Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.[Mg].[C:19](=[O:21])=[O:20]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: Brc1ccc(OCCOC2CCCCO2)cc1
Reactant: O=C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCOC2CCCCO2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 9.45 g (31.4 mmol) of 4-(2-tetrahydropyranyloxyethoxy)bromobenzene, 40 ml of dry tetrahydrofuran (THF) and 0.76 g (31.4 mmol) of magnesium metal is heated to boiling, and after about 15 minutes a spontaneous reaction ensues. The mixture is then maintained, with some external heating, at its boiling point and after 15 minutes 20 ml of THF is added. After an additional 15 minutes at boiling, a final 20 ml of THF is added, and boiling is continued until the total heating time is 2 hours. Most of the magnesium has disappeared at this point. The mixture is then cooled and carbon dioxide gas is introduced, at a slight positive pressure and with vigorous stirring, for 15 minutes. The mixture is filtered and rotoevaporated to remove the solvent. Ethyl acetate (150 ml), water (150 ml) and aqueous 3 N sulfuric acid (20 ml) are added to the residue. The aqueous layer is separated and extracted with ethyl acetate. The combined organic layers are washed with water (100 ml, 2×) and then with saturated aqueous sodium chloride and dried over calcium sulfate. Solvent is removed by rotoevaporation to give 4-(2-tetrahydropyranyloxyethoxy)benzoic acid.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([N:30]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:23]=3[N+:49]([O-])=O)[O:17][N:16]=2)=[CH:11][CH:10]=1>[Pt].C(O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([N:30]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:23]=3[NH2:49])[O:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2[N+](=O)[O-])cc1
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Yield: 112.1 %

Procedure:
Under a nitrogen atmosphere, toluene (2 L) was added to a Parr vessel containing 5% platinum on carbon (3.6 g). N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-3-nitropyridin-2,4-diamine (36.85 g, 61.66 mmol) was added followed by ethanol (300 mL). The vessel was sealed, purged with hydrogen, and placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 18 hours at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 39.25 g of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][C:9]([CH2:11][C:12]2[C:21]([F:22])=[C:20]([F:23])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([F:24])[C:13]=2[F:25])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:34](OCC)(=[O:36])C.O>CN(C)C=O.C[O-].[Na+]>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]([CH:11]([C:12]2[C:13]([F:25])=[C:14]([F:24])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([F:23])[C:21]=2[F:22])[CH2:34][OH:36])=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(F)c(F)c(CC(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Reactant: CCOC(C)=O
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)c(F)c(C(CO)C(=O)OC(c2ccccc2)c2ccccc2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
In 486 ml of N,N-dimethylformamide was dissolved 8.6 g of methyl 4-diphenylmethoxycarbonylmethyl-2,3,5,6tetrafluorobenzoate. To the resulting solution were added 3.54 g of paraformaldehyde and 61 mg of sodium methylate in this order. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 300 ml of ethyl acetate and 800 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 35.0 g (yield: 67.0%) of methyl 4-(1-diphenylmethoxycarbonyl-2-hydroxyethyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.Cl.[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][C@H:20]([NH2:23])[CH2:21][F:22].CN(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:23][C@H:20]([CH2:21][F:22])[CH2:19][CH2:18][C:17]([O:16][CH3:15])=[O:24])=[O:8]
Reactant: COC(=O)CC[C@H](N)CF
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)CC[C@@H](CF)NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.70 g of 2,4-dichlorophenoxyacetic acid, 0.59 g of 4 and 0.44 ml of trimethylamine were mixed with 75 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Then, 0.65 g of N,N'-dicyclohexylcarbodiimide was added and the mixture was stirred at room temperature overnight. Several drops of glacial acetic acid were added and the mixture was filtered. The filtrate was washed successively with water, 1N hydrochloric acid, and half-saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and stripped of solvent. The residue was triturated with ethyl acetate, the mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure. The solid residue was triturated with hexane, the mixture was filtered and the solvent was evaporated from the filtrate. The solid residue was chromatographed over silica gel, first with a 1:3 v:v mixture of ethyl acetate and hexane as eluent, then with a 1:1 v:v mixture of ethyl acetate and hexane as eluent. On workup, 16 was obtained, as a white solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].C(O)(=O)C>CO>[C:67]([CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:69])=[O:68]
Reactant: O=CCCCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
80 mg (0.08 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 192) and 65.4 mg (0.5 mmol) of 6-oxohexanoic acid were combined in 9 ml of methanol and admixed with 10 μl of acetic acid and 37.4 mg (0.4 mmol) of borane-pyridine complex. The reaction mixture was stirred at RT overnight. This was followed by concentration under reduced pressure, and the residue was taken up in 1:1 acetonitrile/water and adjusted to pH 2 with trifluoroacetic acid. The reaction mixture was concentrated again and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions, 70 mg (86% of theory) of N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were obtained as the trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCOCC1>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([CH2:10][N:9]2[C:5]([CH2:4][C:2]([NH2:1])=[S:28])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1ccc(Cn2cncc2CC(N)=O)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(Cn2cncc2CC(N)=S)cc1
Temperature: 80 °C

Procedure:
To a 50 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-[5-(aminocarbonyl-methyl)imidazol-1-ylmethyl]benzonitrile (0.36 g, 1.49 mmol), Lawesson's reagent (0.73 g, 1.8 mmol) and 1,4-dioxane (10 mL). This well stirred mixture was heated at 80° C. for 24 hours. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed (silica gel, 10% 2-propanol in ammonia saturated CHCl3). The title compound was obtained as a yellow, crystalline solid.
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[CH3:28][C:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[N:31](C2CCCCO2)[N:30]=1>>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:32]3[NH:31][N:30]=[C:29]([CH3:28])[CH:33]=3)[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2I)C1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC(C)(O)C2)[nH]n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 89 using N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxy-3-methyl azetidin-1-yl)-5-iodonicotinamide (Stage 90.1) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give the title product as a white solid. HPLC (Condition 7) tR=5.72 min, UPLC-MS (Condition 8) tR=0.99 min, m/z=464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 3H) 2.28 (br. s, 3H) 3.66 (s, 4H) 5.42 (br. s, 1H) 6.16 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.84-7.91 (m, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.71 (s, 1H) 10.21 (s, 1H) 12.63 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C@H:9]([O:17][CH3:20])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: O[C@H](Cc1ccccc1)Cc1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](Cc1ccccc1)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 1-(3-bromophenyl)-3-phenyl-2(R)-propanol (437 mg, 1.50 mmol) in 20 mL of anhydrous THF was added NaH (70% dispersion in mineral oil, 64 mg, 1.87 mmol, 1.24 equiv.) at 0° C. under N2. The mixture was warmed to room temperature and stirred for 30 min, then CH3I (2.1 g, 15 mmol, 10 equiv.) was added at room temperature. The mixture was stirred for 3 h at room temperature. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by CC on silica gel with EtOAc/petroleum ether 1:20 to provide the methyl ether (347 mg, 76%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.36-7.12 (m, 9H), 3.61 (quintet, 1H, J=6.3 Hz), 3.27 (s, 3H), 2.85 (dd, 1H, J=13.8, 6.6 Hz), 2.75 (dd, 3H, J=12.9, 6.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16](CCl)[N:15]=[C:14]([NH2:20])[N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:16]1[CH:17]=[C:12]([Cl:11])[N:13]=[C:14]([NH2:20])[N:15]=1
Reactant: OCc1ccc(Cl)cc1Br
Reactant: Nc1nc(Cl)cc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(OCc2ccc(Cl)cc2Br)n1
Temperature: 100 °C

Procedure:
A mixture of (2-bromo-4-chlorophenyl)methanol (173 mg, 1. mmol), 4-chloro-6-(chloromethyl)pyrimidin-2-amine (178 mg, 1.16 mmol) and K2CO3 (175 mg, 1.00 mmol) in DMF (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided 4-((2-bromo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=O.Cl.[NH2:19][OH:20].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:19][OH:20]
Reactant: Cc1ccccc1-n1ccc(Cl)c(C=O)c1=O
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccccc1-n1ccc(Cl)c(C=NO)c1=O
Temperature: 100 °C
Yield: 94.6 %

Procedure:
A mixture of 4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step B (6.00 g), hydroxylamine hydrochloride (2.53 g), conc. hydrochloric acid (0.0740 mL) and 2-propanol (60 mL) was heated at 100° C. for 2 hr, and the mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.02 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][SH:8].C(O)C.Br[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]>O>[CH3:7][S:8][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]
Reactant: CS
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(SC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A reaction mixture containing 21 g. of potassium carbonate, 25 g. of methanethiol and 30 ml. of ethanol was cooled in an ice-water bath. 33.5 g. of 3-bromo-4-nitro-veratrole were added thereto. The reaction mixture was stirred for 1 hour under cooling and was then allowed to warm up to ambient temperature, at which temperature it was stirred for an additional 24 hours. 3 l. of water were then added and the resulting precipitate of 3-methylthio-4-nitroveratrole formed in the above reaction was separated by filtration. The filter cake was recrystallized from a benzene-ethanol solvent mixture to yield yellow crystals melting at 137°-140° C. (weight = 22.8 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([C:22](OC)=[O:23])[CH2:10]1.[Li+].[BH4-]>C1COCC1.CO>[OH:23][CH2:22][CH:11]1[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: COC(=O)C1CC(c2ccccc2OC)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)C(CO)C1
Reaction time: 8 h

Procedure:
At 0° C., to a solution of 1-tert-butyl 2-methyl 4-(2-methoxyphenyl)piperidine-1,2-dicarboxylate 124 (640 mg, 1.83 mmol) in THF (10 mL) and MeOH (0.5 mL), LiBH4 (60 mg, 2.74 mmol) was added. The reaction solution was stirred at r.t overnight, The reaction was quenched with water and the mixture was extracted with ethyl acetate. After removal of solvent, the crude product of tert-butyl 2-(hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate 125 was obtained without further purification. LC/MS RT (5 min method)=2.027 min. Mass observed: 222.2 (M-Boc+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:18][CH2:17][CH2:15][OH:16])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCCO
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A solution of 3-nitro[1,5]naphthyridin-4-ol (9.14 g, 43.7 mmol) dissolved in 300 mL of CH2Cl2 was treated with ethanolamine (7.9 mL, 130 mmol) and the mixture was stirred under N2. After 3 hours, the reaction mixture was concentrated to give a yellow solid. The yellow solid was treated with 200 mL of H2O and the suspension was heated to reflux, with stirring, for 10 minutes. The mixture was cooled in an ice bath. The resulting yellow solid was isolated by filtration, washed with cold H2O and dried with suction to give 2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (10.02 g) as fine yellow crystals.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15][CH:14]=1)[CH3:10]>C(#N)C>[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[C:17]([Cl:1])[C:16]([NH2:19])=[N:15][CH:14]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc(N)c(Cl)c1
Yield: 79.5 %

Procedure:
N-Chlorosuccinimide (21.7 g, 0.162 mol) was added to a suspension of 6-amino-nicotinic acid ethyl ester (18.0 g, 0.108 mol) in acetonitrile (270 ml) and the mixture was refluxed for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with water and dried. Flash chromatography (2.5% MeOH in CH2Cl2) gave pure 6-amino-5-chloro-nicotinic acid ethyl ester (17.23 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:39][C:35]([CH3:38])([CH3:34])[CH2:36][NH:37][C:29]([C:26]1[CH:27]=[CH:28][C:20]2[C:19]3[S:32][C:16]([C:14]([N:13]([C:3]4[CH:4]=[CH:5][C:6]([C:8](=[O:12])[N:9]([CH3:10])[CH3:11])=[CH:7][C:2]=4[Cl:1])[CH3:33])=[O:15])=[CH:17][C:18]=3[CH2:24][CH2:23][O:22][C:21]=2[CH:25]=1)=[O:30]
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: CC(C)(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)NCC(C)(C)N)cc2OCC3)c(Cl)c1

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-methylpropane-1,2-diamine, HATU and DIPEA in THF to give 340 as a colorless solid after reverse phase HPLC. MS: (ESI+) 555.3
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([N:22]([CH2:23][CH3:24])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCNCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Product: CCCCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Various portions of the 1-chloro-2,6-dinitro-4-(trifluoromethyl)benzene (treated as described above) were aminated with N-n-butyl-N-ethylamine, to produce N-n-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline, or with N-ethyl-N-methallylamine, to produce N-ethyl-N-methallyl-2,6-dinitro-4-(trifluoromethyl)aniline. Each product was analyzed for nitrosamine content. The N-n-butyl-N-ethyl-2,6-dinitro-4-(trifluoromethyl)aniline was found to contain 7 or 20 ppm of N-nitroso-N-n-butyl-N-ethylamine (two different analytical laboratories) and the N-ethyl-N-methallyl-2,6-dinitro-4-(trifluoromethyl)aniline was found to contain 16 ppm of N-nitroso-N-ethyl-N-methallylamine.
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].N1C=NC(S)=N1.[F:32][C:33]([F:41])([F:40])[C:34]1[NH:38][N:37]=[C:36]([SH:39])[N:35]=1>>[F:32][C:33]([F:41])([F:40])[C:34]1[NH:38][N:37]=[C:36]([S:39][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:35]=1
Reactant: N#Cc1cccc(OCCCCl)c1
Reactant: FC(F)(F)c1nc(S)n[nH]1
Agent: N#Cc1cccc(OCCCl)c1
Agent: Sc1nc[nH]n1
Product: N#Cc1cccc(OCCCSc2n[nH]c(C(F)(F)F)n2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 5-(trifluoromethyl)-1H-1,2,4-triazole-3-thiol, the title compound was obtained as a yellow oil (1.25 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([C:3]1[C:2]([NH:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:20]=2)(=[O:26])=[O:25])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of (3-amino-5-chloro-pyridin-2-yl)-phenyl-methanone (40 mg, 0.17 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (72 mg, 0.26 mmol), and DMAP (11 mg, 0.09 mmol) in anhydrous pyridine (0.5 mL) was heated at 60° C. for 4 days. The product was separated by preparative HPLC and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ10.56 (s, 1 H), 8.39 (s, 1 H), 8.17 (s, 1 H), 8.07 (s, 1 H), 7.87 (d, J=8.0 Hz, 1 H), 7.54 (d, J=7.6 Hz, 2 H), 7.61-7.58 (m, 1 H), 7.50 (d, J=8.4 Hz, 1 H), 7.45-7.42 (m, 2 H); MS m/z: 475.0 (M+H).