Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:33][C:34]([NH2:36])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([C:28](=[O:29])[NH:40][CH2:39][CH2:37][OH:38])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:33][C:34]([NH2:36])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCOC(=O)C1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCC(C(=O)NCCO)CC3)cc2)cc1NCc1ccccc1
Yield: 97 %

Procedure:
20 mg of 4-(benzylamino)-6-{[4-(4-ethoxycarbonylpiperidino)phenyl]amino}pyridine-3-carboxyamide (Example 175) and 50 mg of ethanolamine were stirred at 150° C. for 2 hours. After cooling, the reaction mixture was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 20 mg (89%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[CH:13](N(C(C)C)CC)(C)C.[Si](C=[N+]=[N-])(C)(C)C>C(#N)C.CO.CCOCC>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cccc2c(O)cccc12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: CC#N
Product: COc1cccc2c(N)cccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63 %

Procedure:
To a mixture of 10 g of 5-amino-1-hydroxynaphthalene in 250 ml of acetonitrile and 25 ml of methanol was added 15 ml of diisopropylethylamine followed by 44 ml of 2M TMSCHN2 in ether. The mixture was stirred at room temperature for 3.5 h after which it was concentrated to a dark oil. The material was purified by flash chromatography on silica gel, eluting with ethyl acetate/dichloromethane/heptane to provide 6.9 g (63%) of 5-amino-1-methoxynaphthalene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:9]1[CH:14]=CC=C[CH:10]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].C(OCCCC)CCC>[Pt](=O)=O.[Cu].CO.C1(C)C=CC=CC=1.O1CCCC1>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH:9]=[CH:10]1
Reactant: Nc1ccccc1
Reactant: Ic1ccccc1
Agent: O=[Pt]=O
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: C1=CNc2ccccc2C1

Procedure:
In Step A, a substituted benzaldehyde undergoes an aldol condensation with a substituted 2-nitroacetophenone in the presence of an inorganic base, such as NaOH, in a polar protic solvent such as a methanol/water mixture, to give the corresponding α,β-unsaturated ketone of formula (I). This product can then be reduced to the corresponding saturated aniline (II) by hydrogenation in the presence of a catalyst such as platinum (IV) oxide in a polar solvent such as methanol or tetrahydrofuran or a mixture of the above as described in Step B. The aniline (II) can be coupled with iodobenzene by heating at 160° C. in the presence of copper (0), potassium iodide and potassium carbonate in a polar solvent such as butyl ether as described in Step C. In Step D, the aniline of formula (IV) can be acylated by heating at reflux in the presence of an acyl chloride, such as methyl oxalyl chloride, in an apolar solvent such as toluene. The amide (IV) can cyclize by heating at reflux in a polar protic solvent, such as methanol, in the presence of an inorganic base such as potassium carbonate as described in Step E to afford the corresponding 1,4-dihydroquinoline.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:23]([NH:20][C@H:17]1[C@H:15]2[C@H:14]([CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C=O
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)CN[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aS,4R,6aR)-2-(3-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (100 mg, 0.299 mmol) from Step A of Example 254 and pivalaldehyde (0.043 mL, 0.389 mmol) were combined in dichloromethane (1 mL). Acetic acid (0.3 mL) was added. The reaction was stirred at room temperature for 20 minutes, then PS-cyanoborohydride (147 mg, 0.359 mmol) was added. The reaction was stirred at room temperature for 72 hours, then filtered. The reaction mixture was washed with 1 N NaHCO3 and concentrate in vacuo. The crude material was purified using a 12 g silica gel cartridge with a gradient of 0-4% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.40-8.41 (bs, 1H), 8.22-8.25 (m, 1H), 7.92-7.95 (m, 1H), 7.75 (t, J=7.8 Hz, 1H), 3.42 (dd, J=9.8, 3.1 Hz, 1H), 3.17 (dd, J=9.6, 3.1 Hz, 1H), 3.06-3.10 (m, 1H), 2.96 (dd, J=9.6, 7.7 Hz, 1H), 2.74-2.77 (m, 1H), 2.48-2.53 (m, 1H), 2.30 (d, J=11.3 Hz, 1H), 2.22-2.27 (m, 1H), 2.22 (d, J=7.9 Hz, 1H), 1.78-1.92 (m, 2H), 1.18-1.31 (m, 3H), 0.90 (s, 9H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)cc1

Procedure:
0.175 g (0.321 mmol) of (2R*,4S*)-2-benzyl-1-(4-methoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.047 g (1.25 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR100## is obtained (0.100 g, 69%) as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.21, FD-MS:M+ =465; IR:1620 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O:21]CC)=[O:20])=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+:26]>O1CCCC1.O.O1CCCC1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O-:21])=[O:20])=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.[Li+:26]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCOCC3)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cnc2cc(OCCN3CCOCC3)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
Ethyl 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (1 g, 3.13 mmol) was dissolved in tetrahydrofuran/water (4:1, 0.5 M). Lithium hydroxide monohydrate (131 mg, 3.13 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was then further diluted with tetrahydrofuran and concentrated. The resulting material was dried under high vacuum for 6 hours to give lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (979 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.[C-:11]#[N:12].[K+].C([O-])(O)=O.[Na+]>ClCCl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Clc1cc(Br)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a stirred solution of 4-bromo-1-(bromomethyl)-2-chlorobenzene (7.19 g, 25.3 mmol) in dichloromethane (60 mL) and water (60 mL) is added tetrabutylammonium bromide (0.82 g, 2.53 mmol). Potassium cyanide (4.94 g, 75.8 mmol) in water (60 mL) is then added. The resulting solution is stirred 4 h at room temperature and quickly turned orange. A saturated solution of NaHCO3 aq. is then added and the mixture extracted with CH2Cl2 (3×100 mL). The combined organic layer is washed with brine, dried over anhydrous MgSO4 and filtered on a silica gel pad. The pad is rinsed with CH2Cl2 and the filtrate concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-chlorophenyl)acetonitrile (5.38 g, 92%) contaminated with bromoform. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.60 (1H, d, J=1.9 Hz), 7.47 (1H, dd, J=8.3, 1.9 Hz), 7.39 (1H, d, J=8.3 Hz), 3.79 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]#[N:10])[C:3]=1[O:11][CH3:12].[H-].[Na+].[CH2:15](I)[CH3:16]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH2:15][CH3:16])[C:9]#[N:10])[C:3]=1[O:11][CH3:12]
Reactant: CCI
Reactant: COc1c(Cl)ccnc1CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C#N)c1nccc(Cl)c1OC
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
2-(4-Chloro-3-methoxy-2-pyridinyl)-acetonitrile (7.06 g) is dissolved in THF (40 ml) and 60% sodium hydride (1.62 g) is added followed by 3.25 ml of ethyl iodide. The reaction is allowed to stir at 45° C. for 1.5 hour then the reaction mixture is diluted with water and extracted with ethyl acetate. The desired product is purified by chromatography using hexane/ethyl acetate 4/1 as solvent.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([C:3]1([CH3:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of tert-butyl 3-cyanopyrrolidine-1-carboxylate (1.0 g, 5.1 mmol) in THF (20 mL) at −78° C. was slowly added LiHMDS (1.0 M in THF, 5.6 mL, 5.6 mmol). The reaction mixture was stirred at −78° C. for 30 min then iodomethane (0.48 mL, 7.64 mmol) was slowly added. The reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature and quenched with saturated aqueous NH4Cl. Diluted with H2O and extracted with EtOAc (2×) then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 40% EtOAc/hexanes) to afford 0.95 g (89%) of tert-butyl 3-cyano-3-methylpyrrolidine-1-carboxylate as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15](=[S:19])([NH2:18])[CH2:16][CH3:17].C(=O)([O-])O.[Na+]>C(O)C>[CH2:16]([C:15]1[S:19][CH:2]=[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:18]=1)[CH3:17]
Reactant: CCC(N)=S
Reactant: O=C(CBr)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1nc(Cc2ccc([N+](=O)[O-])cc2)cs1
Yield: 95.1 %

Procedure:
A mixture of 1-bromo-3-(4-nitrophenyl)-2-propanone (0.50 g), propanethioamide (0.17 g) and ethanol (10 mL) was heated under reflux for 2 hrs. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-4-(4-nitrobenzyl)-1,3-thiazole as a colorless oil (0.45 g, yield 96%) from a fraction eluted with hexane-ethyl acetate (9:1-4:1, v/v).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]#[N:30])=[CH:24][C:19]=1[C:20]([NH:22][CH3:23])=[O:21].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:17][C:18]2[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:24][C:25]([C:29]#[N:30])=[CH:26][C:27]=2[CH3:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: CNC(=O)c1cc(C#N)cc(C)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 17.5 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 2003/015519 for a method of preparation) (97.4% purity, 15 g, 0.049 mol) and 2-amino-5-cyano-N,3-dimethylbenzamide (see PCT Patent Publication WO 2006/62978 for a method of preparation) (10.0 g, 0.0525 mol) in acetonitrile (80 mL) was added 3-picoline (13.9 g, 0.148 mol). The mixture was cooled to 15 to 20° C., and then methanesulfonyl chloride (8.2 g, 0.071 mol) was added dropwise. After 1 h, water (37.3 g) was added dropwise to the reaction mixture while maintaining the temperature at 15 to 20° C. The mixture was heated at 45 to 50° C. for 30 minutes, and then cooled to 15 to 25° C. for 1 h. The mixture was filtered, and the solids collected were washed with acetonitrile-water (approximately a 5:1 mixture, 2×10 mL) and acetonitrile (2×10 mL), and then dried under nitrogen to afford the title compound (24.0 g, 93.6% corrected yield based on an assay of 91.6%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.Cl[Pd-2](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>[F:1][C:2]1[C:7]([C:17]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1nccnc1I
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1C=C(c2nccnc2F)CCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-Fluoro-3-iodopyrazine (2.5 g, 11.16 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (3.10 g, 13.95 mmol), and sodium carbonate (3.55 g, 33.5 mmol) were suspended in DME (20 ml) and distilled water (5 ml). Argon was bubbled through the resulting mixture for 3 minutes, and dichlorobis(triphenylphosphino)palladium (ii) (0.431 g, 0.614 mmol) was added. The resulting mixture was stirred at 80° C. for 16 hours, the reaction was cooled to RT, and water (200 ml) was added. The resulting mixture was concentrated under reduced pressure and was extracted with EtOAc (3×200 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% to 20% EtOAc in hexanes) afforded 3-(3-fluoropyrazin-2-yl)cyclohex-2-enone as a light yellow solid. MS (ESI, pos. ion) m/z: 193.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[NH2:25][CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:27]1[OH:35]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:25][CH:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]2[OH:35])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NC1Cc2ccccc2[C@@H]1O
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-2-amino-indan-1-ol.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14]Br)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCOc1ccc(Br)c2ccccc12
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc(Br)c3ccccc23)cc1

Procedure:
The solution of 7.0 g. of 2-(4-bromo-1-naphthyloxy)ethyl bromide and 7.9 g. of ethyl 4-aminobenzoate in 50 ml. of hexamethylphosphoramide is heated for 18 hours, then cooled and diluted with 50 ml. of water. The precipitate is collected and crystallized from 200 ml. of methylcyclohexane and then from 100 ml. of ethanol, m.p. 126°-127° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:14]=2[CH:15]=1)[CH2:8][CH2:9][CH3:10].C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl-].C[N+](C)(C)C.O>[CH2:7]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][C:14]=2[CH:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1cc2cc(N)ccc2o1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Methanesulfonyl chloride (0.92 g, 0.6 mL, 8.0 mmol) was added dropwise to a stirred boiling mixture of 2-butyl-5-benzofuranylamine hydrochloride [12a] (0.90 g, 4.0 mmol), tetramethylammonium chloride (0.11 g, 1.0 mmol) and toluene (10 mL) for 1 hour. The mixture was stirred under reflux conditions for 1 hour. Ethyl acetate (20 mL) and water (30 mL) were added to the cold mixture. The organic layer was separated and aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give 1.01 g (94.0%) of N-(2-butyl-5-benzofuranyl)methanesulfonamide [14] with mp 104.9-105.9° C.
Reaction SMILES: [SH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>CN(C)C=O.O>[CH2:27]([O:26][C:24](=[O:25])[C:23]([S:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1)([CH3:30])[CH3:29])[CH3:28]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(S)cc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1cc(C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-mercapto-2-methyl-5-nitrobenzoate (1.17 g) in N,N-dimethyl-formamide (20 ml) were added potassium carbonate (1.42 g), ethyl 2-bromoisobutyrate, and the mixture was stirred at 80° C. for 4 hours. After the reaction was complete, water and 2N hydrochloric acid were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by column chromatography to give a crude product of the title compound (3.56 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH2:15]([O:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2c(OCc3ccccc3)cccc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a mixture of 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (Uchiyama M. et al Org. Lett. 2006, 8(24), 5517-5520) (2.0 g, 10.4 mmol) and benzyl bromide (1.78 g, 10.4 mmol) in DMF in an ice bath was added sodium hydride (60% dispersed in mineral oil, 624 mg, 15.6 mmol). Resulting mixture was stirred at 0° C. for 10 min and then at rt for 6 h. Reaction mixture was quenched with water (250 mL), neutralized using 1 N HCl to pH=6-7 and extracted with EtOAc (2×). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Crude product was triturated with hexanes (50 mL). Solid was collected and dried in vacuo to provide the title compound 2.5 g. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.54 (m, 2H), 7.37 (m, 4H), 6.57 (m, 2H), 5.25 (s, 2H), 1.71 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([C:19]1([NH2:44])[C:25](=[O:26])[N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:20]1=[O:43])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([C:19]2([NH2:44])[C:25](=[O:26])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:20]2=[O:43])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as a white solid (melting point=139-141° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.46 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: Cl[C:2]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:5]([C:6]([N:8]=[C:9]([NH2:11])[NH2:10])=[O:7])=[CH:4][C:3]=1[S:16]([CH3:19])(=[O:18])=[O:17].[C:20]([O-:23])([O-])=O.[K+].[K+]>C[Si](C)(C)OC1C=NC=CC=1>[NH2:10][C:9]([NH2:11])=[N:8][C:6](=[O:7])[C:5]1[C:12]([CH2:14][CH3:15])=[CH:13][C:2]([O:23][C:20]2[CH:9]=[N:8][CH:6]=[CH:5][CH:4]=2)=[C:3]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Agent: C[Si](C)(C)Oc1cccnc1
Agent: [K+]
Product: CCc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
1.5 g of 4-chloro-N-diaminomethylene-3-methylsulfonyl-6-ethyibenzamide [obtainable by reacting guanidine with 3-methylsulfonyl-4-chloro-6-ethyl-benzoic acid], 10 ml of 3-trimethylsilyloxypyridine and 2.9 g of K2CO3 are stirred, at 140° for three hours, in small sealed flasks. After cooling, the solid residue is separated off, washed with a little diethyl ether and dissolved in 50 ml of water. After the customary working-up, N-diaminomethylene-3-methylsulfonyl-6-ethyl-4-(3-pyridyloxy)benzamide is obtained, m.p. 219-223°.