Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:34])[N:28]2[CH2:31][CH:32]=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:32][CH2:31][N:28]2[C:29]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:30]=3)[CH:25]=[CH:26][C:27]2=[O:34])[CH2:4][C@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2c1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3S,4R)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (300 mg, 1.20 mmol) and [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (260 mg, 1.12 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (762 mg, 3.6 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (337 mg, 62%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: N.[Cl:2]CC[N:5](CCCl)C1C=C(Cl)C2OC3C(C)=CC(C(O)=O)=CC=3S(=O)(=O)CC=2C=1.[CH3:31][O:32][C:33]([C:35]1[CH:36]=[C:37]([CH3:60])[C:38]2[O:44][C:43]3[C:45]([Cl:56])=[CH:46][C:47]([N:49]([CH2:53][CH2:54]Cl)[CH2:50][CH2:51]Cl)=[CH:48][C:42]=3[CH2:41][S:40](=[O:58])(=[O:57])[C:39]=2[CH:59]=1)=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(Cl)(Cl)Cl>[ClH:2].[CH3:31][O:32][C:33]([C:35]1[CH:36]=[C:37]([CH3:60])[C:38]2[O:44][C:43]3[C:45]([Cl:56])=[CH:46][C:47]([N:49]4[CH2:50][CH2:51][NH:5][CH2:54][CH2:53]4)=[CH:48][C:42]=3[CH2:41][S:40](=[O:57])(=[O:58])[C:39]=2[CH:59]=1)=[O:34]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCl)cc(Cl)c1O2
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Product: Cl
Temperature: 70 °C
Reaction time: 9 h

Procedure:
Aqueous ammonia solution (25%, 300 mL) was added to 2-[bis-(2-chloroethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid (52 g, 0.109 mol) [prepared by alkaline hydrolysis of compound of Example 12] in methanol (100 mL). The reaction mixture was sealed under nitrogen atmosphere, kept at 110° C. for 9 h, cooled and the seal was opened. The reaction mixture was concentrated to remove solvent and ammonia, and azeotroped with toluene. The product was taken in methanolic HCl solution (300 mL) and stirred at 70° C. for 9 h. The reaction mixture was cooled, solid separated was filtered, washed with methanol and dried under vacuum to obtain the crude product. The crude product was dissolved in chloroform and treated with aqueous sodium carbonate to obtain the free base, which was purified by column chromatography (silica gel, 5% methanol in chloroform) to obtain freebase of the title compound. Yield: 32 g (68%). This was converted to the hydrochloride salt using methanolic HCl. mp: 277-280° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.66 (s, 3H, CH3), 3.19 (m, 4H, 2CH2), 3.40 (m, 4H, 2CH2), 3.85 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.05 (s, 1H, Ar) and 8.20 (s, 1H, Ar); MS: m/e (ES+) 437 (M+1, free base); analysis: C20H22Cl2N2O6S requires C, 50.75; H, 4.68; N, 5.92; Cl, 14.98; S, 6.77. found: C, 50.85; H, 4.62; N, 6.14; Cl, 15.30; S, 6.80%.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[C:25]([CH3:26])[CH:24]=2)([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:21])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(CBr)c1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) slurry of sodium hydride (0.29 g, 12 mmol) in anhydrous dimethylformamide (50 mL), a solution of ethyl N-tert-butoxycarbonyl-3-oxo-piperidine-4-carboxylate (2.73 g, 10 mmol) in DMF (10 mL) was added. The mixture was stirred at 0° C. for 30 min., and at room temp. for 30 min. The resultant solution was cooled back to 0° C. and treated with 3-methylbenzyl bromide (1.63 mL, 12 mmol). The reaction mixture was stirred at room temp. overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 17.5% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>C(#N)C>[CH3:1][N:2]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: CNCCNC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCN(C)c1ncccc1[N+](=O)[O-]

Procedure:
To a solution of N,N'-dimethylethylenediamine (3.2 ml) and potassium carbonate (830 mg) in acetonitrile (15 ml) stirred at 20°-25° under a nitrogen atmosphere is added a solution of 2-chloro-3-nitropyridine (500 mg) in acetonitrile (10 ml) over one hour. The mixture is concentrated under reduced pressure and partitioned between methylene chloride (75 ml) and water (25 ml). The phases are separated and the aqueous phase is extracted with methylene chloride (25 ml) and the total organics are dried with saline and sodium sulfate. Concentration under reduced pressure gives the title compound, NMR (CDCl3) 8.29, 8.10, 6.69, 3.85, 2.90, 2.88 and 2.46 δ.
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[N:10][N:9]([CH3:12])[C:8]=2[CH:13]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CC1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:3]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[C:4]2[CH:5]=[CH:6][C:7]3[N:11]=[N:10][N:9]([CH3:12])[C:8]=3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cn1nnc2ccc(C(Br)c3ccc(Cl)cc3)cc21
Reactant: c1c[nH]cn1
Agent: Br
Solvent: Cc1ccccc1
Product: Cn1nnc2ccc(C(c3ccc(Cl)cc3)n3ccnc3)cc21
Temperature: 80 °C
Yield: 29.7 %

Procedure:
A solution of 203 parts of 6-[bromo(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole monohydrobromide and 170 parts of 1H-imidazole in 1350 parts of methylbenzene was stirred for 28 hours at reflux temperature. The reaction mixture was allowed to cool to 80° C. and then evaporated. The oily residue was dissolved in dichloromethane. The organic layer was washed with a diluted hydrochloric acid solution. The separated aqueous layer was treated with a sodium hydroxide solution and extracted with dichloromethane. The combined dichloromethane layers were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. To the residue were added 210 parts of 1,1'-oxybisethane and the whole was allowed to stand over weekend. The solid product was filtered off and dried at 50° C., yielding 48.1 parts (29.7%) of 6-[(4-chlorophenyl)(1H-imidazol-1 -yl)methyl]1-methyl-1H-benzotriazole; mp. 87.7° C. (compound 63).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26]C2CCCCO2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:33]C2CCCCO2)[CH2:15][C:14]1=[O:40])=[O:4]>C(O)(=O)C.O.O1CCCC1>[CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([OH:33])[CH2:15][C:14]1=[O:40])=[O:4]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC

Procedure:
At 40°, 300 mg. of (5Z,13E)-(8R,11R,12R,15S)-1-(N-methylcarbamoyloxy)-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-9-one was agitated with 9 ml. of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10) for 6 hours. The mixture was then evaporated to dryness under vacuum. After purifying the residue by chromatography on silica gel (ether/ethyl acetate 7+3), 145 mg. of the title compound was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[CH:5]=[C:4]([N:17]2[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18]2)[N:3]=1.C(Cl)(Cl)Cl.[C:27](Cl)(Cl)=[O:28].Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[N:17]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[N:7]3[O:8][C:27](=[O:28])[N:1]=[C:2]3[N:3]=2)[CH2:18][CH:19]=[CH:20][CH2:21][CH2:22]1
Reactant: COCCOC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCOC(=O)Nc1cc(N2CC=CCC2)nc2nc(=O)on12

Procedure:
2 G. of 2-methoxyethyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide are dissolved at 0° C. in 15 ml. of chloroform and 3.7 ml. of triethylamine. The cold stirred mixture is treated with 3.2 ml. of 20% phosgene in toluene. The mixture is then stirred for 4 hours, acidified with hydrochloric acid, washed with water and extracted with methylene chloride. The organic phase is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue obtained is crystallized from methylene chloride and ether, there being obtained pure 2-methoxyethyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-pyrimidine-7-carbamate having a melting point of 195°-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]I>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:20])[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(NCC1CCCO1)c1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.30 g of 4-bromo-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide (compound D2) are dissolved in 150 ml of dry tetrahydrofuran. 590 mg of sodium hydride (strength 60 wt. % dispersion in mineral oil) are added in portions to the solution. After 15 min, 1.67 ml of methyl iodide are slowly added and the reaction mixture is stirred at room temperature for 20 hours. Subsequently, the suspension is concentrated in vacuo, extracted using 200 ml of ethyl acetate and 100 ml of half-saturated brine (sodium chloride solution). The organic layer is dried using Na2SO4, filtered with suction, and concentrated in vacuo to yield 4.53 g of the title compound as an oil. ESI-MS: 334.2/336.0 (MH+, 100%:98%). TLC: Rf=0.78 (dichloromethane/ethanol 20:1 parts by volume).
Reaction SMILES: [C:1]([Si:7]([CH3:10])([CH3:9])Cl)([CH:4](C)[CH3:5])([CH3:3])[CH3:2].N1C=CN=[CH:12]1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25].O>CN(C=O)C>[C:1]([Si:7]([CH3:10])([CH3:9])[O:25][C:17]1[CH2:18][C:19]2[C:24]([CH:16]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:4][CH2:5][CH3:12])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: O=C1Cc2ccccc2C1
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C)(C)[Si](C)(C)OC1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
A solution of thexyldimethylchlorosilane (100.0 g, 559.3 mmol) and imidazole (38.08 g, 559.3 mmol) in DMF (350 mL) was reacted with 2-indanone (67.40 g, 510.0 mmol) and then stirred for two days at room temperature. The reaction mixture was treated with water (300 mL). and extracted with Et2O (3×200 mL). The combined organic phases were washed with water (2×200 mL) and dried over sodium sulfate. Evaporation of the solvents left a red oil. Distillation under reduced pressure gave 116.89 g (83.5%) of the title compound as a yellow oil (bp. 128-130° C./0.4 mbar). 1H NMR (CDCl3, δ): 7.24-7.10 (m, 3H); 7.00 (td, 3J=7.3 Hz, 4J=1.3 Hz, 1H); 5.74 (d, 4J=0.6 Hz, 1H); 3.28 (s, 2H); 1.70 (sept, 3J=6.8 Hz, 1H); 0.93 (s, 6H); 0.92 (d, 3J=6.8 Hz, 6H); 0.29 (s, 6H). 13C NMR (CDCl3, δ): 162.82; 145.71; 137.03; 126.86; 123.45; 122.73; 119.29; 106.92; 40.00; 34.49; 25.51; 20.51; 18.89; −2.26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20].[I-:21]>S([O-])([O-])(=O)=O.[Ag+2].CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([I:21])[C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2F)c(F)c1
Reactant: [I-]
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(F)c1

Procedure:
methyl 2,2′-difluoro-4′-methoxybiphenyl-4-carboxylate (585 mg, 2.10 mmol), methanol (10 mL), iodide (534 mg, 2.10 mmol), silver sulfate (655 mg, 2.10 mmol) were stirred at room temperature. LCMS indicated formation of the desired compound. Reaction crude was worked up w/Na2HSO3 (aq., sat.). All volatiles were removed from the resulting mixture. The pot residue was worked up w/Na2SO4/EtOAc/filtration/concentration to afford a light brown solid. The crude solid was purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by a 0% to 20% EtOAc/hexanes mixture. 5 major fractions were spilled by accident. The remaining related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=403.97; found=404.92 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([Cu])#[N:22]>CC(N(C)C)=O.CCOC(C)=O>[N+:18]([C:3]1[CH:4]=[C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[C:21]#[N:22])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)ccc1Br
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine (0.55 mmol) in DMA (4 mL) add CuCN (0.60 mmol). Stir the mixture 4 hours at 110° C. Cool to room temperature, dilute with 20 ml of EtOAc, and filter through celite pad. Wash the filtrated with brine, dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to give 2-nitro-4(3-trifluoromethyl-pyridin-2-yl)-benzonitrile.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][N:7]=[C:8]=[O:9]>ClCCl>[CH3:6][NH:7][C:8]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:9]
Reactant: CN=C=O
Reactant: CCCCN
Solvent: ClCCl
Product: CCCCNC(=O)NC
Reaction time: 8 h

Procedure:
280.32 Grams (3.84 moles) of butylamine and 300 ml of dichloromethane were charged to a round bottom flask equipped with stirrer, cold bath, thermometer, addition funnel and reflux condenser. 229.8 Grams (4.03 Moles, a 5% excess) of methyl isocyanate were charged to the addition funnel and added to the flask contents over four hours keeping the contents between 0° and 35° C. After an additional hour of stirring the exothermic reaction subsided and the mixture was allowed to stand overnight.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:22][C:23]1[CH:28]=[CH:27]C(B(O)O)=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH3:21].[C:32](=O)([O-:34])[O-:33].[Na+].[Na+].S(=O)(=O)(O)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.O.CO.C(O)CO>[CH2:17]([O:22][C:23]1[CH:28]=[CH:27][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[C:6]([C:32]([OH:34])=[O:33])=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:13][CH:12]=2)=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CCCCCOc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCCO
Solvent: O
Solvent: CO
Product: CCCCCOc1ccc(-c2ccc(-c3ccccc3C(=O)O)cc2)cc1
Temperature: 95 °C

Procedure:
32.4 g of 4′-iodobiphenyl-4-carboxylic acid are introduced together with 25.8 g of glycol ester of 4-n-pentoxyphenylboronic acid and 15.9 g of sodium carbonate into 300 ml of methanol/ethylene glycol 9:1 and, while stirring vigorously, 70 mg of PdCl2(PPh3)2 are added, and the mixture is stirred under reflux for 6 hours. The hot reaction mixture is cautiously poured into a mixture of 30 g of 37% strength sulfuric acid and 200 g of water, and the mixture is heated at 90-100° C. for 30 minutes. After filtration and washing with water, the crude product is dried at 80° C./100 bar and then recrystallized from dimethylacetamide. This affords after drying 28.9 g (80%) of 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid with a purity of >99%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@@H:7]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][C@H:5]1[CH2:29][CH3:30])(=[O:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[C:37]([OH:40])(=[O:39])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:37]([OH:40])=[O:39].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:21]=[CH:20][C:17]([CH2:18][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6][C@@H:5]1[CH2:29][CH3:30])(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC[C@@H]1C[C@H](Nc2ccccc2)c2cc(-c3ccc(C=O)cc3)ccc2N1C(C)=O
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Product: O=CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
A solution of 4-[(2R,4S)-1-acetyl-2-ethyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzaldehyde (for a preparation see intermediate 92) (50 mg, 0.125 mmol), piperidine (0.019 mL, 0.188 mmol) and acetic acid (0.014 mL, 0.251 mmol) in dichloromethane (DCM) (4 mL) was stirred at room temperature under nitrogen for 30 min before being treated with sodium triacetoxyborohydride (34.6 mg, 0.163 mmol) portionwise. The resulting mixture was stirred at room temperature for 72 h then was partitioned between DCM (10 mL) and a saturated NaHCO3 aqueous solution (10 mL). The layers were separated and the organic phase was dried using a hydrophobic frit then concentrated in vacuo. Purification of the residue by MDAP (modifier: formic acid) gave (cis)-1-acetyl-2-ethyl-N-phenyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine formate salt (14.8 mg, 0.029 mmol, 23%).
Reaction SMILES: [C:1](=O)([O-])O.[K+].IC.[F:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C@@H:24]([CH2:29][N:30]([CH3:32])[CH3:31])[CH2:25][C:26]([OH:28])=[O:27])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C@@H:24]([CH2:29][N+:30]([CH3:1])([CH3:32])[CH3:31])[CH2:25][C:26]([O-:28])=[O:27])=[O:22]
Reactant: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium hydrogencarbonate (24 mg, 0.24 mmol) and iodomethane (106 mg, 0.74 mmol) were added to a solution of (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid (77 mg, 0.19 mmol) in methanol (2.5 mL). The reaction mixture was stirred at room temperature for 16 h, then diluted with chloroform (5 mL). Insoluble material was removed by filtration to afford (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-trimethylammonio-butyrate as a light yellow solid, m/e=429.3 ([M+H]+).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH:26]=O)[CH3:21].[NH2:35][C:36]([NH2:38])=[O:37].Cl>CCO>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:26]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=3)[NH:38][C:36](=[O:37])[NH:35]2)[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH3:21]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COCOc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(O)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 44.1 %

Procedure:
A mixture of 1-(4-(methoxymethoxy)phenyl)-2-phenylethanone (Intermediate 20) (100 mg, 0.39 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (69 mg, 0.33 mmol), urea (59 mg, 0.98 mmol), and concentrated HCl solution (0.03 mL, 0.33 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 48 (65.12 mg, yield 45%). 1H NMR (CD3OD 400 MHz): δ 7.62 (s, 1H), 7.20 (s, 1H), 7.10-7.05 (m, 5H), 6.90 (d, J=6.8 Hz, 2H), 6.66 (d, J=8.0 Hz, 2H), 5.31 (s, 1H), 4.11-4.04 (m, 2H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 448.0[M+1]+.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(O)(=O)C.C(NC(=O)[O-])C.[CH3:19][O:20][C:21]1C=C[C:24]2[CH:25]([CH3:33])[CH:26]3[CH2:30][NH:29][CH2:28][CH:27]3[C:31]=2[CH:32]=1.Cl[CH2:35][CH2:36][Cl:37]>>[Cl:37][C:36]1[C:35]2[CH:27]3[CH2:28][NH:29][CH2:30][CH:26]3[CH:25]([CH3:33])[C:24]=2[CH:31]=[C:32]([Cl:8])[C:21]=1[O:20][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Reactant: ClCCCl
Agent: CCNC(=O)[O-]
Solvent: CC(=O)O
Product: COc1c(Cl)cc2c(c1Cl)C1CNCC1C2C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
NCS (63 mg, 0.47 mmol) and acetic acid (1 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (43 mg, 0.16 mmol) in DCE (1 mL), and the reaction solution was stirred for 3 hours at 70° C. The reaction was quenched with H2O and the solution filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The subtitle compound was obtained without further purification. MS calculated for C16H19Cl2NO3+H: 344, observed: 344.