]3[CH:57]=[CH:56][C:55]([CH:58]4[CH2:63][CH2:62][N:61]([C:64](=[O:73])[CH2:65][N:66]5[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]5)[CH2:60][CH2:59]4)=[CH:54][CH:53]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(CC(=O)N2CCC(c3ccc(N)cc3)CC2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C4CCN(C(=O)CN5CCN(C)CC5)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
(4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.24 g (83%) of (4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA salt (52 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.1 Hz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 2H), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].Cl[CH2:16][S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCl
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Reaction time: 5 h
Yield: 88.3 %

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-fluoro-1-nitrobenzene (1.3 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 mL) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added drop wise (18 mL, 18 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2.25 g, 5.3 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CCNCc2ccccc2)cc1OC
Reaction time: 0.04 h

Procedure:
N-benzyl-2-(3,4-dimethoxyphenyl)ethylamine was prepared using a system (FRX200, Syrris Limited) including a microflow reactor. For this purpose, 83 μl (0.5 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine and 5 ml of tetrahydrofuran were added to the first storage unit of the system including the microflow reactor, and then 70 μl (0.5 mmol) of triethylamine was added thereto. Meanwhile, 60 μl (0.5 mmol) of benzyl bromide and 5 ml of tetrahydrofuran were added to the second storage unit of the system. The reactants included in the first and second storage units were transferred through the first and second flow channels to the mixing unit, and then transferred through the third flow channel into the microflow reactor including microchannels. The first and second flow channels could transfer 360 μl (180 μl for each flow channel) of the reactants to the microflow reactor. The microflow reactor was set at a capacity of 250 μl, a temperature of 100° C. and a pressure of 8 bar. The reactants in the first and second storage units were set such that they were passed through the first to third flow channels at a flow rate of 0.05 ml/min and introduced into the microflow reactor. Also, the residence time of the reactants in the microflow reactor was set at 2.5 minutes.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[Cl:22]C(OC(Cl)C)=O>CCOCC>[ClH:22].[F:21][C:18]([F:19])([F:20])[C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: FC(F)(F)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCOCC
Product: Cl
Product: FC(F)(F)c1ccc2c(n1)CCNC2

Procedure:
Treatment of the intermediate from Step A above with 1-chloroethyl chloroformate as described for Intermediate 20, Step C afforded the crude title compound. Trituration with ether provided the title compound as a pale orange powder. LC/MS 203.1 (M+1).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH:9]1([O:13][C:14]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:12][CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:16]([C:15]1[C:14]([O:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[C:21]([O:22][CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=1[N+:7]([O-:8])=[O:6])#[N:17]
Reactant: COc1ccc(C#N)c(OC2CCC2)c1OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])c(C#N)c(OC2CCC2)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Nitronium tetrafluoroborate (4.64 g, 0.035 mol) was added portionwise to an ice cooled solution of 2-cyclobutyloxy-3,4-dimethoxybenzonitrile (6.28 g, 0.027 mol) in acetonitrile (150 ml) and the reaction stirred for 1 hour. Saturated aqueous sodium bicarbonate solution (150 ml) was added and the mixture extracted with ethyl acetate (400 ml). The combined organic extracts were washed with water (150 ml), dried (MgSO4), filtered and evaporated under reduced pressure to give a dark brown oil. The crude product was purified on silica gel eluting with dichloromethane to give the subtitle compound as a pale yellow solid (4.01 g, 53%). Rf 0.23 (hexane:isopropyl alcohol:0.880 aqueous ammonia 90:10:0.75, v/v). MS m/z 296 (MNH4)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.CC1C=CC2C=CC3C=C[C:32](C)=[N:33]C=3C=2N=1.CN>CN(C=O)C.C1COCC1.[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]2[C:5]3[CH:6]=[CH:7][C:2]([NH:33][CH3:32])=[CH:3][C:4]=3[O:21][CH:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Agent: [Cu]I
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Anhydrous DMF was sparged with argon gas for 1 h before being used. Tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (1 g, 2.5 mmol) sodium tert-butoxide (723 mg, 7.5 mmol), neocuproine (52 mg, 0.25 mmol) and copper (I) iodide (290 mg, 1.5 mmol) were dissolved in anhydrous DMF (20 mL). To this mixture was added a 2M solution of methylamine in THF (6 mL) and the reaction shaken at 80° C. for 16 h. The solvent was evaporated and the residue dissolved in DCM and washed with H2O (3×). The solvent was evaporated and the crude residue used as such in the next reaction step.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[CH:22]=1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 416.24 g/mol.