Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N1C(C)(C)CCCC1(C)C.N1CCCCC1.[Li]CCCC.[CH:49](=[O:52])[CH2:50][CH3:51]>C1COCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH:49]([OH:52])[CH2:50][CH3:51])[C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CCC(O)c1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
A −40° C. solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramnethyl piperidine and n-BuLi at 0° C. for 30 min.). The mixture was then allowed to warm to 0° C. for 2 h. The reaction mixture was cooled to −30° C. and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stiffed at −30° C. for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+: 424.2. Other electrophiles such as disulfide may be used to quench the anion.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: NCc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1nc(NCc2ccncc2)c2nc[nH]c2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
To a stirred solution of 6-chloro-2-fluoro-9H-purine (0.9 g, 5.22 mmol) in BunOH (60 mL) under Ar, cooled to −20° C., was added Pri2NEt (2.5 mL, 14.35 mmol) followed by 4-(aminomethyl)pyridine (0.58 mL, 5.69 mmol). The reaction mixture was stirred at-20° C. for 3 h, and then allowed to return to RT over 2 h and stirred at RT for a further 48 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (100:0→90:10), to afford the title compound as a white solid (0.69 g, 54%). Mp>340° C. 1H-NMR (d6-DMSO, 250 ME): δ 4.67 (d, 2H, J=6.35 Hz, —HNCH2-Pyr), 7.34, 8.50 (2×m, 4H, Pyr), 8.14 (s, 1H, —N═CH—NH—), 8.84 (bs, 1H, —HNCH2-Pyr), 13.13 (bs, 1H, —N═CH—NH—). FAB-MS m/z (relative intensity): 245 ([M+H]+, 27), 176 (15), 154 (100), 136 (77). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected:Measured) C11H9N6F.0.6H2O: C, 51.80:52.08; H, 4.03:3.84; N, 32.95:31.29.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[N:7]1)(=[O:5])=[O:4])[CH3:2].CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([S:3]([N:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: [H][H]
Reactant: CCS(=O)(=O)n1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)n1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
Ethanesulfonyl-3-nitro-1H-pyrazole (139 mg, 0.68 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on carbon, wet (˜50 mg) was added to the mixture. The vial was charged with hydrogen gas (via balloon) and the mixture was stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo followed by purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) afforded 1-ethanesulfonyl-1H-pyrazol-3-ylamine (88 mg, 74%) as a faintly yellow wax: ESI-LRMS m/e calcd for C5H9N3O2S [M+] 175.04, found 176.3 [M+H+], 351.2 [2M+H+].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]([NH:12][C@H:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:14][C:15]([OH:17])=[O:16])=[O:11])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].O>CN(C=O)C.C1(B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C@@H:13]([NH:12][C:10]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1)=[O:11])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ncc(C(=O)N[C@@H](CC(=O)O)c2ccccc2Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(C(=O)N[C@@H](CC(=O)O)c2ccccc2Cl)cc1-c1ccccc1
Temperature: 100 °C
Yield: 59.9 %

Procedure:
To a solution of 50 mg (0.13 mmol) of (S)-3-[(5-Chloro-6-methoxy-pyridine-3-carbonyl)-amino]-3-(2-chloro-phenyl)-propionic acid in 3 ml of DMF are added: 25 mg (0.21 mmol, 1.5 eq) phenylboronic acid, 60 mg Na2CO3 (0.56 mmol, 4.2 eq) and 10 mg (0.13 eq) DI-MICRO-CHLOROBIS[2-[(DIMETHYLAMINO)METHYL]PHENYL-C,N]DIPAL as catalyst. After the addition of 1 ml of water the resulting mixture is heated to 100° C. for 6 hours, the reaction is filtered via a pad of celite and the resulting solution subjected to preparative HPLC chromatography yielding 16 mg of product (Yield: 29%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Br:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reaction time: 5 h
Yield: 31.8 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (231) (2.0 g, 4.14 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (2.7 g, 12.41 mmol) in pyridine (25 ml), was added POCl3 (1.16 ml, 12.41 ml) at −10° C. The reaction mixture was stirred at this temperature for 5 h. After completion of the reaction, the reaction mixture was quenched with water and the mixture was extracted with ethyl acetate. The organic part was washed with water, separated and dried over Na2SO4. After evaporation, the crude product was purified by 100-200 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (232) (0.9 g, 32%) as a brown solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].N1CCCC1>C(#N)C.C(OCC)(=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][N:23]2[CH2:24][CH2:25][CH2:22][CH2:21]2)=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Solvent: C1CCNC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Brc1ccc(CCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromophenethyl 4-methylbenzenesulfonate (500 mg, 1.407 mmol) from Example 56A in anhydrous acetonitrile (3 mL) was treated with triethylamine (0.589 mL, 4.22 mmol) and pyrrolidine (0.349 mL, 4.22 mmol). The reaction was stirred 16 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water, saturated ammonium chloride, and brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 5% methanol in dichloromethane, to give the title compound. MS DCI(+) m/z 254.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13]C(OC(C)(C)C)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:31]=1[NH:32][NH:33]C(OC(C)(C)C)=O)=[N:29][CH:28]=[CH:27][CH:26]=2.[N:41]#[C:42]Br>>[N:12]1([NH2:13])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:22]1[NH2:21].[N:32]1([NH2:33])[C:31]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:21]=[C:42]1[NH2:41]
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2cccnc12
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Reactant: N#CBr
Product: Nc1nc2cnc3ccccc3c2n1N
Product: Nc1nc2cnc3cccnc3c2n1N

Procedure:
In step (1) of Reaction Scheme VIII, a tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate or a tert-butyl N′-(3-amino[1,5]naphthyridin-4-yl)hydrazinecarboxylate of Formula XXXIX is reacted with cyanogen bromide to provide a 1H-imidazo[4,5-c]quinoline-1,2-diamine or 1H-imidazo[4,5-c][1,5]naphthyridine-1,2-diamine of Formula LXVI. The reaction can be carried out by adding cyanogen bromide to a solution of compound of Formula XXXIX in a suitable solvent such as ethanol and heating.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:14][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.Cl[Pd](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>[CH:22]1([C:3]2[C:4]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[CH:12][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=Cc1ccccc1B(O)O
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
tert-Butyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., from Step 3) and 2-formyl-phenylboronic acid (1.5 eq.) were dissolved in dioxane (0.1 M) and treated with 2 M Na2CO3 solution (2 eq.). The solution was degassed by bubbling argon through it and Pd(PPh3)2Cl2 (0.1 eq.) was added. The reaction mixture was heated to reflux for 20 min then allowed to cool down to RT, diluted with EtOAc and washed with 1 N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate, evaporated in vacuo and the residue purified by chromatography (PE:EtOAc, 9:1) to afford the pure title compound (68%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 9.70 (s, 1H), 7.96 (dd, J 7.7, 1.3, 1H), 7.91 (s, 1H), 7.84 (dt, J 7.6, 1.5, 1H), 7.80 (t, J 7.7, 1H), 7.47 (d, J 7.6, 1H), 4.93 (d, J 18.2, 1H), 4.76 (d, J 18.2, 1H), 3.48 (s, 3H), 2.15-2.08 (m, 1H), 1.73-1.02 (m, 10H), 1.52 (s, 9H). MS (ES+) m/z: 482 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NNc1ccccc1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C (see starting compounds) and phenylhydrazine as described for compound 35. Crystallized from diethyl ether. M.p. 134°-135° C.
Reaction SMILES: [CH:1](N(CC)C(C)C)(C)C.[CH:10]1([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH3:35])=[C:20]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=3[N+:31]([O-])=O)[CH:21]=2)=[O:15])[CH2:12][CH2:11]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.O>CS(C)=O>[CH:10]1([NH:13][C:14](=[O:15])[C:16]2[CH:17]=[CH:18][C:19]([CH3:35])=[C:20]([N:22]3[C:23](=[O:34])[C:24]4[C:25](=[CH:26][C:27]([N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[CH:28][CH:29]=4)[N:31]=[CH:1]3)[CH:21]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2cc(N3CCN(C)CC3)ccc2c1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (0.30 ml) was added to a stirred mixture of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-fluoro-2-nitrobenzamide (0.30 g) and N-methylpiperazine (0.28 ml) in DMSO (0.5 ml). The mixture was heated to 90° C. and stirred for 16 hours. The reaction mixture was poured into water (100 ml), the resulting solid was filtered, washed with water, diethyl ether and redissolved in methylene chloride. The organic phase was dried (diatomaceous earth column) and evaporated to give the title compound as a solid (0.23 g); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.46 (m, 4H), 2.85 (m, 1H), 3.36 (m, 4H), 7.30 (m, 2H), 7.45 (d, 1H), 7.61 (m, 1H), 7.67 (d, 1H), 7.83 (s, 1H), 8.39 (d, 1H), 10.03 (s, 1H); Mass Spectrum: M+H+ 438.
Reaction SMILES: [Br:1]Br.Cl.[CH3:4][N:5]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13](=[O:22])[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]1[CH3:23].CC#N>CO.O>[Br:1][C:14]1[C:13](=[O:22])[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:23])[N:5]([CH3:4])[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(C)n(C)c(-c2ccccc2)cc1=O
Reactant: BrBr
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c(=O)c(Br)c(-c2ccccc2)n1C
Temperature: 85 °C
Yield: 84.9 %

Procedure:
2.0 g (0.015 mol) of bromine dissolved in 50 ml. of methanol is added dropwise over a 15 min. period to a solution of 2.7 g (0.00877 mol) ethyl 1,2-dimethyl-6-phenyl-4-oxonicotinate hydrochloride (Example 2) in 15 ml of methanol and 15 ml of water. The suspension formed is vacuum filtered and the filter cake, a yellow solid, is suspended in 60 g of 5% aqueous sodium hydroxide. The mixture is stirred and heated at 85° C. for 21/2 hrs. and is acidified with hydrochloric acid. The suspension formed is vacuum filtered to afford 2.4 g (85% yield) of 5-bromo-1,2-dimethyl-6-phenyl-4-oxonicotinic acid, mp 257°-258° C. (CH3CN).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[C:15]([N:17]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:14]([C:15](=[O:16])[N:17]([CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH2:40])[CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:13]=1)[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)C2CCCC2)c1)c1ccncc1
Agent: F[B-](F)(F)F
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(N)=O)C2CCCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 43 h
Yield: 81.8 %

Procedure:
To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-cyclopentyl-amino)-butyric acid (0.049 g), TBTU (0.058 g) and HOBt (0.024 g) in DMF (1 ml) was added DIPEA (0.031 ml) followed a 0.5M solution of ammonia in 1,4-dioxane (0.36 ml) after 15 min. The reaction mixture was stirred at room temperature for 43 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.040 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.CN(CCCN)C.[F:25][C:26]([F:30])=[C:27](F)F.CN(C)C=[O:34]>>[F:25][CH:26]([F:30])[C:27]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:34]
Reactant: CN(C)C=O
Reactant: FC(F)=C(F)F
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Agent: CN(C)CCCN
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 17 h
Yield: 35 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and 3-(N,N-dimethylamino)propylamine (0.77 g, 7.5 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.3 liter/hr), with vigorous stirring at 50° C. for 17 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with diethyl ether. The diethyl ether layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.59 g, 1.8 mmol, yield 35%). Unreacted part of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.50 g) was recovered.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br.O>C(Cl)Cl>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O

Procedure:
206 g (0.83 mol) of 1-(3,5-di-tert.butyl-4-hydroxyphenyl)ethanone were dissolved in 415 ml of methylene chloride while stirring, the solution was heated to boiling, and 144 g (0.9 mol) of bromine were added dropwise over the course of 30 minutes. The mixture was then refluxed for a further 2 hours and cooled, 400 ml of water were added, and the organic phase was separated off and dried over sodium sulfate. After the solvent had been removed under reduced pressure, the solid crude product obtained was recrystallized from 540 ml of methylcyclohexane.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N:10]([O:12]C(C)(C)C)=[O:11].ON1C(=O)C2=CC=CC=C2C1=O.C(C1C=CC=CC=1)(C)=C.OC(C1C=CC=CC=1)(C)C>C(O)(=O)C>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([N+:10]([O-:12])=[O:11])[CH3:3]
Reactant: CC(C)(C)ON=O
Reactant: CC(C)c1ccccc1
Agent: C=C(C)c1ccccc1
Agent: CC(C)(O)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Product: CC(C)(c1ccccc1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Isopropylbenzene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that isopropenylbenzene, (1-hydroxy-1-methylethyl)benzene, and (1-methyl-1-nitroethyl)benzene were formed in yields of 60%, 6%, and 7%, respectively.
Reaction SMILES: C(O[C:9](=[O:26])[CH2:10][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[C:27](#[N:29])[CH3:28].[NH2-].[Na+].[CH2:32]([Mg]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(OC)(C)C>[NH2:29][C:27]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:28][C:9](=[O:26])[CH:10]([N:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CN(Cc1ccccc1)Cc1ccccc1)OCc1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC#N
Agent: [NH2-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: NC(=CC(=O)C(c1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1

Procedure:
The title compound was prepared from N,N-dibenzyl-glycine benzyl ester, 113 mmole, and 6.5 mL, 125 mmole of acetonitrile. Following the procedure described in Example 2 the ester and nitrile mixture was added to 9.8 g, 225 mmole of sodium amide in MTBE. After solvent removal, benzyl magnesium chloride (PhCH2MgCl 250 mmole) was added following the procedure in Example 2. The resulting enamine was purified by chromatography, following the procedure described in Example 4. The yield of enamine was 41 g (102 mmole, 90%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccccc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccccc1OCCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
The above oil of 4-[2-(2-fluorophenoxy)ethyl]piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 12 mmol) in dichloromethane (60 mL) was mixed with trifluoroacetic acid (10 mL) and was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was treated with a saturated solution of NaHCO3. The aqueous solution was extracted with dichloromethane and the organic layer was concentrated to give 1-[2-(2-fluoro-phenoxy)ethyl]piperazine as a white solid (2.25 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ 2.40 (b, 4H), 2.67 (m, 6H), 4.13 (t, 2H), 6.92 (m, 1H), 7.11 (t, 1H), 7.18 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C(N(CC)CC)C>C(#N)C>[N+:8]([C:7]1[C:2]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC(N)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)CNc1ncccc1[N+](=O)[O-]

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.0 g, 0.0063 mole), glycinamide hydrochloride (3.11 g, 0.028 mole), triethylamine (3.1 g, 0.031 mole) in 35 ml of acetonitrile was heated at reflux for 161/2 hrs. The yellow precipitate was filtered off. The precipitate was slurried and filtered successively with water, absolute alcohol and acetone. The yellow solid was dried under high vacuum at room temperature to give 0.9 g (73.2%), of title compound, m.p. 250°-51° C. with decomposition.