Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=2[S:26]([OH:29])(=[O:28])=[O:27])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[Na:30][Na:31].[OH-].[Na+].[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35]>CCOCC.C(O)(=O)C>[NH2:1][C:2]1[C:3]([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:41](=[O:42])[C:40]3[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:45][CH:44]=3)=[CH:21][C:20]=2[S:26]([OH:29])(=[O:28])=[O:27])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[Na:30][Na:31]
Reactant: Nc1ccc(N=Nc2c(N)ccc3cc(S(=O)(=O)O)cc(O)c23)c(S(=O)(=O)O)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1N=Nc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1S(=O)(=O)O
Reaction time: 0.06 h

Procedure:
A solution of 2.0 g of 6-amino-5-(4-amino-2-sulfophenylazo)-4-hydroxy-2-naphthalenesulfonic acid, disodium salt in 14.0 ml of N sodium hydroxide is treated with 2.0 g of p-nitrobenzoyl chloride and a few drops of ether. The reaction mixture is shaken for 3 to 4 minutes and then another 7 ml portion of base is added to the reaction mixture. After shaking for 15 minutes the procedure is repeated with an additional 7 ml portion of base. Finally the reaction mixture is acidified with 2 ml of glacial acetic acid, and extracted several times with ether. After the ethereal layer is separated the aqueous phase is salted with 20 g of sodium acetate trihydrate at 55° C with stirring. The reaction mixture is filtered after standing overnight at room temperature and washed with absolute ethanol and ether to give 6-amino-4-hydroxy-5-[4-(p-nitrobenzamido)-2-sulfophenylazo]-2-naphthalenesulfonic acid, disodium salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]2[O:14][CH2:15][C:16]([O:19][CH3:20])([O:17][CH3:18])[C@@H:9]12)=[O:7])([CH3:4])(C)C.Cl.N1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(OCC1C=CC=CC=1)=O>C(Cl)Cl.CO>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]2[O:14][CH2:15][C:16]([O:17][CH3:18])([O:19][CH3:20])[C@@H:9]12)=[O:7])[C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccncc1
Reactant: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]21
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a stirred solution of compound 12c (3.8 g, 13.13 mmol) in CH2Cl2 (100 mL) was added 2M HCl in MeOH (50 mL). The resulting solution was stirred overnight and then concentrated in vacuo and azeotroped with toluene (3×100 mL). The crude residue was dissolved in CH2Cl2 (100 mL) cooled to 0° C. and pyridine (1071 μL, 13.13 mmol) added followed by dropwise addition of CbzCl (1875 μL, 13.13 mmol). The reaction was stirred at room temperature for 2 hours then washed with 2 M HCl (2×50 mL), saturated NaHCO3 (2×50 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (5-100% isohexane:EtOAc) to obtain the title compound as a clear oil (2510 mg, 59%). MS M+H 324.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19](=[O:29])[C@@H:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:21]([CH3:23])[CH3:22])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]4[CH2:55][CH2:54][CH2:53][N:52]4[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(OCC)(=O)C>[CH3:27][O:26][C:25]([NH:24][C@@H:20]([CH:21]([CH3:23])[CH3:22])[C:19]([N:13]1[C@H:12]([C:10]2[NH:9][C:8]3[C:30]4[C:4]([CH:5]=[CH:6][C:7]=3[N:11]=2)=[CH:3][C:2]([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]5[CH2:55][CH2:54][CH2:53][N:52]5[C:56]([O:58][C:59]([CH3:61])([CH3:62])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)=[CH:32][CH:31]=4)[C@H:17]2[CH2:18][C@@H:14]1[CH2:15][CH2:16]2)=[O:29])=[O:28]
Reactant: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.1 %

Procedure:
Methyl (S)-1-((1S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.300 g, 0.601 mmol), (S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.334 g, 0.721 mmol), and aqueous potassium phosphate (2M, 0.901 mL, 1.802 mmol) were suspended in 1,2-dimethoxyethane (3.00 mL) and sparged with argon gas for 30 minutes. Palladium tetrakis triphenylphosphine (0.069 g, 0.060 mmol) was added and the reaction mixture was capped and placed in a preheated 80° C. oil bath. The solution was heated for 18 hours and subsequently stirred at room temperature for two days. Upon completion, the reaction was diluted with ethyl acetate and washed with brine. The concentrated organic layer was purified by normal phase chromatography (40-100% ethyl acetate (10% MeOH) in hexanes) to give (S)-tert-butyl 2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.305 g, 67%). LCMS-ESI+: calc'd for C44H49N7O5: 755.38 (M+); Found: 756.8 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].C([O-])([O-])=O.[Na+].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[CH2:23]Br)=[C:12]([CH2:25]Br)[CH:11]=1>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]2[C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[CH2:23][N:2]([CH3:1])[CH2:25][C:12]=2[CH:11]=1
Reactant: CN
Reactant: BrCc1cc(Br)ccc1-c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2cc(Br)ccc2-c2ccc(Br)cc2C1
Yield: 99.4 %

Procedure:
MeNH2 (4.9 mL, 9.87 mmol) and Na2CO3 (0.349 g, 3.29 mmol) were added to a THF (6.5 mL) solution of 4,4′-dibromo-2,2′-bis(bromomethyl)biphenyl (0.328 g, 0.658 mmol), and the reaction mixture was refluxed for 3 hours. The volatile component was removed in vacuo, and the residue was passed through MCX (CH3OH wash; 2.0 M NH3/CH3OH elution) to afford 3,9-dibromo-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine as a white solid (0.24 g). 1H NMR (DMSO-d6, δ=2.50, 500 MHz): 2.31 (s, 3H), 3.24 (s, 4H), 7.47 (d, J=7.9, 2 H), 7.55-7.82 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[I:9]N1C(=O)CCC1=O>C(#N)C>[I:9][C:4]1[NH:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]#[N:8]
Reactant: Cc1nc(C#N)c[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1nc(C#N)c(I)[nH]1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Into a 25-mL round-bottom flask, was placed a mixture of 2-methyl-1H-imidazole-4-carbonitrile (compound 16.3, 50 mg, 0.47 mmol), N-iodosuccinimide (116 mg, 0.52 mmol) in ACN (5 mL). The resulting solution was heated at reflux overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/2) to yield 60 mg (55%) of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>CCOCC>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: Cc1ccc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-methyl-pyridine (Acros Organics) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][CH:17]([NH2:21])[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:21][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH3:16])([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CC(N)C(=O)O
Product: CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O
Yield: 14 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-2-aminopropionic acid to provide the title compound in 14% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—10, 1, 0.2 and recrystallization from DMF/water).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:8]([NH:10][C@H:11]([C:18](OC)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].O.[NH2:30][NH2:31]>CO>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:30][NH2:31])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
27.9 g of Boc-Gln-His-OCH3 (Marchiori et al., J. Chem. Soc (C) 1967, 81) are dissolved in 280 ml of highest purity methanol, 28 ml of hydrazine hydrate are added and the mixture is left to stand for 20 hours at 25°C. It is concentrated to dryness in a high vacuum and the residue is recrystallised from methanol-ethyl acetate-petroleum ether. Melting point 187°-189°C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[CH:9]=[CH2:10].[CH3:12][CH:13]=[CH:14][PH:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[CH2:8]([O:11][PH:15]([CH2:14][CH:13]=[CH2:12])=[O:16])[CH:9]=[CH2:10]
Reactant: C=CCO
Reactant: CC=C[PH](=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCO[PH](=O)CC=C
Yield: 29.1 %

Procedure:
202 g of triethyl amine (2 mols) were added while stirring at 0° to 5° C. to a solution of 116 g of allyl alcohol (2 mols) in 1 l of anhydrous chloroform and then 249 g of methylvinyl phosphinic acid chloride (2 mols) were added dropwise over a period of about 1 hour. After suction filtration, the solid residue (triethyl amine hydrochloride) was dissolved in water, the emerging oily layer was separated and combined with the filtrate. To remove the chloride ions the filtrate was shaken 4 times, each time with 600 ml of water, dried over sodium sulfate and the chloroform was distilled off in a rotary evaporator. The brown oily residue was distilled under a pressure of 0.01 mm at a temperature of the oil bath of 40° C. 85 g of a colorless liquid were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:17]=1)(=[O:14])=[O:13].CN(CCO[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1Cl)N)C.BrC1C(OC)=C(OC)C=CC=1S(Cl)(=O)=O>ClC(Cl)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][S:12]([C:3]2[C:2]([C:35]3[CH:36]=[CH:37][CH:39]=[CH:40][CH:41]=3)=[CH:7][C:6]([O:8][CH3:9])=[C:5]([O:10][CH3:11])[CH:4]=2)(=[O:14])=[O:13])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27]
Reactant: CN(C)CCOc1cc(N)ccc1Cl
Reactant: COc1cc(Br)c(S(=O)(=O)Nc2ccc(Cl)c(OCCN(C)C)c2)cc1OC
Agent: COc1ccc(S(=O)(=O)Cl)c(Br)c1OC
Solvent: CC(Cl)Cl
Product: COc1cc(-c2ccccc2)c(S(=O)(=O)Nc2ccc(Cl)c(OCCN(C)C)c2)cc1OC
Yield: 72 %

Procedure:
2-Bromo-4,5-dimethoxybenzenesulfonyl chloride To a cooled (0° C.) solution of 4-bromoveratrole (15 mL, 100 mmol) in dichloromethane (100 mL) was added dropwise chlorosufonic acid (26 mL, 400 mmol). The reaction was allowed to slowly warm to ambient temperature and maintained for 3 hours, at which time it was concentrated and diluted with ether (300 mL). The resultant solution was then washed with ice cold water (2×250 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated to furnish a grayish powder (25 g, 78%). b) 2-Bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide To a solution of 3-[2-(N,N-dimethylamino)ethoxy]-4-chloroaniline (1.9 g, 8.8 mmol) in dichloroethane (50 mL) was added 2-bromo-3,4-dimethoxybenzenesulfonyl chloride (2.8 g, 8.8 mmol). The resultant solution was maintained at ambient temperature for 3 days, then concentrated. Crystallization from ethanol gave the title compound (3.4 g, 72%). MS (ES+) m/e 493 [M+H]+ c) 4,5-Dimethoxy-biphenyl-2-sulfonic acid [4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-amide To a solution of 2-bromo-N-[4-chloro-3-(2-dimethylamino-ethoxy)-phenyl]-4,5-dimethoxy-benzenesulfonamide (50 mg, 0.1 mmol) in dimethoxyethane/water (25:3, 2 mL) was added phenylboronic acid (120 mg, 1.0 mmol), cesium carbonate (820 mg, 2.5 mmol), and tetrakispalladium triphenylphosphine (6 mg, 0.005 mmol). The resultant mixture was heated at 90° C. for 16 hours, at which time it was diluted with ethyl acetate (10 mL) and washed with 5% sodium hydroxide (2×10 mL) and brine (10 mL). The solution was then dried over magnesium sulfate and concentrated to give a yellow oil. Purification by HPLC (gradient; 10% acetonitrile/water to 90% acetonitrile/water) furnished the title compound (15 mg, 31%) as a white solid. MS (ES+) m/e 491 [M+H]+ Example 20 was prepared as outlined in Example 19, substituting the appropriate starting materials.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:32][CH:33]=1)[CH3:23]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(Cl)c2)c2ccccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2cccc(Cl)c2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-chlorophenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:17](=[O:19])[CH3:18])=[N:6][CH:7]=1
Reactant: NCCc1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCCc1ccc(Br)cn1
Temperature: 25 °C

Procedure:
A mixture of 200 mg (1.00 mmol) 2-(5-bromopyridin-2-yl)ethanamine, 86.6 μL (1.09 mmol) pyridine and 2 mL DCM is charged with 103 μL (1.09 mmol) acetic anhydride and stirred at r.t. over night. The mixture is treated with saturated aq. NaHCO3 solution and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is evaporated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11](Cl)[C:10]([CH3:14])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.[CH2:23]([Mg]Br)[CH:24]([CH3:26])[CH3:25].C[Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:10]([CH3:14])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[Mg]Br
Reactant: Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Agent: C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)OC(C)(C)C)cc1CC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-Chloro-6-methyl-nicotinic acid tert.-butyl ester (3.09 g, 13.5 mmol), Fe(acac)3 (719 mg, 2.04 mmol) and NMP (1.95 mL, 20 mmol) are dissolved in THF (3 M, 500 mL) and cooled at −78° C. A solution of isobutylmagnesium bromide in THF (2 M, 13.6 mmol) is slowly added at −75° C. The brown solution turns turbid and yellow. Stirring is continued for 1 h at −75° C. before it is slowly warmed to rt. The reaction is incomplete, further Fe(acac)3 (719 mg, 2.04 mmol) is added and the mixture is cooled again at −70° C. Further methylmagnesium bromide in THF (2 M, 13.6 mmol) is slowly added at −70° C. The dark green mixture is slowly warmed to rt and stirred for 15 h. The mixture is carefully quenched with 0.7 N aq. HCl (150 mL). The mixture is extracted with EA (6×60 mL). The combined org. extracts are dried over Na2SO4, filtered and evaporated. The residue is purified by reversed phase MPLC to give 6-methyl-5-isobutyl-nicotinic acid tert.-butyl ester as black oil (0.50 g); LC-MS: tR=0.84 min, [M+1]+=250.14.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][S:17][CH2:18][CH2:19][NH2:20].CO.C(OC(C)C)(C)C>>[CH3:16][S:17][CH2:18][CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: CSCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CSCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Yield: 66.7 %

Procedure:
A mixture of trans-stilbene oxide (1.18 g, 0.006 mol) and 2-(methylthio)ethylamine (0.78 g, 0.0085 mol) was heated at 140° C. in an oil bath for 15 hours. The cooled solid reaction mixture was triturated with isooctane and the red-brown solid collected. This was triturated with methanol-isopropyl ether giving an off-white solid (1.15 g, 67% yield); mp 163°-165° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[F:19].C([O-])=[O:21].[Na+].C(O)C>O>[F:19][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=2[C:15]([F:18])([F:17])[F:16])[C:3]=1[CH2:2][OH:21]
Reactant: O=C[O-]
Reactant: COc1ccc2c(CBr)c(F)ccc2c1C(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(CO)c(F)ccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 1-bromomethyl-2-fluoro-6-methoxy-5-(trifluoromethyl)naphthalene (11.16 g, 35 mmol), sodium formate (5.85 g, 86 mmol), ethanol (134 mL) and water (34 mL) was heated to reflux with stirring. Dissolution occurred within 20 minutes. After 1.5 hours the heating source was removed, 2.5N NaOH (14 mL) was added, and the reaction mixture was cooled to room temperature. The ethanol was removed, water (100 mL) was added and the solid was filtered. The white solid was washed with water and dried in vacuo to give the product in quantitative yield. A small portion was recrystallized from petroleum ether:ethyl acetate, m.p. 113°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]Cl)[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[NH:12][C:13]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:24]=[CH:25][CH:26]=[CH:27][C:15]=3[C:14]=2[N:28]=1.[C-:29]#[N:30].[Na+]>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:29]#[N:30])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[NH:12][C:13]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:24]=[CH:25][CH:26]=[CH:27][C:15]=3[C:14]=2[N:28]=1
Reactant: ClCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: N#CCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Yield: 45.3 %

Procedure:
A solution of 2-[2,6-dichloro-4-(chloromethyl)phenyl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine (8.7 mg, 0.02 mmol), sodium cyanide (2.0 mg, 0.04 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 25° C. for 1 hour. The reaction mixture was diluted with methanol and purified on preparative LCMS at pH 10 to give the desired product (3.8 mg, 45%). LC/MS: 419 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:21][C@H:22]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH2:23][O:24][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:48](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:17][N:18]([CH3:48])[NH:19][N:20]=3)[CH2:15][C@@:9]1([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:10]([O:21][C@H:22]([C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=1)[CH2:23][O:24][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC[C@H](O[C@@H]1CC[C@H]2[C@H](c3nnn[nH]3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC[C@H](O[C@@H]1CC[C@H]2[C@H](C3=NNN(C)N3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-methoxyethoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 199; 0.05 g, 0.1 mmol), methyl iodide (0.04 g 0.02 ml, 0.3 mmol) and potassium carbonate (0.04 g, 0.3 mmol) in acetonitrile were heated at 60° C. for 1.5 hours. The mixture was quenched with water and concentrated in vacuo, the residue was partitioned between water and dichloromethane using a bond elute cartridge. The organics were collected and concentrated in vacuo and the residue purified by preparative thin layer chromatography eluting with 5% methanol/dichloromethane. The title compound was isolated as a white solid (33 mg, 58%).
Reaction SMILES: [OH-].[Na+].CO.[OH:5][C:6]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[C:15]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40]C)=[O:39])=[C:33]([CH3:42])[CH:32]=3)=[CH:27][CH:26]=2)[C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl>O1CCCC1>[C:11]([O:10][C:8]([C:7]1[C:6]([OH:5])=[C:18]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:16][C:15]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[C:33]([CH3:42])[CH:32]=2)=[CH:27][CH:26]=1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
A 1N aqueous sodium hydroxide solution (3.0 ml, 3.0 mmol) and methanol (0.5 ml) were added to a solution of tert-butyl 2-hydroxy-6-[({4′-[(methoxycarbonyl)methyl]-3′-methyl-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (667 mg, 1.26 mmol) obtained in Example (17-3) in tetrahydrofuran (8.5 ml), and the mixture was stirred at room temperature for 6 hours. After the reaction mixture was poured into 0.5N hydrochloric acid and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was crystallized from a mixture solvent of ethanol-ethyl acetate to give the title compound as a colorless powder (552 mg, yield: 84%).