Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]4[C:14]=3[C:10]([CH:11]=[N:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:25])[O:4][N:3]=1.[Br:26]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[Br:26][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:25])[C:15]2[O:16][CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:13]3[C:14]=2[C:10]=1[CH:11]=[N:12]3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc(C)c1-c1ccc2cnn3c2c1OCC3c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1noc(C)c1-c1cc(Br)c2cnn3c2c1OCC3c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
A solution of 9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazole (0.011 g, 0.033 mmol) in acetonitrile (0.4 mL) at 0° C. was treated with N-bromosuccinimide (8.3 mg, 0.047 mmol) and stirred at 0° C. for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated sodium bicarbonate solution (20 mL), dried over sodium sulfate, filtered, and concentrated to a colorless residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 30 mL/min) gave desired product (9 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (s, 1H), 7.16-7.05 (m, 2H), 5.99-5.89 (m, 1H), 4.81 (dd, J=11.7, 3.4 Hz, 1H), 4.71 (dd, J=11.6, 4.8 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H); LCMS calculated for C20H17BrN3O2 (M+H)+: m/z=410.0, 412.0. found: 410.0, 412.0.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:17]1([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15][B:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:9][CH:10]=2)[O:18]1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(-c3ncccn3)cc2)OC1(C)C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
A degassed solution of 2-bromopyrimidine (1.5 g, 9.4 mmol), 2,2′-(1,4-phenylene)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (5.1 g, 16.0 mmol), 1.0 M aq K3PO4 (28.3 mL, 28.3 mmol), and Pd(PPh3)4 (330 mg, 0.31 mmol) in DMF (140 mL) was heated to 80° C. and stirred at this temperature for 16 h. Water (100 mL) was added to the reaction mixture and was extracted with EtOAc (3×200 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using an eluent of 17% EtOAc in n-heptane to afford the title compound as a white solid (0.7 g, 28%). MS (LCMS) m/z 283.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 12H) 7.19 (t, J=4.68 Hz, 1H) 7.93 (d, J=8.00 Hz, 2H) 8.43 (d, J=7.81 Hz, 2H) 8.81 (d, J=4.68 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([NH:22][CH2:23][C:24]2([N:30]([CH3:32])[CH3:31])[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:8]([CH3:19])=[C:7]([C:20]([NH:22][CH2:23][C:24]2([N:30]([CH3:32])[CH3:31])[CH2:25][CH2:26][S:27](=[O:41])[CH2:28][CH2:29]2)=[O:21])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(C(=O)NCC2(N(C)C)CCSCC2)cc(C(C)(C)C)n1CCc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)NCC2(N(C)C)CCS(=O)CC2)cc(C(C)(C)C)n1CCc1ccc(F)cc1

Procedure:
A 400 mg portion of 5-tert-butyl-N-{[4-(dimethylamino)tetrahydro-2H-thiopyran-4-yl]methyl}-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide was dissolved in 4 ml of chloroform and, under ice-cooling, 210 mg of 3-chloroperbenzoic acid was added, followed by stirring under ice-cooling for 1 hour. Then, 100 mg of 3-chloroperbenzoic acid was added, followed by stirring for 30 minutes. A 10% sodium hydrogen sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol:hexane=1:0:0-100:1:0-50:1:0-30:1:0) to obtain 213 mg of 5-tert-butyl-N-{[4-(dimethylamino)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide as a colorless oil. This product was dissolved in 2.5 ml of acetonitrile at 80° C., 44 mg of oxalic acid was added, followed by stirring at the same temperature for 10 minutes and then stirring at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with acetonitrile to obtain 199 mg of 5-tert-butyl-N-{[4-(dimethylamino)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide oxalate as a colorless solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH2:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[C:15]([O:29][CH3:30])[CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>>[NH2:11][C:9]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[C:15]([O:29][CH3:30])[CH:14]=2)[C:5]2=[N:6][CH:7]=[C:2]([C:34]#[C:33][CH2:32][CH2:31][OH:35])[CH:3]=[C:4]2[N:10]=1
Reactant: C#CCCO
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)cnc43)cc2OC)cn1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(C#CCCO)cnc43)cc2OC)cn1

Procedure:
This compound was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine and but-3-yn-1-ol using the procedure described in Example 3-41-2: 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.93 (s, 1H), 7.74 (dd, J=8.5, 2.0 Hz, 1H), 7.41 (s, 1H), 7.08-6.97 (m, 4H), 6.83 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 4.96 (s, 2H), 4.91 (t, J=5.5 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.61-3.57 (m, 2H), 2.56 (t, J=6.5 Hz, 2H) ppm; (M+1)=460.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[N:21]([C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CCCCN)N(C(=O)OC(C)(C)C)C(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and N,-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=119-121° C.). The reaction was monitored by tlc (Rf=0.46 in 90:10:1 CH2Cl2MeOHNH4OH).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:41][O:42]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClC(Cl)(Cl)C(O)=O.C(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([CH2:41][OH:42])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCC/C=C\CCCCCCCC
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Yield: 86.6 %

Procedure:
1,2-O-Dioleyl-3-O-tritylglycerol (6.10 g, 7.3 mmol) was reacted with 5% trichloroacetic acid/methylene chloride (50 ml, w/v) at ambient temperature for 1 hour. The organic layer was then washed with saturated aqueous sodium hydrogen carbonate solution and water, dried, and concentrated. The residue was purified by column chromatography (silica gel/chloroform) to provide 3.75 g (87%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: Oc1ccc(-c2ncc(F)cn2)cc1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(F)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4-(5-fluoro-pyrimidin-2-yl)-phenol (Preparation 20) and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (85 mg, 49%)
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([Cl:24])=[CH:19][CH:20]=2)[N:15]=1.CN(C)C=O>O>[Cl:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Temperature: 20 °C
Yield: 31.6 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-dimethylaminobenzoic acid (14.9 g), N,N'-carbonyldiimidazole (14.6 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The crude product obtained by filtration of the reaction mixture (6.4 g; m.p. 248° C.) is dissolved in boiling dimethylformamide (95 cc). After cooling for 2 hours at 20° C., water (95 cc) is added. The crystallized solid is separated by filtration, washed with a dimethylformamide/water (50:50 by volume) mixture (2×10 cc), and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-dimethylaminobenzamide (6.2 g), m.p. 248° C., is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[C:4]([C:15](=O)[C:16](OC)=[O:17])=[CH:3]1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:29]=2)[C:24]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:23]1>>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH:29]=2)[C:24]([C:37]2[C:38](=[O:39])[NH:40][C:16](=[O:17])[C:15]=2[C:4]2[C:5]3[C:10](=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:23]1
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Reactant: COC(=O)C(=O)c1cn(C)c2cc(C(F)(F)F)ccc12
Product: Cn1cc(C2=C(c3cn(C)c4cc(C(F)(F)F)ccc34)C(=O)NC2=O)c2ccc(N3CCOCC3)cc21
Yield: 54 %

Procedure:
3-(1-Methyl-6-morpholin-4-yl-1H-indol-3-yl)-4-(1-methyl-6-trifluoromethyl-1H-indol-3-yl)pyrrole-2,5-dione (151 mg, 54%) was prepared from methyl (1-methyl-6-trifluromethyl-1H-indol-3-yl)glyoxylate (172 mg, 0.60 mmol) and (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)acetamide (150 mg, 0.55 mmol).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc2c(c1)OCCC2=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromo-4-chromanone (2.0 g, 8.8 mmol) in dioxane (30 mL) was added 2-methylphenylboronic acid (1.8 g, 13.2 mmol), Pd(PPh3)4 (0.5 g, 0.44 mmol) and Na2CO3 (2.8 g, 26.4 mmol). The mixture was stirred at 100° C. under nitrogen overnight. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give 2.1 g (quantitative) of the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3): δ2.29 (s, 3H), 2.85 (t, J=6.3 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 6.94 (s, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.19-7.32 (m, 4H), 7.93 (d, J=8.1 Hz, 1H). [M+H] Calc'd for C16H14O2, 239. Found, 239.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[NH:29][NH2:30]>C(O)C>[NH2:6][C:5]1[N:29]([C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[Br:22])[N:30]=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:4]=1[C:7]#[N:8]
Reactant: NNc1ccncc1Br
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2ccncc2Br)c1N
Temperature: 25 °C
Yield: 35.5 %

Procedure:
A mixture of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (7.3 g, 0.026 mol) and 3-bromo-4-hydrazinylpyridine (4.2 g, 0.022 mol) in ethanol (300 mL) was stirred at reflux under N2 overnight. The reaction was cooled to RT slowly and stirred at RT for about 4 hr till solid precipitated. The solid was filtered, collected and washed with hexane to get 3.38 g (35%) of 5-amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a light yellow solid. MS (ESI) m/e [M+1]+ 431.8, 433.8.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].[BrH:18]>O.O1CCOCC1.[Cu]Br>[Br:18][C:6]1[CH:8]=[C:2]([F:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc([N+](=O)[O-])c(N)cc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
5-Fluoro-4-methoxy-2-nitroaniline obtained in Reference Example 14 (4.1 g) was dissolved in a mixed solvent of water (20 ml) and 1,4-dioxane (10 ml), 48% hydrobromic acid (12 ml) was added to the solution under refluxing, and then the mixture was refluxed for 15 minutes. The reaction mixture was cooled to 0° C., sodium nitrite was added dropwise thereto, and the mixture was stirred at 0° C. for 15 minutes. The resulting mixture was added dropwise to a solution of copper (I) bromide (3.6 g) in a mixture of water (20 ml) and 48% hydrobromic acid (12 ml) at 0° C. The mixture was stirred at 60° C. for 15 minutes, cooled to room temperature, and further stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (developing solvent:ethyl acetate-hexane=1:8) to obtain the title compound as crystals (5 g, 91%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:13])[O-])[N:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:37]=2)=[O:13])[N:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccncc1-n1nc(C(C)(C)C)cc1NC(=O)[O-]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnccc4C)c3)c2cc1OC
Yield: 86.7 %

Procedure:
3-tert-Butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.30 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) (prepared as described in Example 113A) using the procedure in Example 115C to give 1-(3-tert-butyl-1-(4-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (145 mg, 0.26 mmol, 87%). 1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.58-8.51 (m, 3H), 8.38 (s, 1H), 7.54-7.47 (m, 3H), 7.38-7.32 (m, 2H), 7.12 (d, 1H), 6.91 (d, 1H), 6.36 (s, 1H), 3.98 (s, 6H), 2.06 (s, 3H), 1.24 (s, 9H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: [N:1]([C:4]([F:8])([F:7])[CH2:5][OH:6])=[N+:2]=[N-:3].Br[C:10](F)(F)[C:11](OCC)=[O:12].[N-]=[N+]=[N-].[Na+]>>[N:1]([C:4]([F:8])([F:7])[C:5]([O:12][CH2:11][CH3:10])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: [N-]=[N+]=NC(F)(F)CO
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(F)(F)N=[N+]=[N-]

Procedure:
2-Azido-2,2-difluoroethanol is useful in the preparation of energetic placizers for explosives and propellants. Ethyl 2-bromo-2,2-difluoroacetate reacts with sodium azide to produce ethyl 2-azido-2,2-difluoroacetate which then reacts with sodium borohydride in water to produce the 2-azido-2,2-difluoroethanol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:7].[BH4-].[Na+]>CO.O>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[OH:7])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To a solution of 3,3′-bis(trifluoromethyl)benzophenone (11.4 g, 36 mmol) in MeOH (50 mL) was added sodium borohydride (1.9 ml, 53 mmol) portionwise at rt. The suspension was stirred at rt for 24 h. The reaction was diluted slowly with water and extracted with CH2Cl2. The organic was washed successively with water, brine, dried over Na2SO4, and concentrated to give bis(3-(trifluoromethyl)phenyl)methanol (10.8 g, 94% yield). The crude oil was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([CH2:26][NH2:27])=[N:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Nc2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1csc(Nc2cnc(CN)c3cc(OC)c(OC)cc23)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
2-[1-(tert-Butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-ylamino]-thiazole-4-carboxylic acid ethyl ester (40 mg, 0.0818 mmol) in CH2Cl2 (1.0 mL) was treated with a 4.0 M HCl solution in dioxane (0.21 mL) at room temperature. After the reaction mixture was stirred at room temperature for 15 h, the suspension was filtered. The yellow solid was dried in vacuo to give 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-ylamino)thiazole-4-carboxylic acid ethyl ester hydrochloride salt (32.3 mg; 93%). 1H-NMR (D2O): δ, 8.81 (s, 1H), 7.46 (s, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 4.63 (s, 2H), 4.14 (q, 2H, J=7.1 Hz), 3.86 (s, 3H), 3.83 (s, 3H), 1.20 (t, 3H, J=7.3 Hz); MS: calculated for C18H21N4O4S (M−Cl) 389.0; found: 389.0.
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=5)[N:19]=[CH:18][C:17]4=[O:27])[CH2:12][CH2:13]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 3 mL of a chloroform solution containing 631 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 6 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=5:1], to give 400 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a brown solid.