Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]([C:13]2[S:17][C:16]([C:18]([OH:20])=O)=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:21])[C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.Cl.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:18]([C:16]1[S:17][C:13]([CH:9]([S:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=3)=[C:4]([CH3:21])[CH:5]=2)[CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=1)=[O:20]
Reactant: Cc1cc(SC(c2ccc(C(=O)O)s2)C(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(C(Sc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)C(C)C)s1
Yield: 69.8 %

Procedure:
To a mixture of (±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxylic acid (0.420 g, 0.905 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.148 g, 1.06 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.151 g, 1.12 mmol) in DMF (9.0 mL) is added N, N-diisopropylethylamine (0.49 mL, 2.81 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.0.228 g, 1.19 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate, gradient from 0% to 75% to provide (±)-3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.347 g, 70%) as a white foam. MS (ES): 548.1 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak AD-H 4.6×150 mm; eluent: 10:90 3A alcohol/Heptane; flow rate: 0.6 mL/min; UV absorbance wavelength: 280 nm) to provide Isomer 1 (0.126 g, >99% ee) and Isomer 2 (0.119 g, 94.5% ee).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[O:22].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([CH:21]([OH:22])[C:20]([O:24][CH2:25][CH3:26])=[O:23])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1cc(O)c2sc(Br)nc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)c1c(C)cc2nc(Br)sc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
To a solution of 27 (3.90 g, 16.0 mmol) in CH2Cl2 (80 mL) at 0° C. was added triethylamine (2.45 mL, 16.8 mmol) then a solution of titanium tetrachloride in CH2Cl2 (1.0 M, 16.8 mL, 16.8 mmol). After 15 min, ethyl glyoxalate (50% in toluene, 3.49 mL, 17.6 mmol) was added. The reaction mixture was stirred for 2 h while warming to room temperature. Water (50 mL) and a saturated solution of potassium sodium tartrate (50 mL) were added. The mixture was stirred vigorously for 2 h. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography to give 2.48 g of 28 and recovered ˜500 mg of 27. 1H-NMR: 400 MHz, (CD3OH) δ: 7.33 (s, 1H), 5.69 (s, 1H), 4.17 (m, 2H), 2.50 (s, 3H), 1.18 (t, 3H, J=7 Hz). LCMS-ESI+: calc'd for C12H13BrNO4S: 346.0 (M+H+); Found: 346.1 (M+H+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:7]=1[CH2:8][N:9]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11][C@H:10]1[C:34](O)=[O:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:3][CH2:2][CH2:1][NH:4][C:34]([C@H:10]1[N:9]([CH2:8][C:7]2[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:6]=2[F:5])[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11]1)=[O:35]
Reactant: NCCN
Reactant: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)NCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
ethane-1,2-diamine (18 mg, 0.290 mmol) was added to a stirred mixture of (2S,5R)-1-(2-fluoro-6-methoxybenzyl)-5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)-piperidine-2-carboxylic acid (50 mg, 0.097 mmol), N,N-DIISOPROPYLETHYL-AMINE (0.084 ml, 0.483 mmol), HATU (73.5 mg, 0.193 mmol) in dimethylformamide and the mixture was stirred at room temperature for Overnight. The reaction was rotovap to dryness and the residue was purified by column chromatography on silica gel Isolute Flash Si; 50 g prepacked, eluting with 5% MeOH/NH3(2M)CH2Cl2 to give the desired (48.1 mg, 0.085 mmol, 88% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N:6][CH:7]=1.[OH:19]O>C(Cl)Cl.C[Re](=O)(=O)=O>[Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N+:6]([O-:19])[CH:7]=1
Reactant: Clc1cccc(Cl)c1-n1cc2cncc(Br)c2n1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1cc(Br)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a solution of 7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (3.43 g, 10 mmol) and methyltrioxorhenium (249 mg, 1.0 mmol) in DCM (35 mL) was added hydrogen peroxide (30% aq., 1.95 mL, 20 mmol) and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM and sodium bicarbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% methanol in DCM) to afford the title compound as a beige solid (1.7 g, 47% yield). LCMS (Method D): RT=2.46 min, m/z: 360 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]2([CH3:20])[OH:13])=[C:4]([O:21][CH3:22])[N:3]=1.C1C(=O)N([Br:30])C(=O)C1>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Br:30])[N:8]2[C@H:11]2[C@:12]([CH3:20])([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][OH:19])[O:17]2)=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: COc1nc(N)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
2-Amino-6-methoxy-9-(2-C-methyl-β-D-ribofuranosyl)purine (1.5 g, 4.82 mmol) was suspended in MeOH (50 mL) and 1 mol eq. of NBS (1.03 g, 4.82 mmol) was added. The mixture was stirred at room temperature for 4 h. After that time, solution was concentrated and the resulting solid was purified by silica gel chromatography using 1-4% (gradient) of MeOH in chloroform to yield 1.65 g (88% yield) of the desired product.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:10]2[CH3:27])=[CH:5][C:4]=1[S:29](=[O:34])(=[O:33])[N:30]([CH3:32])[CH3:31]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:27])[C:11](=[N:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:29](=[O:34])(=[O:33])[N:30]([CH3:31])[CH3:32]
Reactant: COc1cc(N=C2SCC(O)(c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)N2C)cc(OC)c1OC
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc(OC)c1OC

Procedure:
Obtained by a procedure analogous to that indicated in Example 1(b), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(3,4,5-trimethoxyphenyl-imino)-thiazolidin-4-ol hydrobromide, by boiling for 30 minutes in glacial acetic acid and precipitating with diisopropyl ether. Melting point 246° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1O.IC1C=CC=CC=1.[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29]C.CCCCCCCCCCCC>[Cu]I.O.C(OCC)C>[C:12]1([CH2:16][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH2:31])[CH:11]=[CH:10][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCN
Reactant: Cc1cccc(C)c1O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: CCOCC
Solvent: O
Product: NCCCCCCc1ccccc1
Temperature: 80 °C

Procedure:
Copper (I) iodide (10 mg, 0.05 mmol, 5 mol %), anhydrous fine powder potassium phosphate (425 mg, 2.0 mmol) and 2,6-dimethylphenol (24 mg, 0.2 mmol, 20 mol %) were put into a screw-capped test tube with a Teflon septum. The tube was evacuated and back-filled with argon (3 cycles). Iodobenzene (112 μL, 1.0 mmol) and n-hexylamine (158 μL, 1.0 mmol) were added by micro-syringe at room temperature. The reaction mixture was heated at 80° C. for 18 hours. The reaction mixture was then allowed to reach room temperature. Diethyl ether (2 mL), water (2 mL) and dodecane (internal standard, 227 μL) were added. The organic layer was analyzed by GC to give 41% GC yield of N-phenylhexylamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH3:19])[C:8]([N+:20]([O-])=O)=[CH:7][C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH3:19])[C:8]([NH2:20])=[CH:7][C:6]=1[OH:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (3.0 g, 9.5 mmol) in methanol (30 mL) was added Raney Ni (300 mg). The mixture was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether-ethyl acetate, 6:1) to afford 2-tert-butyl-4-(2-ethoxyphenyl)-5-aminophenol (C-15) (2.35 g, 92%). 1H NMR (DMSO-d6) δ 8.89 (s, 1H), 7.19 (t, 1H, J=4.2 Hz), 7.10 (d, 1H, J=1.8 Hz), 7.08 (d, 1H, J=1.8 Hz), 6.94 (t, 1H, J=3.6 Hz), 6.67 (s, 1H), 6.16 (s, 1H), 4.25 (s, 1H), 4.00 (q, 2H, J=6.9 Hz), 1.26 (s, 9H), 1.21 (t, 3H, J=6.9 Hz); ESI-MS 286.0 m/z (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)c(C)n2)n1
Reactant: Brc1cncnc1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=339.3 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-Bromopyridine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4].[O:15]1[CH2:19][CH2:18][O:17][CH:16]1[CH2:20][NH:21][CH3:22]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:21]([CH2:20][CH:16]2[O:17][CH2:18][CH2:19][O:15]2)[CH3:22])=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1nnc(N=C=O)s1
Reactant: CNCC1OCCO1
Solvent: CCOC(C)=O
Product: CN(CC1OCCO1)C(=O)Nc1nnc(S(=O)(=O)N(C)C)s1

Procedure:
5-(N,N-Dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams), N-(1,3-dioxolan-2-ylmethyl)-N-methylamine (6 grams) and ethyl acetate (20 ml) were charged into a glass reaction vessel fitted with a mechanical stirrer. The reaction mixture was heated on a steam bath for a period of about 2 hours. Solvent was then stripped off using a rotary evaporator to yield the desired product N-[5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]-N'-(1,3-dioxolan-2-ylmethyl)-N'-methylurea as the residue. Melting point 100°-110° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:20]=1)=[O:10])[CH3:7].[C:32](=O)([O-])[OH:33].[Na+]>CN(C)C=O>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:32]=[O:33])[S:13][C:12]=1[NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:20]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(C)csc1NC(=O)c1cccc(CN(CC)CC)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(NC(=O)c2cccc(CN(CC)CC)c2)sc(C=O)c1C
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Separately, phosphorus oxychloride (200 μl) was added dropwise to N,N-dimethylformamide (73 mg) at 0° C., and the mixture was stirred at that temperature for 5 min. The reaction system was heated to 80° C., 2-(3-diethylaminomethyl-benzoylamino)-4-methyl-thiophene-3-carboxylic acid ethyl ester (187 mg) synthesized by the above process was then added thereto, and the mixture was stirred at that temperature for 3 hr. After the completion of the reaction, the reaction solution was neutralized with a saturated sodium hydrogencarbonate solution, and was then subjected to separatory extraction with chloroform, and the organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-diethylaminomethyl-benzoylamino)-5-formyl-4-methylthiophene-3-carboxylic acid ethyl ester as a useful intermediate (110 mg, yield 53%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13]Cl)[CH2:2][CH:3]=[CH2:4].[C:15]1([C:21](=[N:28][CH2:29][C:30]#[N:31])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH:29]([N:28]=[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:30]#[N:31])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(F)cc1CCl
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCCOc1ccc(F)cc1CC(C#N)N=C(c1ccccc1)c1ccccc1
Reaction time: 44 h
Yield: 74.9 %

Procedure:
To a solution of 1-(but-3-en-1-yloxy)-2-(chloromethyl)-4-fluorobenzene (1 g, 4.66 mmol, 1 equiv), 2-((diphenylmethylene)amino)acetonitrile (1.13 g, 5.12 mmol, 1.1 equiv), and benzyltrimethylammonium chloride (87 mg, 0.466 mmol, 0.1 equiv) in DCM (8 mL) was added 10 N NaOH (0.84 mL, 8.39 mmol, 1.8 equiv). After 44 h, add to water and extract with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-30% EtOAc/hexane) to provide the product (1.39 g, 75%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.62-7.54 (m, 2H), 7.49-7.33 (m, 5H), 6.96-6.74 (m, 5H), 6.61 (dd, J=8.8, 4.3 Hz, 1H), 5.58 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.18-4.97 (m, 2H), 4.65 (dd, J=9.2, 4.6 Hz, 1H), 3.81 (dt, J=8.7, 6.3 Hz, 1H), 3.62-3.45 (m, 1H), 3.37 (dd, J=13.1, 4.8 Hz, 1H), 3.15 (dd, J=13.1, 9.3 Hz, 1H), 2.24 (q, J=6.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2].Br[CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Temperature: -17 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (5.0 g, 24.5 mmol) in DMF (100 mL) was added potassium bistrimethyl silyl amide (49 mL of 0.5 M solution in toluene, 24.5 mmol) at 0° C. The reaction mixture was stirred for 20 minutes and was cooled to −17° C. A solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1(A) (6.9 g, 27 mmol) in DMF (50 mL) was added dropwise so the internal temperature remained below −15° C. The reaction mixture was stirred at −16° C. for 1 hour, was warmed to room temperature and was diluted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and was concentrated. The resulting pale brown solid was triturated with ether to obtain 3.2 g of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide as a white powder. The filtrate was concentrated and the residue was triturated with ether/hexanes. The solid was collected by filtration to give a second crop of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (3.4 g). MS 380.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>>[CH3:14][C:5]1[O:4][C:3]([CH2:2][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[O:19])=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1oc(CCl)nc1-c1ccccc1
Reactant: O=Cc1ccccc1O
Product: Cc1oc(COc2ccccc2C=O)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 45, 2-chloromethyl-5-methyl-4-phenyloxazole was allowed to o-hydroxybenzaldehyde to give 2-(5-methyl-4-phenyl-2-oxazolylmethoxy)benzaldehyde. Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.95°-96° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.[C:14](Cl)([Cl:16])=[O:15].C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>O1CCCC1>[Cl:16][C:14]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)=[O:15]
Reactant: Oc1cccc(-c2cccnc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: O=C(Cl)Oc1cccc(-c2cccnc2)c1
Temperature: 25 °C

Procedure:
A solution of 3-pyridin-3-yl-phenol in tetrahydrofuran was treated with 20% phosgene in toluene (1.0 eq.) at 25° C. The reaction mixture was then treated with N,N-dimethylaniline (1.3 eq) at 0° C. The reaction mixture was stirred at 25° C. over night. The volatiles were removed under reduced pressure. The crude product 3-pyridin-3-yl-phenyl chloroformate was used without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[C:13]1([N:3]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=[CH:4]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Clc1nccc2ccccc12
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(-n3ccc4cccnc43)nccc2c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
0.894 g of 60% sodium hydride (37.25 mmol) was added with stirring to 20 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C. and then a solution of 4 g (33.86 mmol) of 1H-pyrrolo[2,3-b]pyridine in 20 cm3 of dimethylformamide was gradually added. After stirring at a temperature in the region of 20° C. for 30 minutes, a solution of 5.816 g (35.55 mmol) of 1-chloroisoquinoline in 20 cm3 of dimethylformamide was added and then the reaction mixture was heated at a temperature in the region of 100° C. for 15 h. After concentrating to dryness under reduced pressure (2.7 kPa), the residue was taken up in 2 times 50 cm3 of water. The residual oil was taken up in 30 cm3 of diethyl ether. The white crystals that formed were filtered off and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 20° C. 4.36 g of 1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine were thus obtained in the form of an off-white solid melting at 87° C.
Reaction SMILES: Br.Br[C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:7]2[CH:6]=[N:5][CH:4]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:6]1[C:7]2[N:8]([N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:3]=[CH:4][N:5]=1)[NH2:18]
Reactant: FC(F)(F)c1nc2cncc(Br)n2n1
Reactant: NN
Agent: Br
Solvent: O
Solvent: CCO
Product: NNc1nccn2nc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.15 mmol) of 5-bromo-2-(trifluoromethyl) [1,2,4]triazolo[1,5-a]pyrazine hydrobromide in 2.5 mL of dry ethanol was treated dropwise with 0.799 mL (11.5 mmol) of hydrazine hydrate, and stirring was continued at ambient temperature overnight. The reaction mixture was concentrated to dryness, and the residue was extracted with dichloromethane and then with tetrahydrofuran. The organic extracts were washed with saturated sodium bicarbonate aqueous solution, filtered, and concentrated. Purification of the residue by preparative HPLC (C18 reverse phase column, 10-60% acetonitrile in water containing 0.05% trifluoroacetic acid) afforded the title compound as a yellow solid. LC-MS 219 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.O.[NH2:14][NH2:15]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:12])[NH:15][N:14]=[C:8]2[CH3:9]
Reactant: NN
Reactant: CC(=O)c1cc(Br)c(F)cc1F
Solvent: OCCO
Solvent: O
Product: Cc1n[nH]c2cc(F)c(Br)cc12
Temperature: 160 °C
Reaction time: 26 h
Yield: 67 %

Procedure:
To a solution of 1-(5-bromo-2,4-difluorophenyl)ethanone (4.9 g) in ethylene glycol (15 ml) was added hydrazine monohydrate (1.2 g) at room temperature, and the mixture was stirred at 160° C. for 26 hr. The reaction mixture was cooled to room temperature, and the insoluble material was removed. The filtrate was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.2 g).