Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]=32)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:2][C:3]1[CH:16]=[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]=32)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc3c(c2c1)CCC(=O)O3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCc2c(ccc3ccc(O)cc23)O1
Temperature: 25 °C

Procedure:
A mixture of 2.57 g (11.3 mmol) of 1,2-dihydro-9-methoxy-3H-naphtho[2,1-b]pyran-3-one from the preceding example and 7.86 g (68.0 mol) of pyridine hydrochloride was heated at 200°-230° C. for 2.5 hr. After being cooled to room temperature, the reaction mixture was treated with 100 mL of water and worked-up with ethyl acetate in the usual manner. The crude product (2.52 g) was dissolved in 150 mL of toluene, treated with 0.31 g (1.63 mmol) of p-toluenesulfonic acid monohydrate, and the resulting solution was stirred at reflux for 3.5 hr, with removal of water using a Dean-Stark trap. The solution was diluted with 300 mL of ethyl acetate, washed three times with saturated sodium bicarbonate solution, and work-up was completed in the usual manner. The crude product was purified by flash chromatography on 300 g of silica gel, eluting with hexane-ethyl acetate (3:1) to give 2.06 g (85.3%) of the title compound as a light-brown solid, mp 194°-202° C. (recrystallized from ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9](=O)[CH3:10])[S:5][C:6]=1[CH3:7].[H-].[Na+].Cl.[CH3:15][N:16](CCCl)[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:17])[CH2:10][CH2:9][NH:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=1
Reactant: CN(C)CCCl
Reactant: CC(=O)Nc1nc(C)c(C)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(NCCN(C)C)sc1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Dissolve 30.0 g. (0.176 moles) of N-(4,5-dimethyl-2-thiazolyl) acetamide in 375 ml. of dimethylformamide under nitrogen followed by 7.7 g. of 50% sodium hydride in 2 portions at room temperature. When gas evolution ceases, 27.5 g. (0.191 moles) of dimethylaminoethylchloride hydrochloride is added along with 8.35 g. of 50% sodium hydride. The mixture is stirred at 60°-70° C. for 1/2 hour, 90° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue is taken up in 200 ml. of 6 N hydrochloric acid and refluxed for 24 hours. The mixture is extracted with hexane and made basic with sodium hydroxide with cooling. The aqueous layer is extracted with methylene chloride, the organic layer washed with saturated sodium chloride, dried over sodium sulfate and evaporated. The residue is distilled and the fraction boiling at 110°-113° C./0.7 mm. of Hg. collected (29.2 g.) and identified as N,N-dimethyl-N'-(4,5-dimethyl-2-thiazolyl)-1,2-ethanediamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].[C:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:23]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:24]=[CH:25][C:26]([CH2:27][N:6]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:29][CH:30]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 3-bromo-9H-carbazole (7.38 g, 30 mmol, prepared as described in Tetrahedron (1992), 48, 4779) in N,N-dimethylformamide (200 ml) was added portion wise sodium hydride (1.6 g, 39 mmol, 60% in mineral oil) during 15 min. After stirring at room temperature for 1 h, 4-phenyl-benzylchloride (6.21 g, 30 mmol) was added portion wise during 10 min. The resulting reaction mixture was stirred at room temperature for 20 h poured onto water (300 ml) and stirred for 4 h. The precipitate was filtered off, washed with water (3×150 ml) and dried in vacuo at 50° C. for 18 h. The crude product was washed with heptane, filtered off and dried in vacuo at 50° C. affording 12 g (100%) of 9-(biphenyl-4-ylmethyl)-3-bromo-9H-carbazole as a solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=1>CN(C=O)C>[C:1]1([O:7][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1C=C(OCCCCCCOc2ccccc2)c2ccccc2C1=O
Reaction time: 48 h
Yield: 42.8 %

Procedure:
Phenol (28 mg, 0.3 mmol) was treated with tetrabutylammonium hydroxide (0.3 mL of 1.0 M solution in methanol) and the reaction mixture was concentrated to dryness in vacuo. Iodonaphtoquinone 5 (115 mg, 0.3 mmol) in DMF (3 mL) was added to the tetrabutylammonium salt, stirred for 48 h and quenched with H2O (10 mL). The product was extracted with CHCl3, the extract was washed with H2O, then brine, dried (Na2SO4), and purified by chromatography (5% EtOAc in benzene) to give 12 as a yellow solid (45 mg, 43%) 1H NMR (CDCl3) 8.13 (d, J=7.4 Hz, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H),7.15-7.40 (m, 2H), 6.85-7.10 (m, 3H), 5.96 (s, 1H), 4.17 (t, J=6.5 Hz, 2H), 3.99 (t, J=6.2 Hz), 1.70-2.10 (m, 4H), 1.35-1.70 (m, 4H).
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][C:9]1[O:13][N:12]=[C:11]([CH2:14][NH2:15])[CH:10]=1.[F:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30](O)=[O:31])[C:23]2=[O:36])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30]([NH:15][CH2:14][C:11]3[CH:10]=[C:9]([CH3:8])[O:13][N:12]=3)=[O:31])[C:23]2=[O:36])=[CH:37][CH:38]=1
Reactant: Cc1cc(CN)no1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: Cc1cc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)no1
Yield: 55 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (5-methylisoxazol-3-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methylisoxazol-3-yl)methyl)isonicotinamide was obtained as a colorless solid in 55% yield: mp 153-155° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.37-7.35 (m, 1H), 7.28-7.23 (m, 2H), 7.07-6.99 (m, 3H), 6.01 (s, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.36 (t, J=8.1 Hz, 2H), 2.37 (s, 3H); MS (ES+) m/z 409.9 (M+1).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[NH:7][CH:6]=1)C.CI.[Si]([C:22]#[N:23])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.ClCCl>[CH3:15][O:14][C:12]1[CH:13]=[C:8]2[C:9]([C:5]([CH2:4][C:22]#[N:23])=[CH:6][NH:7]2)=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(CN(C)C)c[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CI
Product: COc1ccc2c(CC#N)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
To a solution of 6-methoxygramine (1.0 g, 4.9 mmol, 1.0 eq.) in a mixture of anhydrous dichloromethane (16 mL) and toluene (30 mL) was added, under an argon atmosphere, methyl iodide (610 μL, 9.8 mmol, 2.0 eq.). The mixture was stirred at room temperature for 16 hours and then, concentrated under reduced pressure. To the residue taken up in anhydrous THF (40 mL) were added, under an argon atmosphere, TMSCN (920 μL, 7.3 mmol, 1.5 eq.) and TBAF (14.7 mL, 1M, 14.7 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated under reduced pressure. The crude was taken up in ethyl acetate and the organic layer was washed with aqueous bicarbonate solution and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel pad filtration (eluent: EtOAc) to afford (6-methoxy-1H-indol-3-yl)-acetonitrile as a beige powder (0.87 g, 95%). mp: 100° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:29]C(=O)C)[CH2:6]1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:27][Si:25]([CH3:26])([CH3:28])[O:24][CH2:23][C@@:20]12[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:29])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@H:7]1[CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]2
Reactant: CC(=O)O[C@H]1CC[C@@]2(CO[Si](C)(C)C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O

Procedure:
A solution of 19-trimethylsiloxy-5α-androstane-3β,17β-diol diacetate in ether is added to a lithium aluminum hydride suspension in ether. After refluxing for one hour, the excess hydride is destroyed with water. The ether solution is separated, dried over sodium sulfate and concentrated under vacuum. The residue which remains is crystallized from methanol to yield 19-trimethylsiloxy-5α-androstane-3β,17β-diol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>[Cu]I.CS(C)=O>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:39][CH:36]3[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:34][CH2:35]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COCCN1CCC(N)CC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COCCN1CCC(Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.123 g, 0.25 mmol, prepared according to Example 7, Step B), 1-(2-methoxyethyl)piperidin-4-amine (0.119 g, 0.750 mmol), copper(I)iodide (0.00952 g, 0.0500 mmol), (S)-pyrrolidine-2-carboxylic acid (0.0115 g, 0.100 mmol), K2CO3 (0.173 g, 1.25 mmol), and DMSO (0.5 mL) was stirred at 100° C. for 3 days in a sealed vessel. The reaction was partitioned between EtOAc and water. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with water, dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (1 mm thickness) eluting with 10% MeOH/CHCl3. Yield: 42 mg (32%). LRMS (APCI+): 100% purity, 220 nm, m/z 521 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:33])=[CH:27][CH:26]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([C@H:63]1[CH2:67][CH2:66][O:65][CH2:64]1)[C:60](O)=[O:61])=[O:57]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:60](=[O:61])[C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[C@H:63]3[CH2:67][CH2:66][O:65][CH2:64]3)=[O:18])=[CH:12][CH:11]=2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C@@H:34]3[CH2:38][CH2:37][CH2:36][N:35]3[C:39](=[O:53])[C@@H:40]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:41]3[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]3)=[O:33])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)[C@H]1CCOC1
Reactant: O=C(Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@@H]1CCCN1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@H]1CCOC1

Procedure:
The product from Example 114C (0.040 g, 0.056 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid (0.014 g, 0.067 mmol) were processed as in Example 81A to give the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.29-1.38 (m, 2 H) 1.39-1.47 (m, 4 H) 1.68-1.78 (m, 1 H) 1.79-1.90 (m, 4 H) 1.93-2.06 (m, 4 H) 2.10-2.22 (m, 1 H) 3.14-3.25 (m, 1 H) 3.41-3.50 (m, 4 H) 3.53 (s, 3 H) 3.58-3.70 (m, 4 H) 3.71-3.79 (m, 2 H) 3.80-3.90 (m, 2 H) 4.20-4.28 (m, 2 H) 4.31 (dd, J=7.64, 4.07 Hz, 1 H) 4.44 (dd, J=7.97, 4.93 Hz, 1 H) 4.56 (s, 4 H) 6.64 (dd, J=9.22, 4.34 Hz, 2 H) 6.91 (t, J=8.95 Hz, 2 H) 7.18 (d, J=8.13 Hz, 4 H) 7.25-7.37 (m, 3 H) 7.42 (d, J=6.83 Hz, 2 H) 7.51 (dd, J=8.57, 1.84 Hz, 4 H) 7.60 (d, J=8.02 Hz, 1 H) 9.96 (s, 1 H) 9.98 (s, 1 H); MS ESI− m/z 900.6 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][OH:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C.C(OCC)C>C(Cl)Cl.C1COCC1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc2ccc(Br)cc2c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc2ccc(Br)cc2c2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
To a solution of 3-bromo-9-(hydroxymethyl) phenanthrene, 4 (5.96 g, 20.8 mmol) and t-butyldimethylsilyl chloride (4.7 g, 31 mmol) in 100 ml of CH2Cl2 and 20 ml of THF was added triethylamine (4.9 ml, 35 mmol) followed by 4-dimethylaminopyridine (250 mg, 2.05 mmol). After stirring at room temperature for 20 hours, the solution was poured into 300 ml of ethyl ether and washed successively with sat. NH4Cl, sat. NaHCO3, H2O, and brine. Drying (Na2SO4) and evaporation gave a brown solid which was purified by flash chromatography through 400 g of silica gel (1:4 CH2Cl2 -hexane) to yield 7.23 g (87%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccc(C(CC(=O)O)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Wang resin (Advanced Chemtech, 2.5 g, 0.8 mmol/g, 2 mmol equivalent) in a mixture of DMF (20 ml) and DCM (20 ml) was treated with 3-(9-fluorenylmethoxycarbonylamino)-3-(4-nitrophenyl)propanoic acid (2.6 g, 6 mmol), 4-dimethylaminopyridine (244 mg, 2 mmol) and 1,3-diisopropylcarbodiimide (940 μl, 6 mmol) and the mixture agitated under nitrogen at room temperature for 24 h. The resin was filtered and washed with DMF and DCM. The resin was treated with a 1M solution of stannous chloride dihydrate in DMF (50 ml) at room temperature for 8 h then washed as before to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([C:14]([NH:16][NH2:17])=[O:15])[O:12][CH:13]=2)=[CH:5][CH:4]=1.C([O:27][CH2:28][CH3:29])(=O)C>>[C:14]([C:11]1[CH:10]=[C:9]([CH:6]=[CH:29][C:28]=1[OH:27])[C:13]([NH:17][NH:16][C:14]([C:11]1[O:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:12])#[N:16]
Reactant: COc1ccc(-c2coc(C(=O)NN)c2-c2ccccc2)cc1
Reactant: CCOC(C)=O
Product: COc1ccc(-c2coc(C(=O)NNC(=O)c3ccc(O)c(C#N)c3)c2-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-(4-methoxyphenyl)-3-phenyl-2-furancarboxylic acid hydrazide (compound of Reference Example 10, 0.31 g) and the compound of Reference Example 63 (0.33 g) in ethyl acetate (10 ml) was heated at reflux while stirring overnight. The thus-precipitated crystals were collected by filtration and recrystallized from ethyl acetate/diisopropyl ether, thereby giving 0.31 g of the desired compound. Melting point: 146-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1.Br[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cn1nccc1-c1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 44.3 %

Procedure:
4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (2 g, 10.6 mmol) was dissolved in acetone (100 mL). Tert-butyl 2-bromoethylcarbamate (4.74 g, 21.2 mmol) and potassium carbonate (2.92 g, 21.2 mmol) were then added to the solution. The reaction was refluxed for 15 hours at 60° C. After the reaction was completed, the reaction mixture was filtered, concentrated, and dissolved in CH2Cl2. The unreacted 4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol was removed from the product through extraction with 1N NaOH. The product was purified by column chromatography (40% EtOAc/60% Hexanes) to yield tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (1.56 g, 4.70 mmol, 44.4%) as a white solid. LCMS m/z (%)=333 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (s, 9 H), 3.33 (q, J=5.31 Hz, 2 H), 3.55 (s, 2 H), 3.74 (s, 3 H), 3.90 (t, J=5.05 Hz, 2 H), 4.63 (br. s., 1 H), 6.22 (d, J=1.77 Hz, 1 H), 6.61 (d, J=3.03 Hz, 1 H), 6.73 (dd, J=8.84, 2.78 Hz, 1 H), 6.84 (d, J=8.84 Hz, 1 H), 7.51 (d, J=1.77 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.Cl[Sn]Cl>C(OCC)C.Cl>[ClH:1].[NH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C@@H:8]1[CH2:12][NH:11][C:10](=[O:13])[CH2:9]1
Reactant: O=C1C[C@H](c2ccc(Cl)cc2[N+](=O)[O-])CN1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Product: Nc1cc(Cl)ccc1[C@@H]1CNC(=O)C1
Temperature: 25 °C
Yield: 192.7 %

Procedure:
To a solution of (4R)-4-(4-chloro-2-nitrophenyl)pyrrolidin-2-one (150 mg, 0.714 mmol) in diethyl ether (1 mL) was slowly added a solution of SnCl2 (2 g, 3.21 mmol) in 2 mL of conc. hydrochloric acid. The reaction was vigorous. The reaction mixture was cooled to room temperature and a portion of ice/water was poured onto the reaction mixture. After a few minutes, the mixture was filtered. The solid was collected and washed with cold water to afford the title compound (170 mg, 90% yield). MS (ESI) m/z 211.06 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24]Br.[K]>O.CS(C)=O.C(O)C>[Br:1][C:2]1[N:11]([CH2:24][C:23]2[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:22]=2[Cl:21])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c2c(nc(Br)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A solution of 8-bromotheophylline (10 g, 39 mmol) in 30 mL water was treated with potassium carbonate (2.6 g, 48 mmol). The reaction mixture was refluxed until dissolved. Ethanol (30 mL) was added to the hot reaction mixture and the resulting potassium salt was filtered, washed with acetone, and dried in a 100° C. vacuum oven. A solution of 2-chloro-6-fluorobenzyl bromide (5.3 g, 24 mmol) in 10 mL DMSO was treated with the solid potassium salt The reaction mixture was heated to 100° C. for 1 hour and cooled. Upon addition of 5 mL water, the mixture was collected by filtration and dried in a vacuum oven to yield a white solid (6.0 g, 89% yield): 1H NMR (CDCl3, 300 MHz) 7.37-7.21 (m, 2H), 7.07-6.96 (m, 1H), 5.87 (s, 2H), 3.60 (s, 3H), 3.42 (s, 3H); MS (ESP+) m/e 402 (MH+).
Reaction SMILES: BrC1C=C2C(=CC=1)N=C(O)C=C2.[CH2:13]([NH:17][C:18](=[O:43])[CH:19]=[C:20](C)[CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Br:41])[CH:37]=2)[N:32]=1)[CH:14]([CH3:16])[CH3:15].CCOC(/C=C/CP(OCC)(OCC)=O)=O>>[CH2:13]([NH:17][C:18](=[O:43])/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Br:41])[CH:37]=2)[N:32]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C=CCCCCCCCOc1ccc2cc(Br)ccc2n1)=CC(=O)NCC(C)C
Agent: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: Oc1ccc2cc(Br)ccc2n1
Product: CC(C)CNC(=O)/C=C/C=C/CCCCCCCOc1ccc2cc(Br)ccc2n1

Procedure:
Starting from 6-bromo-2-hydroxyquinoline (prepared as for Compound 17) and triethyl 4-phosphonocrotonate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[N:8]=[CH:7]1
Reactant: Clc1cnccn1
Reactant: NCCc1c[nH]cn1
Solvent: CC(C)O
Product: c1cnc(NCCc2c[nH]cn2)cn1

Procedure:
1 g (8.9 mmol) of histamine and 1.03 g (8.9 mmol) of 2-chloropyrazine are brought to reflux in 20 ml of 2-propanol for 72 h, evaporated and the crude solid residue is chromatographed through silica gel, using chloroform/methanol mixtures (1%, 5%, 10% and 20% respectively). The product is converted to the dioxalate in absolute ethanol and addition of ether gives the title compound which is recrystallized from a 2-propanol/diethyl ether mixture in the form of a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)[CH:10]=3)[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH:21]=[O:22])[CH2:17][CH2:16]2)[CH:10]=3)[CH2:2][CH2:3]1
Reactant: OC[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Product: O=C[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of {trans-4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]cyclohexyl}methanol (3.50 g) in acetonitrile (100 mL) was added Dess-Martin reagent (5.93 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (3.30 g).