Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=O.O=[O+][O-].[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=C)([O-:8])=[O:7].CSC>C(Cl)Cl>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:1])([O-:8])=[O:7]
Reactant: C=Cc1ccccc1[N+](=O)[O-]
Reactant: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: O=Cc1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 91.5 %

Procedure:
Oxygen enriched with 10 m-moles of ozone are introduced at -20° C. in the course of 15 minutes into a solution of 1.50 g of o-nitrostyrene in 160 ml of methylene chloride. The faintly blue solution is scavenged with nitrogen until the colour has disappeared, treated with 10 ml of dimethyl sulphide and left to stand overnight at room temperature. The clear solution is concentrated in vacuo and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water and sodium chloride solution, dried over sodium sulphate and concentrated. The crude product (1.75 g) is taken up in benzene and the solution is chromatographed through a column of silica gel (15 g). The first 100 ml of eluate are concentrated in vacuo, affording 1.39 g of pure o-nitrobenzaldehyde. Yield: 91.5% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H][H]>CCOC(C)=O.CO.[Pd]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)O)cc(OC)c1
Yield: 96.5 %

Procedure:
To a solution of 3-(3,5-Dimethoxy-phenyl)-acrylic acid (12 g, 57.7 mmol) in EtOAc (100 ml) and MeOH (100 ml) was added carefully 10% Pd/C (1.3 g), the reaction mixture was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen, then the solution was passed through a celite pad, the filtrate was concentrated and dried at 50° C. under reduced pressure to give product (11.7 g, 96.55%). LC-MS: m/e 209 (M−1)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.Cl.CO>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:17]=[C:7]2/[O:8][C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]/2=[O:9])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(/C=C2/Oc3cc(O)ccc3C2=O)cc1OC
Reaction time: 18 h
Yield: 41.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4dimethoxybenzaldehyde 1.23 g were dissolved in acetic acid 20 ml, concentrated hydrochloric acid 1.1 ml was added, and the mixture was stirred for 18 hours, and methanol 15 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.82 g.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:20][CH2:21][CH:22]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C@@H:6]1[NH:41][C:42]([O:44]CC(Cl)(Cl)Cl)=O)(=[O:3])[CH3:2].[C:50](OC(=O)C)(=O)C>[Zn]>[C:42]([NH:41][C@@H:6]1[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7]1[O:20][CH2:21][CH:22]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:44])[CH3:50]
Reactant: CCCCCCCCCCC(CO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(=O)OCC(Cl)(Cl)Cl)NC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: [Zn]
Product: CCCCCCCCCCC(CO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 49 %

Procedure:
tert-Butyl 1-{[3,4,6-tri-O-acetyl-2-deoxy-2-(2,2,2-trichloro-ethoxycarbonyl-amino)-β-D-glucopyranosyloxy]methyl}-(R/S)-undecyl-carbamate 50(27.0 mg, 0.0353 mmol) was dissolved in acetic anhydride (1 ml) into which activated zinc powder (4.6 mg, 0.0706 mmol) had been added. The reaction was stirred for 6 hours, after which it was filtered and evaporated (and co-evaporated with benzene and toluene). The residue was purified by column chromatography to give 51 (11 mg, 49%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:13])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a stirred solution of 3-tert-butylsalicylaldehyde (5.13 g, 28.8 mmol) in acetic acid (15 mL) was added a solution of bromine (1.65 mL, 32.25 mmol) in acetic acid (7.0 mL) dropwise within 20 min. The reaction mixture was stirred at room temperature for 3 h. Analytical HPLC analysis after 3 h shows the desired product ˜72% and the unreacted starting material ˜28%. A second batch of bromine (0.5 mL) in acetic acid (3 mL) was added and the reaction mixture was stirred at room temperature for another 3 h. Analytical HPLC analysis of the reaction mixture after 3 h (6 h total) shows the desired product ˜85% and still shows the starting material ˜15%. After 6 h of stifling, the reaction mixture was diluted with dichloromethane (50 mL) and the organic layer was washed with 39% sodium bisulfite solution (1×10 mL), water, saturated NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the desired product as a pale yellow crystalline solid (7.2421 g). Purification by silica-gel flash chromatography on silica gel column and elution with 0-5% ethyl acetate in n-heptane afforded the desired product as a pale yellow crystalline solid (4.792 g, 64% yield). LC-MS analysis of the product in negative mode shows the desired product's mass: m/z 255 (79BrM+−H) and m/z 257 (81BrM+−H). GC-MS analysis of the product in CI mode (Methane) shows the desired product's mass: m/z 256 (91BrM+) and m/z 258 (81BrM+), calc'd. for C11H13BrO2: 257.124. 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H, t-Bu-), 7.50 (s, 1H, H-4), 7.56 (s, 1H, H-6), 9.79 (s, 1H, —CHO), 11.70 (s, 1H, —OH). 1H NMR of the isolated product was identical with that of a previously reported sample of the product (Girsch et al., 2007).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C@@:24]12(O)[N:31](C)[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=C2.[Na].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][C@@:9]12[N:31]([CH3:24])[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=[CH:10]2)=[O:7]
Reactant: CCOC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1)CC2

Procedure:
4.27 g (0.013 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water, shaking from time to time. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4, and evaporated to dryness. The residue remaining is mixed with diethylether/petroleum ether (1:9), suction filtered and washed. Yield: 2.50 g (46% of theory); TLC: Rf value: 0.29 (eluent: sec-butanol/formic acid/water (75:15:10)); melting point: 147° C.-148° C.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH3:13])=O)(C)(C)C.C[Si](C)(C)[N:16]1[C:20](=O)[CH:19]=[CH:18][C:17]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:13][CH:12]1[CH:19]2[CH:18]([CH2:17][NH:16][CH2:20]2)[CH:9]([NH:8][CH3:6])[CH:10]=[CH:11]1
Reactant: C[Si](C)(C)N1C(=O)C=CC1=O
Reactant: CC=CC=CNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNC1C=CC(C)C2CNCC12

Procedure:
Analogously to Example A, method I, 21.9 g (0.12 mol) of 1-(tert.-butyloxycarbonylamino)-1,3-pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide and the product is then reduced with 15.2 g (0.4 mol) of lithium aluminiumhydride. The crude product is recrystallised from tetrahydrofuran.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][C:13]=3[O:12][CH:11]([CH3:34])[C:10]=12)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:15]1[CH:16]=[CH:17][C:18]2[C:9]3[C:10](=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=[CH:7][CH:8]=3)[CH:11]([CH3:34])[O:12][C:13]=2[CH:14]=1
Reactant: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Reaction time: 12 h
Yield: 88.1 %

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((4-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.15 g, 0.319 mmol) in dichloromethane (25 mL) at room temperature was added TFA (0.246 mL, 3.19 mmol) and the mixture stirred for 12 h. After completion of reaction, the solvent was removed under reduced pressure to afford N-(8-(((S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (0.18 g, 0.281 mmol, 58% yield) as a brown oil. The product was carried forward into the next step without further purification. LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H28N3O3 370.2]; LC/MS retention time (Method C): tR=1.14 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[SH:9].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCBr
Reactant: Cc1cccc(C)c1S
Product: CCCCCCSc1c(C)cccc1C

Procedure:
This compound was synthesized from 2,6-dimethylthiophenol and hexyl bromide according to general method 4 as described above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:39])[NH:32][C:33]2([C:36]([OH:38])=O)[CH2:35][CH2:34]2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C1(C2C=CC=CC=2)C=CC=CC=1.[C:52]1([P:58](=[CH:60][C:61]#[N:62])=[O:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]1([C:15]2[CH:16]=[CH:17][CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:61]([C:60](=[P:58]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:59])[C:36]([C:33]1([NH:32][C:31]([NH:30][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:11])[F:12])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:39])[CH2:34][CH2:35]1)=[O:38])#[N:62]
Reactant: O=C(NC1(C(=O)O)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: N#CC=[P+]([O-])c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: N#CC(C(=O)C1(NC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)CC1)=[P+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81.3 %

Procedure:
To a solution of (R)-1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-cyclopropanecarboxylic acid (84 mg, 0.153 mmol), prepared by the method described in Procedure 30, in DCM (0.5 mL) was added 2-(phenylphosphinylidene)acetonitrile compound with biphenyl (1:1) (51 mg, 0.168 mmol), EDCI (32 mg, 0.168 mmol) and DMAP (3 mg, 0.024 mmol). The reaction mixture was stirred at room temperature for 4.5 h, concentrated under reduced pressure and purified by ISCO chromatography (12 g column, eluting with 0-100% hexane/EtOAc) to yield (R)-1-(1-(2-cyano-2-(phenylphosphinylidene)acetyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea compound with biphenyl (1:1) as a white solid (53 mg, 42% yield). LCMS: RT=3.49 min [M+H] 836.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-100% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 0.78-1.00 (m, 2H), 1.34-1.49 (m, 2H), 3.79-3.95 (m, 2H), 5.62-5.98 (m, 3H), 6.67-6.94 (m, 7H), 6.98-7.20 (m, 5H), 7.37-7.66 (m, 15H).
Reaction SMILES: [CH:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(#N)C>[N:46]1([C:12]([C:9]2[CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[S:11][CH:10]=2)=[O:14])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: O=C(O)c1csc(C2CCCCC2)c1
Reactant: C1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(C2CCCCC2)c1)N1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
5-(Cyclohexyl)-thiophene-3-carboxylic acid (0.03 g, 0.14 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.42 mmol), HATU (0.15 mmol) and azepane (0.14 mmol) were added and the reaction stirred at room temperature overnight. The resulting solution was purified directly by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.022 g). LCMS m/z 292.22 [M+H]+ RT=13.57 min (Analytical Method 1). 1H NMR δ (ppm) (CHCl3-d): 7.2 (s, 1H), 6.95 (s, 1H), 3.7-3.4 (m, 4H), 2.8 (m, 1H), 2.1 (m, 2H), 1.9-1.2 (m, 16H).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9]([Cl:15])=[C:10]([Cl:14])[C:11]([OH:13])=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[Cl:14][C:10]1[C:11]([O:13][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[S:8][C:7]=2[C:9]=1[Cl:15]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Yield: 42.6 %

Procedure:
To a solution of 9.0 g of 2-acetyl-6,7-dichloro-5-hydroxybenzo[b]thiophene and 200 ml of 2-butanone is added a solution of 6.62 g of ethyl bromoacetate in 50 ml of 2-butanone, 5.2 g of potassium carbonate and 2.2 ml of dimethylformamide. The reaction mixture is heated under reflux for 2 hrs, allowed to cool and filtered. The filtrate is extracted with ether (3 times). The layers are separated and the organic phase is washed with water, saturated sodium chloride solution, dried and filtered. The filtrate is evaporated. The residue is dissolved in dichloromethane and chromatagraphed on alumina, using dichloromethane as the eluant. Evaporation of the eluant gives 5.1 g of ethyl [(6,7-dichloro-2-acetylbenzo[b]thien-5-yl)oxy]acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:24]([NH:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:30][CH2:29][CH2:28][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)NCCN
Product: CC(C)NCCNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 16.7 %

Procedure:
Synthesized as in Example 26 using 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.500 g, Example 25b) and N-isopropylethylenediamine (0.186 g) to give the title compound as a solid (0.105 g).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:47][C:48]1[N:53]2[CH:54]=[C:55]([NH2:57])[N:56]=[C:52]2[C:51]([N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)=[N:50][CH:49]=1>C(Cl)Cl>[Br:47][C:48]1[N:53]2[CH:54]=[C:55]([NH:57][C:1]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[O:13])[N:56]=[C:52]2[C:51]([N:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)=[N:50][CH:49]=1
Reactant: Nc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2c(Br)cnc(N3CCOCC3)c2n1)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of quinaldic acid (236 mg, 1.36 mmol) in DCM (10 mL) were added HATU (519 mg, 1.36 mmol) and DIEA (201 μL, 1.15 mmol) at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. and treated with compound 21b (313 mg, 1.04 mmol). The resulting mixture was stirred at rt overnight. The solids formed were collected by filtration, and the organic phase was washed with saturated aqueous NH4Cl (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (9:1 DCM/EtOAc) to give compound 21c. Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H17BrN6O2: 453.0 (M+H). Found 453.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccc3)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) in dichloro methane (5 mL) was added benzoyl chloride (0.04 mL, 0.35 mmol) with ice cooling. Upon completion of addition, the resultant solution was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 70 mg of methyl 2-(4-benzamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 53%. MS (ESI+APCI) M+1=415.20.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCN(C2CCCC2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (31%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20].O>CN(C=O)C>[OH:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCCO)c1
Yield: 96.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, 3-bromo-1-propanol (500 mg, 3.6 mmol) were added. The mixture was heated to reflux for 2 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried on Na2SO4. After evaporation of the solvent the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 2/1); 520 mg (yield 95%) of title product were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1c(-c2cccc(F)c2)ccnc1Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: OCc1c(-c2cccc(F)c2)ccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.8 %

Procedure:
To a solution of 2-chloro-4-(3-fluorophenyl)nicotinic acid (8.37 g) in tetrahydrofuran (70 ml) was added thionyl chloride (11.9 g), and the mixture was heated under reflux for 2.5 hrs. The reaction mixture was concentrated and the obtained residue was dissolved in tetrahydrofuran (50 ml). This solution was added dropwise to an ice-cooled aqueous sodium borohydride (4.58 g) solution, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give [2-chloro-4-(3-fluorophenyl)pyridin-3-yl]methanol (3.07 g) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[CH2:32]O)=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:32][CH:31]=[CH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=1[N+:34]([O-:36])=[O:35]
Reactant: BrBr
Reactant: COc1ccc(/C=C/CO)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C=CCBr)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a stirred slurry of triphenyl phosphine (16.4 g, 0.627 mol) in dry DCM (150 mL) under nitrogen at 0° C., is added dropwise a solution of bromine (3.2 mL, 0.0627 mol) in DCM (30 mL). After stirring for 15 min, a solution of (2E)-3-(4-methoxy-2-nitrophenyl)prop-2-en-1-ol (10 g, 0.044 mol) in dry DCM (100 mL) is added dropwise to the reaction mixture followed by a dropwise addition of pyridine (5.05 mL, 0.06 mol) at 0° C. After stirring at room temperature for another 4 h, the reaction mixture is quenched with ice and the product extracted with DCM. The organic layer is washed with water then brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by chromatography using silica-gel (60-120 mesh) and petrol ether/EtOAc as eluent to afford (7 g, 53%) of the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.52-7.55 (m, 1H), 7.42-7.47 (m, 1H), 7.11-7.16 (m, 1H), 7.06-7.09 (m, 1H), 6.23-6.29 (m, 1H), 4.15-4.18 (m, 2H), 3.88 (s, 3H).