Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([CH:42]=[CH:43][CH3:44])[CH:39]=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1>CCO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH3:44])[CH:39]=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:33])[F:34])[N:3]=1
Reactant: CC=Cc1ccc(-c2cccc(S(C)(=O)=O)c2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(-c2cccc(S(C)(=O)=O)c2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-(prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.26 mmol) in EtOH (10 mL) was added 10% Pd/C (200 mg) and the reaction mixture was stirred under 1 atm H2 for 12 h. The solids were filtered and the filtrate was concentrated to afford (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid that is used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)-methoxy)acetate (1 eq.) was dissolved in dichloromethane (10 ml/mmol) and cooled, and trifluoroacetic acid (13 eq.) was added slowly at 0° C. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo and dried. The crude product was used in the next stage without being purified further. Yield: quantitative
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO.Cl>[Cl:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccccc1
Temperature: 80 °C
Yield: 41 %

Procedure:
Ethyl 4,6-dichloronicotinate (10.0 g, 45.44 mmol) in EtOH (100 mL) was stirred till a clear solution was obtained followed by addition of aniline (3.90 mL, 43.17 mmol) and 10 drops of conc. HCl. The resulting solution was heated to 80° C. for 2-3 h. The reaction mass was cooled to room temperature, poured onto ice-cold water and then extracted with EtOAc (3×250 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was then purified over silica gel (100-200 M, 2% EtOAc-hexane) to obtain the desired product ii (4.90 g, 39%). 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (br s, 1H), 8.66 (s, 1H), 7.28-7.49 (m, 5H), 6.77 (s, 1H), 4.35 (q, J=7.20 Hz, 2H), 1.34 (t, J=7.20 Hz, 3H). [M+H]+ m/z=277.17.
Reaction SMILES: [Na].[OH:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][CH:5]=[CH:6][C:7]([OH:9])=[O:8]>>[OH:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCC(O)CC=CC(=O)O
Agent: [Na]
Product: CCCCCC(O)CCCC(=O)O
Reaction time: 52 h

Procedure:
A 21 bioreactor containing 1 1 medium of pH 6 and 35° C. was seeded with an inoculum of 50 ml of Clostridium tyrobutyricum I-776. The mixture was stirred at 300/min, and strict anaerobic and sterile conditions were maintained. After several hours, when the culture started to grow, indicated by the evolution of gas from the solution, the medium was fed with the sodium salt of 5-hydroxy-2-decenoic acid. After 52 h, 5-hydroxy-decanoic acid was obtained in a concentration of 1.75 g/l, corresponding to a conversion of 27%. 8δDecalactone can be obtained by acidification of the primary product.
Reaction SMILES: C12N([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][NH:31]2)[CH2:28]1)=[O:26].ClC1C=NC2C(=CC=CC=2)N=1>>[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][N:31]2[C:9]2[CH:18]=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:28]1)=[O:26]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Clc1cnc2ccccc2n1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3cnc4ccccc4n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 19 and 2-chloro-quinoxaline. MS (ESI) mass calcd. for C26H22N4O, 406.49; m/z found, 407.2 [M+H]+.
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].O=S(=O)=O.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:11]1[C:10]([OH:16])=[CH:15][CH:14]=[C:13]([S:2]([OH:5])(=[O:3])=[O:1])[CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Agent: O=S(=O)=O
Product: O=S(=O)(O)c1ccc(O)cc1
Reaction time: 1 h

Procedure:
440 parts of 66% oleum are added slowly at from 60° to 70° C. to 500 parts of melted phenol, and the mixture is subsequently sulfonated at 100° C. for 1 hour. The phenolsulfonic acid formed is then slowly heated at from 160° to 165° C. in a vacuum of from about 11 to 13 mm, so that only a little phenol distils off, and is maintained at this temperature until 1 g of the condensation product neutralizes 3.5 to 3.7 cm3 of 1N sodium hydroxide solution against Congo red. 90 to 100 parts of phenol are added to the condensation product thus formed, and, after the phenol has been mixed in thoroughly, the reaction mixture is again placed slowly under vacuum and heated at 165° C. in a vacuum until 1 g of the condensation product neutralizes only 2.7 to 2.5 cm3 of 1-normal sodium hydroxide solution against Congo red. 100 parts of this condensation product are melted carefully with 54 parts of 30% sodium hydroxide solution, 22 parts of 37% formaldehyde solution are added, and the mixture is then subjected to condensation at from 100° to 105° C. (about 6 hours) until a sample diluted with a little water remains clear down to a pH of 3.5 when acidified with dilute sulfuric acid.
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].CC1C=CC(S(O[CH2:16][C:17]2([CH3:21])[CH2:20][O:19][CH2:18]2)(=O)=O)=CC=1.C(OCC)(=O)C>C(O)C.CCCCCC>[CH3:16][C:17]1([CH2:21][S:3][C:1]#[N:2])[CH2:20][O:19][CH2:18]1
Reactant: N#C[S-]
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(CSC#N)COC1
Temperature: 85 °C
Yield: 304.4 %

Procedure:
KSCN (0.75 g, 7.81 mmol) was added to a solution of (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (1 g, 3.90 mmol) in ethanol (25 mL) and the resulting reaction mass was heated at 85° C. overnight. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure to afford 1.7 g of the crude product which was used for the next step without further purification.
Reaction SMILES: Cl[SiH:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:10]([C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[C:28]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]=1[OH:40])[C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]=1[OH:25].C(N(CC)CC)C>>[C:32]([C:30]1[CH:29]=[C:28]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]2[O:40][SiH:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:25][C:12]3[C:13]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16][C:11]=3[S:10][C:26]=2[CH:31]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cl[SiH](Cl)c1ccccc1
Reactant: CC(C)(C)c1cc(Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[SiH](c1ccccc1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)S2
Yield: 40.8 %

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 5.3 grams (0.03 mole) dichlorophenylsilane, 13.3 grams (0.03 mole) 2,2'-thio-bis(4,6-di-t-butylphenol), and 6.1 grams (0.06 mole) triethylamine. Recrystallization from acetone gives 6.7 grams (41% yield) of white solid, mp 175°-177° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][S:15]([O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)[CH:7]=1)(=[O:17])=[O:16]
Reactant: OCc1cccc(-c2nnn[nH]2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
50 mg (0.28 mmol) of the compound from Example 49A are dissolved in 5 ml of dry dichloromethane, and 33 μl (0.43 mmol) of methanesulfonyl chloride and 0.06 ml (0.43 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 10 h. The reaction mixture is then diluted with 10 ml of dichloromethane and washed in each case once with in each case 5 ml of water, 1 N hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. Removal of the solvent on a rotary evaporator gives a solid which is used in the next reaction without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]=[C:14]1[SH:21].C(N(CC)CC)C>C(O)C>[CH3:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]=[C:14]1[S:21][CH2:2][C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cc(=O)n(C)c(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(=O)n(C)c(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of 2-(bromomethyl)-1,3,4-trichlorobenzene (576 mg, 2.1 mmol), 3,6-dimethyl-2-sulfanyl-3,4-dihydropyrimidin-4-one (300 mg, 1.9 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The solid product was suspended in water (30 mL). The solid material was recovered by filtration, washed with water (2×10 mL) and hexanes (2×20 mL), and dried in vacuo, affording the title compound (475 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.31 (s, 3H), 4.77 (s, 2H), 6.08 (s, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.68 (d, 1H, J=8.8 Hz); M+ 350; HPLC purity: 95.8%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([CH2:35]O)[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)C.O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([O:6][CH2:35][C:22]1([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]1)=[O:5]
Reactant: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc([N+](=O)[O-])c2N)(c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-5-chloro-3-nitrobenzoic acid (500 mg, 2.3 mmol), tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (714 mg, 2.3 mmol), and dimethylaminopyridine (282 mg, 2.3 mmol) in dichloromethane (6.6 mL) was added 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (664 mg, 3.46 mmol) in one portion. The suspension was stirred overnight. The reaction was poured into water and diluted with diethyl ether. The ethereal was washed with water, then saturated sodium bicarbonate, then water. The ethereal was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→30% ethyl acetate/n-hexane) gave 0.88 g (75%) as a yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.31 (d, J=2.4 Hz, 1H), 8.27 (bs, 2H), 7.87 (d, J=2.8 Hz, 1H), 7.36 (dd, J=8.9, 5.2 Hz, 2H), 7.09 (dd, J=8.9, 8.6 Hz, 2H), 4.25 (s, 2H), 3.81 (m, 2H), 3.06 (m, 2H), 2.25 (m, 2H), 1.86 (m, 2H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 165.5, 161.8 (d, J=248 Hz), 154.9, 145.8, 138.6, 136.8, 133.5, 131.6, 128.8 (d, J=7.7 Hz), 118.9, 115.8 (d, J=21 Hz), 115.4, 79.8, 73.2, 40.8, 39.9, 32.2, 28.5.
Reaction SMILES: Cl.[CH2:2]([C@H:9]([N:25]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:43][CH:42]=1)C(=O)C=CC1C=CC(C(F)(F)F)=CC=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C(C1C=CC(C=O)=CC=1)CCCC.[BH4-].[Na+]>CO.O>[CH2:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[C@@H:9]([NH:25][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:45][CH:46]=2)[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Agent: CCCCCc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.7 %

Procedure:
N—[(S)-1-Benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide hydrochloride (2 g, 5.55 mmol) was dissolved in methanol (50 mL), followed by the addition of triethylamine (0.562 g, 5.55 mmol) and 4-n-pentylbenzaldehyde (1.076 g, 6.10 mmol). The mixture was heated to reflux for 5 h, cooled to rt and sodium borohydride (0.6 g, 15.8 mmol) was added in several portions over a period of 60 min. Stirring at rt was continued for 12 h, followed by the addition of water (2 mL). The mixture was concentrated under reduced pressure, to the residue was added water (100 mL) and the product was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silicagel, heptane/EtOAc=1/1) to give 906 mg (32%) of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one. LC-MS: tR=0.77 min; [M+H]+=484.44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[Mg].II.[Cl:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=[O:25]>C1COCC1.O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]([OH:25])[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: COc1cccc(CBr)c1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CC(O)c2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 304.8 %

Procedure:
A mixture of 3-methoxy-benzylbromide (40 mg, 0.2 mmol), magnesium turnings (172 mg, 7.1 mmol) and a small crystal of iodine in dry THF (0.6 mL) was heated at 40° C. until an exothermic reaction to initiated. A solution containing a mixture of 1-(3,5-dichloro-benzyl)-1H-imidazole-2-carbaldehyde (255 mg, 1.0 mmol) and 3-methoxy-benzylbromide (241 mg, 1.2 mmol) in THF (2.5 mL) was then added dropwise to the stirred reaction mixture. After the addition was complete, the mixture was poured into cold water (20 mL) and extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20:1 CH2Cl2/iPrOH) to provide the desired 1-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-2-(3-methoxy-phenyl)-ethanol (230 mg, 61%) as an off-white solid: ESI MS m/z 377 [C19H18Cl2N2O2+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4]>CS(O)(=O)=O>[OH:10][C:7]1[C:6]([CH3:11])=[C:5]2[C:3](=[C:2]([CH3:1])[C:8]=1[CH3:9])[O:4][C:3](=[O:4])[CH2:2][C:8]2([CH3:9])[CH3:7]
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: CS(=O)(=O)O
Product: Cc1c(C)c2c(c(C)c1O)C(C)(C)CC(=O)O2
Temperature: 70 °C
Yield: 75 %

Procedure:
A mixture of 2,3,5-trimethyl hydroquinone (10 g, 0.0657 mol) and methyl 1,1-dimethylacrylate (7.5 g, 0.0657) in 50 ml of methanesulfonic acid was heated to 70° C. for 2 hours. Upon cooling to room temperature, the mixture was poured into 100 ml of ice-cold water. The resulting mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with water and dried over sodium sulfate. After removal of the majority of ethyl acetate, the mixture was cooled −20° C. The pale white solid was collected by filtration, washed with cold ethyl acetate and dried under vacuum oven. The yield was 75%. 1H NMR (300 MHz, CD2Cl2) δ ppm: 4.69 (s, 1H, OH), 2.59 (s, 2H, CH2), 2.53 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.20 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.44 (s, 3H, CH3); MS (m/e): 235 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:18][CH2:19][OH:20])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].[CH3:23]I>CN(C)C=O.CCOCC>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH2:18][CH2:19][O:20][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: Cc1c(Br)cnn1CC1(OCCO)CCCC(C)(C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCOC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 180B (2.2 g) in N,N-dimethylformamide (20 mL) was added sodium hydride (0.38 g). After stirring for 30 minutes, methyl iodide (0.60 mL) was added. The reaction mixture was stirred for 2 hours at room temperature, diluted with ether (100 mL) and washed with water (2×75 mL) and brine (75 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 25% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([OH:12])=O.[N+:22]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([O-:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[N+:22]([O-:24])=[O:23])=[O:12]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2ccccc2[N+](=O)[O-])ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
To thionyl chloride (20 mL) was added 3-methoxy-4-(pyridin-2-yl)benzoic acid (500 mg, 2.2 mmol). The mixture was heated at reflux for 3 h, cooled to rt, and concentrated. The resultant acid chloride was taken up in 20 mL of CH2Cl2 and the mixture cooled to 0° C. before addition of 2-nitroaniline (301 mg, 2.2 mmol) and triethylamine (0.3 mL, 2.2 mmol), and the solution warmed to rt overnight. The reaction mixture was diluted with CH2Cl2, washed successively with water, saturated Na2CO3, and brine, and the organic layer dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:1 to 1:1) to afford the desired 3-methoxy-4-(pyridin-2-yl)-2′-nitrobenzanilide as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2([NH2:11])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:12]C1C=CC(C#N)=CC=1>>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: NC1(c2cccc(Cl)c2)CC1
Reactant: N#Cc1ccc(Cl)cc1
Product: NC1(c2ccc(Cl)cc2)CC1

Procedure:
was prepared using the same procedure as for the preparation of 1-(3-chloro-phenyl)-cyclopropylamine starting from 4-chlorobenzonitrile. MS (UPLC-MS): 170 [M+H]+, 168 [M−H]; tR (HPLC conditions f): 1.21 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]([N+:27]([O-:29])=[O:28])[CH:22](O)[CH2:23][O:24][CH3:25])[CH3:18].C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]([N+:27]([O-:29])=[O:28])[CH:22]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:12][CH:11]=1)[CH2:23][O:24][CH3:25])[CH3:18]
Reactant: c1ccc(Cc2cccc3[nH]ccc23)cc1
Reactant: CCOC(=O)C(C(O)COC)[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C(COC)c1c[nH]c2cccc(Cc3ccccc3)c12)[N+](=O)[O-]
Yield: 87 %

Procedure:
Under argon, 2.80 g (13.5 mmol) of 4-benzylindole is refluxed for 15 hours with 7.48 g (18 mmol) of a 50% strength solution of 4-methoxy-3-hydroxy-2-nitrobutyric acid ethyl ester in 84 ml of toluene with 8.3 ml of glacial acetic acid. After cooling, the reaction mixture is diluted with ethyl acetate and washed with water. The organic phase is dried, filtered, and concentrated, and the residue is chromatographed over silica gel with methylene chloride as the eluent, thus producing 4.7 g (87%) of 3-(4-benzylindol-3-yl)-2-nitro-5-oxahexanoic acid ethyl ester, which latter is hydrogenated in 50 ml of ethanol with 4.7 g of Raney nickel B 115-Z under normal pressure and at room temperature. After separation of the catalyst and evaporation, the product is chromatographed over silica gel with methylene chloride:ethanol=10:1, thus obtaining 1.16 g (24%) of 2-amino-3-(4-benzylindol-3-yl)-5-oxahexanoic acid ethyl ester; this product is combined with 349 mg of glyoxylic acid hydrate in 4 ml of ethyl acetate and 4 ml of water, adjusted to pH 4 with 10% potassium carbonate solution, and stirred overnight at room temperature. After the ethyl acetate has been removed by distillation, the product is diluted with water, extracted with methylene chloride, and the organic phase is dried, filtered, and concentrated, thus obtaining 1.7 g of a crude product which, without further purification, is refluxed in 40 ml of xylene for 5 hours. After concentration, the mixture is taken up in 40 ml of dimethyl sulfoxide, combined with 200 mg of sulfur, and heated for 75 minutes to 140° C. After the dimethyl sulfoxide has been removed by distillation, the mixture is chromatographed twice over silica gel, first with methylene chloride:ethanol=10:1 and then again with hexane:acetone=1:1, yielding 45 mg of 5-benzyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 160°-168° C.