Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([C:4](=[O:22])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3].[CH:24]([Mg]Cl)=[CH2:25].O>O1CCCC1>[CH3:3][C:2]([CH3:23])([C:4]([CH:24]=[CH2:25])([OH:22])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)C(CCCCOc1ccccc1)n1cncn1
Reactant: C=C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)(C(CCCCOc1ccccc1)n1cncn1)C(C)(C)C

Procedure:
A solution of 12.6 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-8-phenoxyoctan-3-one was added dropwise to a solution of 8.7 g of vinyl magnesium chloride in 70 ml of tetrahydrofuran, while stirring. After the weakly exothermic reaction was complete, the mixture was refluxed for a further 5 hours and then cooled. Thereafter, a mixture of 5 ml of water and 5 ml of tetrahydrofuran was added dropwise, while cooling with ice, the reaction mixture was stirred for a further 2 hours at room temperature, the precipitated magnesium salts were then filtered off, and the filtrate was concentrated under reduced pressure. The residue from the filtrate was taken up in 100 ml of dichloromethane, the solution was washed with 100 ml of water and then with 100 ml of saturated ammonium chloride solution, and the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. 8.0 g of pale yellowish crystals of melting point 66°-69° C. (diastereomer mixture 2:1) crystallized from the residual oil on trituration with diisopropyl ether.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH:32]1([C:35]2[N:40]=[C:39]([NH:41][C@@H:42]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][C@@H:43]3[OH:51])[C:38]([CH2:52][CH3:53])=[N:37][C:36]=2[C:54]2[CH:55]=[N:56][C:57]([N:61]([CH3:63])[CH3:62])=[CH:58][C:59]=2[CH3:60])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[N:40]=[C:39]([NH:41][C@@H:42]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][C@@H:43]3[O:51][CH2:2][CH3:3])[C:38]([CH2:52][CH3:53])=[N:37][C:36]=2[C:54]2[CH:55]=[N:56][C:57]([N:61]([CH3:63])[CH3:62])=[CH:58][C:59]=2[CH3:60])[CH2:34][CH2:33]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2cnc(N(C)C)cc2C)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({6-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3-ethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.81-1.19, 1.28-1.33, 2.67-2.73, 3.11-3.14, 3.42-3.51, 3.65-3.73, 4.32-4.35, 5.40-5.42, 5.72-5.75, 6.497.22-7.39, 8.19; MS (ESI+) for C28H35N5O m/z 458 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:43])[C:15]2([CH:18]3[CH2:22][CH2:21][N:20]([C:23]4[C:32]([O:33][CH3:34])=[C:31]5[C:26]([C:27](=[O:41])[C:28]([C:38]([OH:40])=[O:39])=[CH:29][N:30]5[CH:35]5[CH2:37][CH2:36]5)=[CH:25][C:24]=4[F:42])[CH2:19]3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C>[CH:35]1([N:30]2[C:31]3[C:26](=[CH:25][C:24]([F:42])=[C:23]([N:20]4[CH2:21][CH2:22][CH:18]([C:15]5([N:14]([CH3:43])[CH:11]6[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]6)[CH2:17][CH2:16]5)[CH2:19]4)[C:32]=3[O:33][CH3:34])[C:27](=[O:41])[C:28]([C:38]([OH:40])=[O:39])=[CH:29]2)[CH2:37][CH2:36]1
Reactant: COc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COc1c(N2CCC(C3(N(C)C4CCNCC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 7-(3-{1-[(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl-amino]-cyclopropyl}-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid in dichloroethane (2.0 mL) was added trifluoroacetic acid (1.0 mL, ˜13 mmol) at 0° C. during a period of 5-6 minutes. The resulting solution was stirred at room temperature for one hour. The solvent was removed to yield yellow oil, which was partitioned between CH2Cl2 and sat. aq NaHCO3. The separated aqueous phase was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was isolated as a yellow solid (85 mg, 100%). ESI MS m/z 499.4 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>O>[CH3:20][O:13][C:12](=[O:14])[CH2:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: O=C(O)CC1Cc2ccccc2C1=O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC1Cc2ccccc2C1=O
Reaction time: 2 h

Procedure:
To a solution of (1-Oxo-indan-2-yl)-acetic acid (Step 1, 2.00 g) in methanol (10 mL) at 0° C. was added sulphuric acid (2 mL). The solution was stirred for 2 h and then diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with sat. sodium hydrogenocarbonate, dried and concentrated to give (1-Oxo-indan-2-yl)-acetic acid methyl ester (pale yellow oil, 2.15 g, quantitative). C12H12O3; MW: 204.23; LCMS (method A) RT 1.40 min; ES 227 (25%, MNa+), 205 (25%, MH+), 173 (100%); IR: 2952, 1734, 1710, 1608, 1436 cm−1; 1H NMR (400 MHz, CDCl3) 7.78 (1H, d), 7.61 (1H, t), 7.47 (1H, d), 7.39 (1H, t), 3.70 (3H, s), 3.47 (1H, dd), 2.95-3.08 (2H, m), 2.89 (1H, dd), 2.63 (1H, dt) ppm. The compound was used without further purification for the next step
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:34][CH2:33][C:32]([O:31][CH3:30])=[O:35])=[O:6]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.050 g, 0.13 mmol) and glycine methyl ester hydrochloride (0.019 g, 0.15 mmol), according to Reference S and the general procedure for amide formation afforded methyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)acetate. MS (ESI) m/z: Calculated: 461.1; Observed: 462.0 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 57 %

Procedure:
To a suspension of 4-hydroxy-3-methoxybenzoic acid (25 g, 0.15 mole) in ethanol (150 ml), 2N NaOH aq. (74.3 g, 0.15 mole) and benzyl chloride (56.5 g, 0.45 mole) were added, continued to stir for 1 hour under reflux. Then, 5N NaOH aq. (150 ml) was added dropwise with stirring under reflux, and continued to stir for 1 hour under reflux. After reaction, the solvent was removed, and H2O was added to the residue and acidified with conc. hydrochloric acid to make pH 1. The precipitate was filtered, washed with H2O and dried to give 22.1 g of 4-benzyloxy-3-methoxybenzoic acid as pale yellow crystals having a m.p. of 171°-172.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:49]1[CH2:54][CH2:53][CH:52]([N:55]2[CH2:61][CH2:60][C:59]3[CH:62]=[CH:63][CH:64]=[CH:65][C:58]=3[NH:57][C:56]2=[O:66])[CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:49]4[CH2:50][CH2:51][CH:52]([N:55]5[CH2:61][CH2:60][C:59]6[CH:62]=[CH:63][CH:64]=[CH:65][C:58]=6[NH:57][C:56]5=[O:66])[CH2:53][CH2:54]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
(S)-2-(1,4-Dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl)acetic acid(95 mg, 0.232 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). TBTU (79 mg, 0.246 mmol) was added to the mixture followed by 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (72 mg, 0.293 mmol) and then N,N-diisopropylethylamine (150 μl, 0.861 mmol). Reaction stirred at room temperature for 4 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 59% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.88 (s, 1H) 8.49 (s, 1 H) 7.35 (s, 1H) 7.00-7.09 (m, 3H) 6.70-6.87 (m, 1H) 5.42 (s, 2H) 4.49 (d, J=12.51 Hz, 1H) 4.36-4.45 (m, 1H) 4.25-4.36 (m, 1H) 4.11-4.24 (m, 1H) 3.91-4.10 (m, 2H) 3.34-3.41 (m, 2H) 3.19 (d, J=18.01 Hz, 1H) 3.05-3.15 (m, 1H) 2.93-3.03 (m, 1H) 2.83-2.93 (m, 3H) 2.53-2.65 (m, 1H) 2.32-2.47 (m, 1H) 1.57-1.87 (m, 3H) 1.44-1.57 (m, 1H). High resolution MS m/e (M+H)−=637.1735.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][N:14]=1)[NH:11][C:10](=[O:15])[CH:9]1[CH2:16][N:5]2[CH2:6][CH2:7][CH2:8]1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:17])[C:10](=[O:15])[CH:9]1[CH2:16][N:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N2CCCC1C2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C2CCCN(C2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.075 g (0.00032 mole) of (rac)-4-chloro-1,3,5,8-tetraaza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-9-one (VI-67), 0.8 mL of dimethylformamide, 0.17 g (0.0005 mole) of cesium carbonate and 0.055 g (0.0004 mole) of iodomethane was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give (rac)-4-chloro-8-methyl-1,3,5,8-tetraaza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-9-one (VII-67), which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=O)=[CH:30][C:29]=6[CH3:38])=[CH:24][CH:23]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.O.[NH2:40][NH2:41]>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:19]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:23]=[CH:24][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([NH:40][NH2:41])=[O:36])=[CH:30][C:29]=6[CH3:38])=[CH:26][CH:27]=5)=[O:21])[C:17]=4[CH:18]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)N3CCCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1
Solvent: O
Product: Cc1cc(C(=O)NN)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 2,3,5,6,7,8-hexahydro-1'-methyl-5-(4'-methoxycarbonyl-2'-methylbiphenyl-4-carbonyl)spiro[furo[2,3-g]quinoline-3,4'-piperidine] (E48) and hydrazine monohydrate, using a procedure similar to that of Example 25 (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CO.[OH-].[Li+].Cl>O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-chloro-4-(methoxycarbonyl)phenyl]methyl]piperazine-1-carboxylate (3.54 g, 9.60 mmol, 1.00 equiv), methanol (20 mL), H2O (10 mL), lithium hydroxide (0.690 g, 28.8 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride (1 mol/L). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with brine (1×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 2.90 g (crude) of 4-([4-[(tert-butoxy)carbonyl]piperazin-1-yl]methyl)-3-chlorobenzoic acid as a white solid. 1H NMR 300 MHz (CDCl3) δ 7.89-8.06 (m, 3H), 3.88 (s, 2H), 3.56 (br, 4H), 2.68 (br, 4H), 1.46 (s, 9H). LCMS (ESI, m/z): 355 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:5]([C:13]2[CH:14]=[CH:15][C:10]([CH3:18])=[CH:11][CH:12]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(I)c1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cccc(I)c2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodobenzaldehyde (10 g) in tetrahydrofuran (50 mL) at 30° C. is added a 0.43M solution of p-tolylmagnesium bromide in tetrahydrofuran. After stirring at 50° C. for 1 hour, the reaction mixture is hydrolyzed with a saturated aqueous solution of ammonium chloride and extracted ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient heptane/ethyl acetate 95/5 to 90/10) to yield (3-iodophenyl)-p-tolylmethanol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Br:34][C:35]1[CH:44]=[CH:43][C:42](O)=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([Cl:46])=[N:40]2>C1COCC1>[Br:34][C:35]1[CH:44]=[CH:43][C:42]([O:33][CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:26])[CH2:28][CH2:29]2)=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([Cl:46])=[N:40]2
Reactant: Oc1ccc(Br)c2cnc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of triphenylphosphine (2 eq) in THF was added di-terbutylazodicarboxylate (2 eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that was added tert.butyl-4-hydroxypiperidine-1-carboxylate (5 eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 5-bromo-2-chloroquinazolin-8-ol (1 eq). The mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue was purified by flash column chromatography (25% EtOAc/Hexane) to provide product as a white solid in 90% yield. ES/MS m/z 442.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[Pd]>[C:19]1(/[CH:18]=[CH:17]\[C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Fc1ccc(-c2n[nH]c3ccc(C#Cc4ccccc4)cc23)cc1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2n[nH]c3ccc(/C=C\c4ccccc4)cc23)cc1
Reaction time: 5 h
Yield: 45.7 %

Procedure:
A mixture of 3-(4-fluorophenyl)-5-(2-phenylethynyl)-1H-indazole (0.050 g, 0.16 mmol), quinoline (0.030 g), and palladium (5 wt. % on barium carbonate, 0.015 g) in ethyl acetate (10 mL) was stirred under hydrogen for 5 hours. It was filtered with celite and washed with ethyl acetate. The filtrate was washed with 5% hydrochloric acid solution and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) and by HPLC to provide the title compound (0.023 g, 46% yield): 1H NMR (CDCl3) δ 10.15 (br s, 1H), 7.83 (s, 1H), 7.70 (m, 2H), 7.29 (m, 7H), 7.11 (t, 2H), 6.72 (d, 1H), 6.68 (d, 1H); ES-MS (m/z) 315 [M+1]+.
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>>[CH2:7]([NH:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Yield: 93.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 195(A), from phenylmethanamine (3.51 g, 32.78 mmol) and 1-fluoro-2-nitrobenzene (4.40 g, 31.22 mmol). 6.65 g of N-benzyl-2-nitrobenzenamine (Yield: 93%) was obtained as an orange crystalline solid which was used without further purification.
Reaction SMILES: [P:1]([Cl:5])(Cl)(Cl)=[S:2].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14]>C(N(CC)CC)C>[P:1]([Cl:5])([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[CH3:6])([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[CH3:6])=[S:2]
Reactant: Cc1ccc(O)c(C)c1
Reactant: S=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(OP(=S)(Cl)Oc2ccc(C)cc2C)c(C)c1
Temperature: 20 °C
Yield: 89.9 %

Procedure:
Thiophosphoryl chloride (17.0 g) was dissolved in tuoluene (250 cm3) and triethylamine (21.5 g) was added. The solution was stirred at 20° C. and 2,4-dimethylphenol (24.4 g) was added in portions during 1 hr. The mixture was stirred for 2 hr. and then heated and stirred at 80° C. for a further 2 hr. and then cooled and filtered to remove thriethylamine hydrochloride. The toluene was distilled under reduced pressure leaving bis(2,4-dimethylphenyl) chlorothiophosphate (oil, 30.6 g. 31P NMR in CDCl3, singlet 54.57 ppm downfield of H3 PO4).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O[CH:18](OCC1C=CC=CC=1)[N:19]([CH3:21])[CH3:20])C1C=CC=CC=1>C1C=CC=CC=1>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccncc1
Reactant: CN(C)C(OCc1ccccc1)OCc1ccccc1
Solvent: c1ccccc1
Product: CN(C)C=CC(=O)c1ccncc1

Procedure:
A mixture of 0.10 mole of 4-acetylpyridine and 0.12 mole of N,N-dimethylformamide dibenzylacetal in benzene was refluxed for 8 hours, giving 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][N:18]=1.C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[N:14]1[C:6]2[C:5]3[S:15][C:2]([C:20]4[CH:21]=[CH:22][C:17]([NH2:16])=[N:18][CH:19]=4)=[CH:3][C:4]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: Brc1cc2c(s1)-c1ncccc1OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Yield: 36 %

Procedure:
A mixture of 9-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (113 mg, 0.400 mmol), 2-aminopyridine-5-boronic acid, pinacol ester (96.8 mg, 0.440 mmol) and bis(triphenylphosphine)palladium(II) chloride (14.0 mg, 0.0200 mmol) in 1.0 M of sodium carbonate in water (0.500 mL) and acetonitrile (3 mL, 60 mmol) was degassed and microwaved on 300 watts at 140° C. for 20 minutes. The reaction mixture was partitioned between ethyl acetate and water and filtered from inorganic salts. The organic layer was washed with water, brine, dried over MgSO4 and evaporated to dryness. The crude residue was purified on silicagel column, eluting with 50% of ethyl acetate in methylene chloride to give 142 (yield 43 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=2.3, 1H), 8.21 (dd, J=1.4, 4.5, 1H), 7.68 (dd, J=2.5, 8.6, 1H), 7.38 (dd, J=1.4, 8.1, 1H), 7.21 (s, 1H), 7.17 (dd, J=4.5, 8.1, 1H), 6.50 (d, J=8.7, 1H), 6.21 (s, 2H), 4.32 (t, J=4.8, 2H), 3.19 (t, J=4.8, 2H). MS: (ESI+) 296.1
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8](=[O:18])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[Cl:17])[C:4]([O:6][CH3:7])=[O:5].[F:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[C:8]([C:3](=[CH:2][NH:1][C:23]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:18]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C(=CN)C(=O)c1cc(F)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl

Procedure:
The preparation was carried out analogously to Example 10 with 1.0 g of the product from Example 5, 1.01 g of p-fluoroaniline and 0.69 g of p-toluenesulphonic acid.H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH3:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:13]([C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]=1)[CH3:14]
Reactant: CCc1nc(-c2ccc(Cl)cc2)no1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nc(-c2ccc(Cl)cc2)no1
Temperature: 100 °C
Yield: 30.2 %

Procedure:
To a solution of 3-(4-Chloro-phenyl)-5-ethyl-[1,2,4]oxadiazole (0.29 g, 1.38 mmol) in CCl4 (10 mL) was added NBS (0.24 g, 1.38 mmol) and AIBN (0.02 g, 0.0001 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate/hexane as eluent to give the desired product (0.12 g, 30%).